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WO2024201299A1 - Procédé de traitement du cancer du sein précoce avec du ribociclib en combinaison avec un inhibiteur d'aromatase - Google Patents

Procédé de traitement du cancer du sein précoce avec du ribociclib en combinaison avec un inhibiteur d'aromatase Download PDF

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WO2024201299A1
WO2024201299A1 PCT/IB2024/052897 IB2024052897W WO2024201299A1 WO 2024201299 A1 WO2024201299 A1 WO 2024201299A1 IB 2024052897 W IB2024052897 W IB 2024052897W WO 2024201299 A1 WO2024201299 A1 WO 2024201299A1
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breast cancer
patient
treatment
ribociclib
day
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Inventor
Arunava CHAKRAVARTTY
Zheng Li
Tetiana TARAN
Juan Pablo ZARATE
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Novartis AG
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Novartis AG
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Priority to AU2024244511A priority Critical patent/AU2024244511A1/en
Priority to KR1020257035128A priority patent/KR20250163966A/ko
Publication of WO2024201299A1 publication Critical patent/WO2024201299A1/fr
Priority to IL323411A priority patent/IL323411A/en
Priority to MX2025011364A priority patent/MX2025011364A/es
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • BC Breast cancer
  • BC incidence varies between individuals of different ethnicities and in different geographic locations around the world, with rates ranging from 27 per 100,000 in Middle Africa and Eastern Asia to 92 in Northern America (GLOBOCAN: Estimated Cancer Incidence, Mortality and Prevalence Worldwide 2012 [Internet][cited 2018 Jun 26], https://publications.iarc.fr/Databases/Iarc- Cancerbases/GLOBOCAN-2012-Estimated-Cancer-Incidence-Mortality-And-Prevalence- Worldwide-In-2012-V1.0-2012).
  • BC was projected to be the most common cancer diagnosed in 2018 with an estimated incidence of 268,670 new cases and 41,400 deaths (CA Cancer J Clin 68:7–30, 2018).
  • BC in European countries in 2012 was 458,337 (Eur J Cancer Oxf Engl 199049:1374–1403, 2013). BC in men is not common, with a reported frequency of approximately 1% of all BC but its incidence is continuously rising (Breast Cancer Res Treat 137:465–470, 2013).
  • EBC early breast cancers
  • lymphatics which are potentially treatable with locoregional treatment modalities such as surgery and radiation therapy.
  • EBC Based on Surveillance, Epidemiology and End Results (SEER) Program data collected between the years 1975 and 2012, 93% of cases diagnosed were EBC, with 62% limited to the breast tissue and 31% localized within the breast tissue and regional lymph nodes (SEER Cancer Statistics Review, 1975-2015 [Internet]. Bethesda, MD, National Cancer Institute, 2018, https://seer.cancer.gov/csr/1975_2015/). Besides primary surgery, management of EBC usually includes additional anti-neoplastic treatment modalities such as radiation therapy and adjuvant or neoadjuvant systemic therapy.
  • additional anti-neoplastic treatment modalities such as radiation therapy and adjuvant or neoadjuvant systemic therapy.
  • EBC Trialists Collaborative Group (EBCTCG) meta-analysis of almost 150,000 women in 200 randomized clinical trials, approximately 36% and 20% of patients with EBC without any adjuvant systemic therapy will experience recurrence and death due to BC, respectively, during 5 years of follow- up (Lancet Lond Engl 365:1687–1717, 2005).
  • systemic adjuvant therapies is based on individual risk of recurrence and may be guided by several clinical, pathological and genomic predictive and prognostic factors of tumor and patient such as tumor stage, histopathological grade, tumor HR status, human epidermal growth factor receptor-2 (HER2) status, multi-gene testing recurrence scores, proliferation markers like Ki67, menopausal status, patient’s comorbidities, age, and others.
  • EBC can be classified as having low, intermediate/moderate or high risk for recurrence after surgery (BMC Med 13:195, 2015).
  • the cdk4/6 inhibitor abemaciclib was first approved for treatment of patients with HR+ HER2- advanced or metastatic breast cancer either alone or in combination with endocrine therapy, and was later shown in the monarchE clinical trial to be efficacious in treatment of patients with HR+ HER2- high risk early breast cancer (Johnston et al., 2023. Lancet 24(1), pp.77-90).
  • the cdk4/6 inhibitor palbociclib combined with endocrine therapy demonstrated clinically relevant efficacy in patients with HR+ HER2- metastatic breast cancer (PALOMA3 trial, described in Turner et al., 2015.
  • results from the PALLAS clinical trial in patients with HR+ HER2- early-stage breast cancer indicated that combination of palbociclib with endocrine therapy did not improve iDFS when compared with endocrine therapy alone (Mayer et al., 2021. Lancet, v22 (2), p212-222). Therefore, new therapeutic strategies may improve clinical outcomes in patients with HR- positive, HER2-negative EBC.
  • SUMMARY OF THE INVENTION Accordingly, disclosed herein are methods of treating early breast cancer using the CDK4/6 inhibitor Kisqali® (ribociclib) plus endocrine therapy (ET).
  • the present disclosure provides methods of treatment for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC).
  • FIG.1 provides a schematic of the study design of the NATALEE clinical trial.
  • FIG.2 shows simulated ANC Mean Profiles at Ribociclib 200 mg, 400 mg, and 600 mg QD, 3 weeks on/1 week off; mean ANC profiles are predicted by the ANC exposure-response model developed based on data from studies CLEE011X2101, CLEE011X1101, CLEE011X2107, CLEE011A2301, CLEE011E2301 and CLEE011F2301.
  • FIG.3 provides a schematic of the inclusion according to anatomic stage group in the NATALEE clinical trial.
  • FIG.4 provides a schematic of ECG and PK Relative to Dosing (C1D15).
  • FIG.5 illustrates a questionnaire (i.e., EORTC QLQ-C30) for use, for example, of assessment of quality of life and healthcare resources utilization.
  • FIG.6 illustrates a questionnaire (i.e., EORTC QLQ-BR23) for use, for example, of assessment of quality of life and healthcare resources utilization.
  • FIG.7 illustrates a questionnaire (i.e., EQ-5D-5L) for use, for example, of assessment of quality of life and healthcare resources utilization.
  • FIG.8 illustrates a questionnaire (i.e., Hospital Anxiety Depression Scale (HADS)) for use, for example, of assessment of quality of life and healthcare resources utilization.
  • HADS Hospital Anxiety Depression Scale
  • FIG.9 shows a Kaplan-Meier Plot (Full analysis set) for the Primary Invasive Disease-Free Survival Analysis.
  • FIG.10 shows a (q) Forest Plot of iDFS by stratum (per eCRF) (Full analysis set).
  • FIG.11A shows a Forest Plot of iDFS – subgroup analysis.
  • FIG.11B shows a Forest Plot of iDFS – subgroup analysis.
  • FIG.11C shows a Forest Plot of iDFS – subgroup analysis.
  • FIG.11D shows a Forest Plot of iDFS – subgroup analysis.
  • FIG.12 shows iDFS - Kaplan-Meier survival curves of iDFS by Anatomic Stage II (eCRF stratum) (Full analysis set).
  • FIG.13 shows iDFS - Kaplan-Meier survival curves of iDFS by Anatomic Stage III (eCRF stratum) (Full analysis set).
  • FIG.14 shows Kaplan-Meier curves for RFS (Full analysis set).
  • FIG.15 shows Kaplan-Meier curves for DDFS (Full analysis set).
  • FIG.16 shows Kaplan-Meier curves for OS (Full analysis set).
  • the present disclosure relates to methods for treating patients suffering from breast cancer (BC).
  • the methods are based, inter alia, on surprising results from the NATALEE clinical trial which indicate that a combination of a CDK inhibitor plus endocrine therapy can provide beneficial effects in patients with early breast cancer, for example, an early breast cancer that is hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-).
  • HR+/HER2- hormone receptor-positive/human epidermal growth factor receptor 2-negative
  • A. Treatment of early breast cancer One aspect of the present disclosure relates to a method of treatment for breast cancer in an adult patient in need thereof, comprising administering to the patient a treatment comprising a cyclin-dependent kinase (CDK) inhibitor in combination with endocrine therapy, wherein the breast cancer is early breast cancer (EBC).
  • CDK cyclin-dependent kinase
  • EBCs may be characterized by localization of cancer cells (e.g., forming a tumor) in the breast tissue and regional lymphatics. In EBC, cancer cells are typically not detected beyond the breast or the axillary lymph nodes.
  • Early breast cancer may be stage 0, stage I, stage II, or stage III cancer (e.g., stage 0, stage I, stage IIA, stage IIB, stage IIIA, stage IIIB, or stage IIIC). Due to its localization, EBC may be differentiated from advanced breast cancer (also called metastatic cancer) where the cancer has spread to one or more parts of body, such as the bones, lungs, liver, etc.
  • the EBC is a carcinoma of the breast, such as an adenocarcinoma.
  • the EBC may be an invasive carcinoma.
  • Invasive carcinomas also known as infiltrating or invasive ductal carcinomas (IDC)
  • IDC invasive ductal carcinomas
  • the EBC may be a noninvasive carcinoma, such as a ductal carcinoma in situ (DCIS) of the breast.
  • DCIS ductal carcinoma in situ
  • Signs and/or symptoms of early breast cancer may be one or more of a lump in the breast or armpit, thickening or swelling of part of the breast, irritation or dimpling of breast skin (e.g., dimpling that resembles an orange peel), redness or flaky skin in the nipple area of the breast, pulling in the nipple or pain in the nipple area, nipple discharge other than breast milk, including blood, any change in the size or shape of the breast, and/or pain in any area of the breast.
  • irritation or dimpling of breast skin e.g., dimpling that resembles an orange peel
  • redness or flaky skin in the nipple area of the breast pulling in the nipple or pain in the nipple area
  • nipple discharge other than breast milk including blood, any change in the size or shape of the breast, and/or pain in any area of the breast.
  • Additional signs and/or symptoms of early breast cancer may comprise the presence of a breast cancer cell or cells, the presence of a breast cancer tumor, or the presence of biochemical or genetic markers in a patient’s tissues or body fluids which indicate that the presence of breast cancer (e.g., breast cancer biomarkers in a tissue biopsy or a blood sample).
  • the presence may be a physical presence, detected using tests such as ultrasound, mammogram, magnetic resonance imaging, analysis of tissue samples (e.g., a biopsy) and/or analysis of samples of body fluids (e.g., a blood sample). Any known test may be used for detecting signs and/or symptoms of cancer.
  • No evidence of disease may be used when there is no detectable sign and/or symptom of a cancer.
  • Breast cancers may be graded according to their histology.
  • a histologic grade (or “grade”) may refer to the extent that a cancer cell differs from a normal cell, for example, by differing in the degree of cell differentiation.
  • Grade 1 refers to breast cancer cells that resemble normal breast cells and are usually slow growing.
  • Grade 2 refers to breast cancer cells that may not resemble normal breast cells and grow fast.
  • Grade 3 refers to breast cancer cells that do not resemble normal breast cells and are usually fast growing.
  • Grade 4 refers to breast cancer cells that least resemble normal breast cells and tend to grow and spread faster than lower grade tumors.
  • a staging method may be a pathologic staging method, e.g., based on a pathologist’s study of the tumor tissue and any lymph nodes removed during surgery, or a clinical staging method, e.g., based on a clinician’s physical exam, tests, and/or imaging.
  • staging methods are used to categorize breast cancers based on the size of the cancer (e.g., a primary tumor) and how far the cancer has spread in the body.
  • PAT059494-WO-PCT One method used to categorize breast cancers or tumors based on their stage is the TNM classification or staging method.
  • a tumor may be classified as T0 when there is no evidence of a tumor, while classifications of T1, T2, T3, or T4 may be used for to identify the size and extension of the tumor.
  • Tx may indicate that the tumor cannot be assessed.
  • N node
  • a tumor may be classified as N0 when there is no spread of the tumor to regional nodes, while classifications of N1-N3 may be used to indicate nodal spread.
  • M metastasis describes metastasis (e.g., spread of cancer to other parts of the body).
  • T3 may be defined as a tumor more than 50 mm in greatest dimension.
  • T4 may be defined as a tumor of any size with direct extension to the chest wall and/or the skin (e.g., ulceration or skin nodules).
  • T4a may be extension to the chest wall.
  • T4b may be defined as edema of the skin or ulceration of the skin of the breast, or satellite skin nodules confined to the same breast.
  • T4c may be defined as both T4a and T4b.
  • T4d may be defined as inflammatory cancer, e.g., cancer characterized by diffuse erythema and edema involving approximately a third or more of the skin of the breast.
  • Regional lymph nodes near the breast may comprise one or more of (1) axillary lymph nodes, the interpectoral (Rotter’s nodes), and lymph nodes along the axillary vein and its tributaries.
  • Axillary lymph nodes may be Level I (low-axilla), Level II (mid-axilla), or Level III (apical axilla); (2) internal mammary lymph nodes; (3) superclavical lymph nodes; and (4) intramammary lymph nodes.
  • N0 indicates that the cancer has not spread to nearby lymph nodes; N1 indicates that the cancer has spread to 1 to 3 axillary lymph nodes, and/or is found in internal mammary lymph nodes on sentinel lymph node biopsy; N2 indicates that the cancer has spread to 4 to 9 axillary lymph nodes, or has enlarged the internal mammary lymph nodes; and N3 indicates that the cancer has spread to 10 or more axillary lymph nodes, with at least one area of cancer spread greater than 2 mm, or has spread to infraclavicular nodes, with at least one area of cancer spread greater than 2 mm, or is found in at least one axillary lymph node (with at least one area of cancer spread greater than 2 mm) PAT059494-WO-PCT and has enlarged the internal mammary lymph nodes, or has spread to 4 or more axillary lymph nodes (with at least one area of cancer spread greater than 2 mm), and to the internal mammary lymph no
  • Node categorization may be a clinical categorization or may be a pathological categorization.
  • Clinical categorization may comprise cN1 defined as metastasis in ipsilateral level I, II axillary lymph nodes; cN2a defined as metastasis in ipsilateral level I, II axillary lymph nodes fixed to one another (matted); cN2b defined as metastasis only in clinically detected ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph node metastasis; cN3a defined as metastasis in ipsilateral infraclavicular (level III axillary) lymph nodes with our without level I, II axillary lymph node involvement; cN3b defined as metastasis in clinically detected ipsilateral internal mammary lymph node(s) and clinically evident axillary lymph node(s); or cN3c defined as metastasis in ips
  • An add-on to the TMN classification system is the R classification system, or residual tumor classification system, which may be used to indicate the tumor status following treatment.
  • the R classification may indicate the effects of treatment and may be used to predict prognosis.
  • a patient may be diagnosed with a tumor that is classified using the TMN classification system and then treated, after which any residual tumor may be classified according to the R classification system.
  • the extent of resection of a tumor can is classified as R0, R1, or R2.
  • R0 there is no residual tumor after surgery, e.g., the surgical margin is microscopically negative for residual tumor.
  • R1 there is no residual macroscopic tumor but microscopic margins still demonstrate the presence of tumor.
  • the gross (macroscopically- visible) tumor remains post-surgery.
  • the TNM classification system predates many genetic tests and/or biochemical marker (or “biomarker”) tests that are now routinely used to provide additional predictive or prognostic information about cancer types, and may be used together with these and/or other tests for categorizing cancers.
  • the TNM classification system may be used in combination with measures such as tumor grade, estrogen receptor (ER) status, progesterone receptor (PR) status, and human epidermal growth factor receptor 2 (HER2) status.
  • ER estrogen receptor
  • PR progesterone receptor
  • HER2 human epidermal growth factor receptor 2
  • An example of such a combination is provided in Table 1 of Ann Surg Oncol.2018 Jul;25(7):1783-1785. doi: 10.1245/s10434-018-6486-6. Epub 2018 Apr 18.
  • Ki-67 is the nuclear antigen Ki-67.
  • Ki-67 levels may be measured in breast cancer cells, for example, using immunohistochemical staining.
  • the anti-human Ki-67 antibody MIB1 may be used for the immunohistochemistry.
  • Ki-67 values are PAT059494-WO-PCT calculated as a percentage of positively marking malignant cells among the total number of malignant cells assessed (Breast Cancer Res Treat.2013; 139(2): 539–552). In general, Ki-67 expression correlates with high levels of cell proliferation (J Clin Oncol.2005 Oct 1;23(28):7212- 20).
  • Genetic tests such as multigene or multiparameter expression assays may be used to evaluate characteristics of a breast cancer, risk of metastasis, and/or risk of recurrence.
  • One exemplary test is the Oncotype DX® test, where a breast recurrence score of ⁇ 26 (on a scale of 0-100) indicates a risk for recurrence.
  • the Prosigna®/PAM50 (Prediction Analysis of Microarray 50) test tumors are assigned a score of low risk, intermediate risk, or high risk for metastasis, depending on the expression levels of 50 genes in the tumor.
  • exemplary tests include but are not limited to the MammaPrint®, EndoPredict®, and Breast Cancer Index® tests, which may be used to determine risk scores for cancer recurrence.
  • Another method for categorizing tumors is the “Stage Grouping” categorization system. This method, which may be used alone or together with the TNM classification system and other tests, groups breast cancers in Anatomic Stage Groups (or “stages”). Thus, breast cancer may be categorized according to a stage group (or “Anatomic Stage Group”) 0, I, II, III, or IV. In particular, the stage group may be stage 0, Ia, Ib, IIa, IIb, IIIa, IIIb, IIIC, or IV.
  • Stage 0 Stage zero (0) may describe disease that is only in the ducts of the breast tissue and has not spread to the surrounding tissue of the breast. It is also called non-invasive or in situ cancer (Tis, N0, M0).
  • Stage IA may refer to a tumor that is small, invasive, and has not spread to the lymph nodes (T1, N0, M0).
  • Stage IB may refer to cancer that has spread to the lymph nodes and the cancer in the lymph node is larger than 0.2 mm but less than 2 mm in size. There may be either no evidence of a tumor in the breast or the tumor in the breast is 20 mm or smaller (T0 or T1, N1mi (also called “N1 micrometastatic”), M0).
  • Stage IIA may refer to cancer meeting any one of these conditions: a. There is no evidence of a tumor in the breast, but the cancer has spread to 1 to 3 axillary lymph nodes. It has not spread to distant parts of the body (T0, N1, M0). b. The tumor is 20 mm or smaller and has spread to 1 to 3 axillary lymph nodes (T1, N1, M0). c. The tumor is larger than 20 mm but not larger than 50 mm and has not spread to the axillary lymph nodes (T2, N0, M0). PAT059494-WO-PCT Stage IIB may refer to either of these conditions: a.
  • the tumor is larger than 20 mm but not larger than 50 mm and has spread to 1 to 3 axillary lymph nodes (T2, N1, M0).
  • the tumor is larger than 50 mm but has not spread to the axillary lymph nodes (T3, N0, M0).
  • Stage IIIA may refer to a tumor of any size that has spread to 4 to 9 axillary lymph nodes or to internal mammary lymph nodes. It has not spread to other parts of the body (T0, T1, T2, or T3; N2; M0).
  • Stage IIIA may also be a tumor larger than 50 mm that has spread to 1 to 3 axillary lymph nodes (T3, N1, M0).
  • Stage IIIB may refer to a tumor that has spread to the chest wall or caused swelling or ulceration of the breast, or it is diagnosed as inflammatory breast cancer. It may or may not have spread to up to 9 axillary or internal mammary lymph nodes. It has not spread to other parts of the body (T4; N0, N1, or N2; M0).
  • Stage IIIC may refer to a tumor of any size that has spread to 10 or more axillary lymph nodes, the internal mammary lymph nodes, and/or the lymph nodes under the collarbone. It has not spread to other parts of the body (any T, N3, M0).
  • Stage IV may refer to a tumor that can be any size and has spread to other organs, such as the bones, lungs, brain, liver, distant lymph nodes, or chest wall (any T, any N, M1). Metastatic cancer found when the cancer is first diagnosed occurs about 6% of the time. This may be called de novo metastatic breast cancer. Most commonly, metastatic breast cancer is found after a previous diagnosis of early-stage breast cancer. Recurrent cancer is cancer that has come back after a treatment and can be described as local, regional, and/or distant (Breast Cancer: Stages, from Cancer.Net). Recurrence may be evaluated by medical imaging and confirmed histologically (or cytologically, when applicable).
  • Recurrences may be classified into local, regional, or distant recurrence, or contralateral invasive breast cancer or second primary non-breast invasive cancer according to the following guidelines: - Local invasive breast cancer recurrence or ipsilateral invasive breast tumor recurrence: invasive breast cancer involving the same breast as the original primary tumor. Ductal and lobular carcinoma in situ and tumors in the contralateral breast and/or contralateral lymph nodes are not considered a local invasive recurrence. May be confirmed histologically.
  • PAT059494-WO-PCT Regional breast cancer recurrence: invasive breast cancer in the ipsilateral axilla, regional lymph nodes (all levels), chest wall, or skin of the ipsilateral breast. A tumor in the contralateral breast is not considered a regional recurrence. May be confirmed histologically (preferred) or cytologically.
  • - Distant recurrence distant metastasis of breast cancer (bones, distant lymph nodes, internal organs, CNS, bone marrow, etc.) or any areas of invasive breast cancer recurrence that are not local or regional. Distant recurrence may be confirmed histologically (preferred) or cytologically.
  • bone metastases were identified by a bone scan, it may be confirmed histologically (preferred) or radiographically (CT, MRI, or FDG-PET-CT) if biopsy confirmation is not possible.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • FDG-PET-CT radiographically
  • All other sites of metastases may be confirmed histologically (preferred) or cytologically unless there is an unacceptable risk to the patient due to the procedure.
  • Contralateral invasive breast cancer any invasive breast cancer in the contralateral breast with or without contralateral lymph nodes involvement. Contralateral invasive breast cancer has to be confirmed histologically.
  • Second primary non-breast invasive cancer any second primary non-breast invasive cancers.
  • Second primary non-breast invasive cancer has to be confirmed histologically.
  • In situ/non-invasive cancers and basal or squamous cell carcinomas of the skin are not considered as second primary non-breast invasive cancers.
  • Table B1 summarizes Anatomic Stage Groups from the AJCC 8 th Edition Table B1 Anatomic Stage T-category N-category Group 0 Tis N0 PAT059494-WO-PCT IB T0-1 N1mi IIA T0-1 N1 IV T1-T3 N1-N3 Note that T2, T3, and T4 tumors with nodal micrometastases (N1mi) may be staged using the N1 category.
  • the adult patient treated with the methods herein has an EBC that is a ductal carcinoma in situ, a stage I breast cancer, a stage II breast cancer such as a IIA breast cancer or a stage IIB breast cancer, or a stage III breast cancer such as a stage IIIA, a stage IIIB, or a stage IIIC breast cancer.
  • the patient has a stage II or III early breast cancer.
  • the patient has a stage IIA cancer or a stage IIB cancer.
  • the patient has a stage IIIA cancer, a stage IIIB cancer, or a stage IIIC cancer.
  • the patient may be node-positive (e.g., cancer has spread to their lymph nodes) or node-negative (e.g., cancer has not spread to their lymph nodes).
  • the treatment methods as described herein are performed irrespective of the nodal status of the patient’s breast cancer.
  • the EBC is a hormone receptor-positive (HR+) breast cancer, e.g., a breast cancer comprising cells expressing one or more type of hormone receptor.
  • Exemplary hormone receptors may be estrogen receptors (ERs), such as ER ⁇ or ER ⁇ , and/or progesterone receptors (PRs) such as PRA and PRB.
  • EBCs may comprise breast cancer cells expressing either estrogen receptors (ER+) or progesterone receptors (PR+), or a combination of both estrogen receptors and progesterone receptors (ER+/PR+).
  • the EBC is ER+/PR-, ER-/PR+, or ER+/PR+.
  • PAT059494-WO-PCT In certain embodiments, the EBC is positive for human epidermal growth factor receptor 2 (HER2).
  • Certain embodiments relate to a method of preventing or reducing signs or symptoms of early stage breast cancer, comprising administering to the patient a treatment comprising ribociclib, a freebase form thereof or a pharmaceutically acceptable salt thereof in combination with an aromatase inhibitor, preferably letrozole or anastrozole.
  • the ribociclib is a freebase form thereof or a pharmaceutically acceptable salt thereof, and is administered to the patient in a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle.
  • the aromatase inhibitor is administered on every day of the 28-day cycle.
  • CDK Inhibitors and Endocrine Therapy One aspect of the present disclosure relates to a method of treatment for early breast cancer in an adult patient in need thereof, comprising administering to the patient a treatment comprising a cyclin-dependent kinase (CDK) inhibitor in combination with endocrine therapy (ET).
  • CDKs Cyclin-dependent kinases
  • ETS endocrine therapy
  • CDKs In healthy cells, various extra- and intra-cellular cues closely regulate the formation of the CDK/cyclin complex and control its phosphorylation of target proteins involved in the cell cycle, such as retinoblastoma (Rb) proteins, lamins, histone H 1, and components of the mitotic spindle. In cancer cells, however, CDKs can become hyperactivated, leading to uncontrolled tumor proliferation.
  • CDK4 and CDK6, which bind to D-cyclins, are exemplary CDKs that have been shown to promote growth of certain breast cancer tumors.
  • CDK inhibitors have been shown to block the unregulated cell growth and division resulting from hyperactivation of CDKs and/or overexpression of cyclin proteins.
  • inhibitors of CDK/cyclin complexes, and of CDK4/6 in particular have been used for treating patients suffering from certain types of cancer.
  • CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib have been approved by regulatory authorities for treatment of advanced or metastatic breast cancer that is hormone receptor positive (HR+ or HR-positive), and human epidermal growth factor receptor 2 negative (HER2-) (Fassi et al., Science.2022 Jan 14; 375(6577): eabc1495).
  • HR+ or HR-positive hormone receptor positive
  • HER2- human epidermal growth factor receptor 2 negative
  • ribociclib has been approved by a number of regulatory authorities including the United States Food and Drug Administration (FDA) and the European Commission.
  • the ET may be combined with a luteinizing hormone-releasing hormone agonist.
  • the CDK inhibitor used in the methods disclosed herein may be a CDK4/6 inhibitor, for example, an inhibitor of a CDK4/6/cyclin complex.
  • the cyclin may be a D cyclin, such as cyclin-D1 in a CDK4/cyclin-D1 complex or cyclin-D3 in a CDK6/cyclin-D3 complex.
  • the CDK4/6 inhibitor may be a compound described by Formula A1 below or a salt thereof.
  • the compound of Formula A1 is known by the international non-proprietary name ribociclib.
  • the CDK4/6 inhibitor may be a compound having the international non-proprietary name ribociclib.
  • Ribociclib may be in the form of its free base or may be a pharmaceutically acceptable salt of ribociclib. Salts can be present alone or in mixture with free compound, e.g. ribociclib, and are preferably pharmaceutically acceptable salts.
  • Such salts of ribociclib are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of ribociclib with a basic nitrogen atom. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, e.g., succinic acid, carboxylic acids, or sulfonic acids, such as fumaric acid or methansulfonic acid.
  • PAT059494-WO-PCT for example picrates or perchlorates.
  • ribociclib may be in the form of racemates, diastereoisomers, enantiomers, and tautomers, as well as the corresponding crystal modifications where present, e.g. solvates, hydrates, and polymorphs.
  • Ribociclib may be in the form of a pharmaceutically acceptable salt, for example, a succinic acid salt such as ribociclib succinate.
  • a succinic acid salt such as ribociclib succinate.
  • the chemical name of ribociclib succinate is butanedioic acid— 7-cyclopentyl-N,N-dimethyl-2- ⁇ [5-(piperazin1-yl)pyridin-2-yl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidine- 6-carboxamide (1:1) corresponding to the molecular formula C 27 H 36 N 8 O 5 . It has a relative molecular mass of 552.6 g/mol (EMA Assessment report for Kisqali, Procedure No. EMEA/H/C/004213/0000, dated June 22, 2017).
  • ribociclib Oral tablet forms of ribociclib are known in the art (e.g. WO2016/166703) and have been approved as the KISQALI® product.
  • KISQALI® product Various ribociclib salts have been described (e.g. see claim 85 of WO2022/207788), and the approved KISQALI® product contains ribociclib succinate. Quantities of any salt will be adjusted to provide the desired quantity of ribociclib (e.g.254.40mg of ribociclib succinate corresponds to 200mg of ribociclib).
  • ribociclib succinate e.g.
  • the methods described herein may be implemented using the approved KISQALI® product, e.g., along with approved endocrine therapies.
  • the CDK inhibitor e.g, a CDK4/6 inhibitor such as ribociclib or a pharmaceutically acceptable salt thereof, such as ribociclib succinate
  • the endocrine therapy is an aromatase inhibitor.
  • Endocrine therapy has been used to slow or stop the growth of hormone-sensitive cancers (also called hormone- dependent cancers).
  • Hormone-sensitive tumors express receptors for hormones such as estrogen and/or progesterone, and the hormones may promote growth of the cancer.
  • endocrine therapy refers to a therapy that either (1) interferes with the effects of the hormones on the cancer cells and/or (2) blocks the body’s ability to produce hormones.
  • Exemplary compounds that interfere with the effects of hormones on breast cancer cells are selective estrogen receptor modulators (SERMs), which bind to estrogen receptors and prevent estrogen from binding. SERMs may mimic the effects of estrogen.
  • SERMs selective estrogen receptor modulators
  • SERMs approved by the FDA for treatment of breast cancer are tamoxifen (Nolvadex®) and toremifene (Fareston®).
  • Other PAT059494-WO-PCT anti-estrogen drugs may bind to estrogen receptors without mimicking the effects of estrogen, and may instead target the estrogen receptor for destruction.
  • An exemplary anti-estrogen compound is fulvestrant (Faslodex®). The production of hormones may be blocked by ablating tissues or organs that produce the hormones.
  • ovarian ablation e.g., by oophorectomy (also called ovariotomy or ovariectomy) or treatment with radiation
  • ovarian ablation e.g., by oophorectomy (also called ovariotomy or ovariectomy) or treatment with radiation
  • the production of hormones may be blocked by administering compounds that suppress synthesis and/or release of the hormones.
  • Gonadotropin-releasing hormone (GnRH) agonists administered over a prolonged period may cause desensitization and consequently suppression of gonadotropin secretion.
  • GnRH antagonists in contrast, inhibit GnRH signal transduction and gonadotropin secretion (Reprod Biomed Online.2002;5 Suppl 1:1-7.
  • GnRH agonists are goserelin (Zoladex®) and leuprolide (Lupron®), which suppress release of estrogen from the ovaries in women and suppress the release of testosterone from the testicles in men.
  • goserelin is used in the methods disclosed herein.
  • a further class of compounds that block production of estrogen, in particular, are aromatase inhibitors.
  • Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens in a process called aromatization.
  • aromatase inhibitors may be combined with a compound that suppresses ovarian function (e.g., goserelin or leuprolide).
  • a compound that suppresses ovarian function e.g., goserelin or leuprolide
  • postmenopausal women produce estrogen primarily in peripheral tissues and not in the ovaries, so aromatase inhibitors may be sufficient to inhibit production of estrogen in these women.
  • aromatase inhibitors There are two types of aromatase inhibitors: (1) steroidal inhibitors, such as exemestane (Aromasin®) which forms a permanent and deactivating bond with the aromatase enzyme; and (2) non-steroidal inhibitors (NSAIs), such as anastrozole (Arimidex®) or letrozole (Femara®).
  • steroidal inhibitors such as exemestane (Aromasin®) which forms a permanent and deactivating bond with the aromatase enzyme
  • NSAIs non-steroidal inhibitors
  • Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system. Letrozole acts by highly selective inhibition of conversion of androgens (mainly from adrenal glands, the primary source of estrogens in postmenopausal women) to estrogens.
  • Letrozole induces a 75% to 95% decrease of estrogen levels after two weeks of treatment with daily doses of 0.1 to 5 mg, with no significant clinical and laboratory toxicities or changes in levels of other hormones of the endocrine system (Lancet Lond Engl 386:1341–1352, 2015; Cancer 75:2132–2138, 1995).
  • PAT059494-WO-PCT Anastrozole is a selective NSAI. It significantly lowers serum estradiol concentrations with no detectable effect on formation of adrenal corticosteroids or aldosterone.
  • the endocrine therapy administered with the CDK inhibitor is an aromatase inhibitor, e.g., anastrozole or letrozole.
  • the therapy further comprises a gonadotropin-releasing hormone agonist such as goserelin.
  • exemplary aromatase inhibitors are described in Breast Cancer Res Treat.2007 Oct; 105(Suppl 1): 7–17.
  • the aromatase inhibitor may be a non-steroidal aromatase inhibitor described by one of the formulas below, or a pharmaceutically acceptable salt thereof.
  • the aromatase inhibitor may be letrozole.
  • the aromatase inhibitor may be a pharmaceutically acceptable salt of letrozole.
  • the chemical name of letrozole is 4,4'-(1H- 1,2,4-Triazol-1-ylmethylene)dibenzonitrile.
  • Letrozole may be freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31 g/mol, empirical formula C 17 H 11 N 5 , and a melting range of 184°C to 185°C.
  • letrozole may be in the form of racemates, diastereoisomers, enantiomers, or tautomers, as well as the corresponding crystal modifications where present, e.g. solvates, hydrates and polymorphs.
  • the aromatase inhibitor may be anastrozole or a pharmaceutically acceptable salt thereof.
  • the chemical name of anastrozole is ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyl-5-(1H-1,2,4- triazol-1-ylmethyl)-m-benzenediacetonitrile.
  • Anastrozole is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile.
  • anastrozole may be in the form of a solvate, hydrate or polymorph.
  • endocrine therapy may comprise an aromatase inhibitor (such as letrozole or anastrozole) for postmenopausal women.
  • the endocrine therapy may comprise an aromatase inhibitor (such as letrozole or anastrozole) and PAT059494-WO-PCT may further comprise a compound that suppresses gonadal function (e.g., a GnRH agonist such as goserelin).
  • the GnRH agonist may be a compound according to the formula below or a pharmaceutically acceptable salt thereof: Formula (F1)
  • the aromatase inhibitor may be goserelin or a pharmaceutically acceptable salt thereof.
  • Goserelin is sold under the tradename Zoladex®.
  • a further aspect of the present disclosure relates to a method of treatment for early breast cancer in an adult patient in need thereof, comprising administering to the patient a treatment comprising a dose of a cyclin-dependent kinase (CDK) inhibitor, in combination with a dose of an endocrine therapy.
  • CDK cyclin-dependent kinase
  • the CDK inhibitor is a CDK4/6 inhibitor such as ribociclib or a pharmaceutically acceptable salt thereof (such as ribociclib succinate) and the endocrine therapy is an aromatase inhibitor such as letrozole.
  • the endocrine therapy is letrozole. Ribociclib at a dose of 600 mg daily from days 1 to 21 of a 28-day cycle has been shown to be tolerable and efficacious when combined with ET in clinical trials in patients with advanced BC (N Engl J Med 375:1738–1748, 2016).
  • ribociclib in combination with ET may be administered at a dose of less than 600 mg daily.
  • ribociclib or a pharmaceutically acceptable salt thereof such PAT059494-WO-PCT as ribociclib succinate
  • This exemplary dose may be administered as 2 x 200 mg daily.
  • the ribociclib (or a pharmaceutically acceptable salt thereof such as ribociclib succinate) may be administered at dose of about 400 mg/day.
  • the dose of ribociclib or a pharmaceutically acceptable salt thereof (such as ribociclib succinate) may be administered once per day in a tablet form, for example, as 2 x 200 mg tablets (it being understood that these two tablets may be taken simultaneously or sequentially within the single daily dosing).
  • the dose may be administered as an oral solution.
  • the dose may be administered orally (by mouth).
  • the dose of the ribociclib or a pharmaceutically acceptable salt thereof (such as ribociclib succinate) is about 200 mg/day.
  • This dose may be administered in a tablet form, for example, as 1 x 200 mg tablet.
  • the dose may be administered orally (by mouth).
  • the dose may be a flat fixed dose, e.g., not calculated by body weight or body surface area.
  • a dose adjustment may be made, for example, to administer a dose of ribociclib or a pharmaceutically acceptable salt thereof (such as ribociclib succinate) that is less than about 400 mg/day.
  • a dose of about 350 mg/day, about 300 mg/day, about 250 mg/day, about 200 mg/day, or about 150 mg/day of ribociclib or a pharmaceutically acceptable salt thereof (such as ribociclib succinate) may be administered.
  • a dose of about 200 mg/day is administered after an earlier dose of 400 mg/day has been administered.
  • the dose is administered in tablet form, such as 1 x 200 mg tablet.
  • the dose of about 200 mg/day may be administered orally.
  • a patient who had previously received a dose of about 400 mg dose of ribociclib or a pharmaceutically acceptable salt thereof (such as ribociclib succinate) (e.g., 2 x 200 mg tablets orally) may receive a dose of about 200 mg/day instead (e.g., 1 x 200 mg tablets orally).
  • the dose may taken once daily (e.g., 1 x 200 mg tablets once daily, or 2 x 200 mg tablets once daily).
  • the dose adjustment may be made for patients who do not tolerate a dose of about 400 mg/day.
  • the dose of ribociclib may range from about 150 mg/day to about 450 mg/day.
  • the dose may be about 150 PAT059494-WO-PCT mg/day, about 200 mg/day, about 250 mg/day, about 300 mg/day, about 350 mg/day, or about 450 mg/day.
  • the dose may be taken once daily.
  • the dose of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) is not about 600 mg/day.
  • the aromatase inhibitor is letrozole.
  • the dose of letrozole may be selected according to data (e.g., clinical data) indicating disease-free survival in patients, which may be combined with data about adverse effects such as renal impairment and/or hepatic impairment, to establish an effective dose.
  • the dose may be selected by testing efficacy and tolerance in an individual patient.
  • the dose of letrozole may range from about 1 mg/day to about 4 mg/day.
  • the dose of letrozole may be about 1 mg/day, about 1.25 mg/day, about 1.5 mg/day, about 1.75 mg/day, about 2 mg/day, about 2.25 mg/day, about 2.5 mg/day, about 2.75 mg/day, about 3 mg/day, about 3.25 mg/day, about 3.5 mg/day, about 3.75 mg/day, or about 4 mg/day.
  • the dose of letrozole is about 2.5 mg/day.
  • the dose may be a flat fixed dose, e.g., not calculated by body weight or body surface area.
  • the dose of letrozole may be administered orally (e.g., by mouth).
  • any of the dosages listed above such as a dose of letrozole that is about 2.5 mg/day, may be administered.
  • the dose of letrozole may be administered orally.
  • the dose may be administered in tablet form.
  • the dose may be taken once daily.
  • the aromatase inhibitor is anastrozole.
  • the dose of anastrozole may be selected according to data (e.g., clinical data) indicating disease-free survival in patients, which may be combined with data about adverse effects such as renal impairment and/or hepatic impairment, to establish an effective dose.
  • the dose may be selected by testing efficacy and tolerance in an individual patient.
  • the dose of anastrozole may range from about 0.5 mg/day to about 1.5 mg/day.
  • the dose of anastrozole may be about 0.5 mg/day, about 0.75 mg/day, about 1 mg/day, about 1.25 mg/day, or about 1.50 mg/day. In some embodiments, the dose of anastrozole is about 1 mg/day.
  • the dose of anastrozole may be administered orally (e.g., by mouth). Accordingly, any of the dosages listed above, such as a dose of anastrozole that is about 1 mg/day may be administered.
  • the dose of anastrozole may be administered orally.
  • the dose may be administered in tablet form. The dose may be taken once daily.
  • patients may receive a gonadotropin-releasing hormone agonist such as goserelin.
  • goserelin a gonadotropin-releasing hormone agonist
  • patients who are premenopausal women and patients who are men may receive a dose of goserelin.
  • the dose of goserelin may be selected according to data (e.g., clinical data) indicating efficacy in patients, or by testing efficacy and tolerance in an individual patient.
  • the dose of goserelin may range from about 2 mg to about 5 mg.
  • the dose of goserelin may be about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5 mg.
  • the dose of goserelin is about 3.4 mg, 3.5 mg, 3.6 mg, or 3.7 mg.
  • the dose of goserelin is 3.6 mg.
  • the dose may be a flat fixed dose, e.g., not calculated by body weight or body surface area.
  • the dose of goserelin may be administered subcutaneously.
  • the dose may be administered subcutaneously at time intervals ranging from 2 weeks to 4 weeks.
  • goserelin is administered subcutaneously at a dose of 3.6 mg.
  • the compounds may be administered separately, for example, when the compounds are administered by different routes of administration and/or administered according to different treatment schedules. If administered separately, the compounds may be administered simultaneously, or sequentially.
  • two compounds are administered to the patient in two separate doses, but are administered on the same day as each other. In this example, the two compounds may be administered at the same time, or they may be administered at different times.
  • the compounds may be administered separately in two or more separate unit doses (e.g., where a unit dose is the amount of the compound administered to the patient in a single dose) and/or unit dosage forms.
  • Compounds may be combined for administration together.
  • Compounds may be administered together in a single pharmaceutical composition, for example, the compounds may be administered together in a single dose (e.g., a unit dose).
  • the unit dosage form may also be a fixed combination.
  • a dose of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) (about 400 mg/day, or about 200 mg/day) and a dose of endocrine therapy (e.g., letrozole (dose about 2.5 mg/day) or anastrozole (dose about 1 mg/day) are administered together.
  • the doses may be administered at the same time each day, such as in the morning.
  • the doses may be administered in the afternoon or evening.
  • the doses are not administered in the evening.
  • PAT059494-WO-PCT A further aspect of the present disclosure relates to a method of treatment for early breast cancer in an adult patient in need thereof, comprising administering to the patient a treatment comprising a dose of a cyclin-dependent kinase (CDK) inhibitor, in combination with a dose of an endocrine therapy, according to a treatment schedule.
  • the treatment schedule comprises a treatment cycle of about 28 days. In this cycle, the CDK inhibitor may be administered once daily on days 1 to 21 of the 28-day cycle, followed by 7 days off the CDK inhibitor, wherein during the off days the endocrine therapy is administered once daily continuously.
  • the endocrine therapy may be administered on every day of the 28-day cycle.
  • the CDK inhibitor is ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) administered at a dose of about 400 mg/day (or about 200 mg/day) and the endocrine therapy is letrozole administered at a dose of about 2.5 mg/day or anastrozole administered at a dose of about 1 mg/day, wherein the ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) is administered once daily on days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) (days 22-28 of the cycle), and the letrozole or anastrozole is administered once daily continuously during the 28-day period (e.g., on every day of the 28-day
  • the ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) may be administered orally, for example, in tablet form.
  • the letrozole or the anastrozole may be administered orally, for example, in tablet form.
  • goserelin e.g., at a dose of about 3.6 mg
  • this may be administered once during the 28-day cycle.
  • the goserelin may be administered every 2-4 weeks, for example, every 4 weeks.
  • the goserelin is administered on day 1 ( ⁇ 3 days) of each 28-day cycle.
  • the goserelin may be administered on day -3, day -2, day -1, day 1, day 2, or day 3 of the 28-day cycle.
  • the treatment may be administered for at least about 12 months.
  • the treatment may be administered for at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, or longer.
  • the ribociclib and letrozole are administered for at least about 48 months (about 4 years), or at least about 60 months (about 5 years).
  • the treatment is administered for at least 36 months.
  • An exemplary dose and treatment schedule is shown in Table B1.1. Table B1.1.
  • Exemplary dose and treatment schedule PAT059494-WO-PCT Trial Treatment Pharmaceutical form and Dose Frequency and/or Regimen route of administration Ribociclib Tablets for oral use 400 mg Once daily on days 1 to 21 in each (LEE011200 mg) 28-day cycle Letrozole 2.5 mg Tablets for oral use 2.5 mg Once daily given continuously Anastrozole 1 mg Tablets for oral use 1 mg Once daily given continuously Goserelin 3.6 mg Implant, in pre-filled 3.6 mg Day 1 ⁇ 3 of each 28-day cycle syringe and Subcutaneous use
  • the patient has not received a loading dose prior to treatment.
  • the patient has received a loading dose prior to treatment.
  • the patient may have received a loading dose of ribociclib (e.g., or a ribociclib salt such as ribociclib succinate) and/or an endocrine therapy (e.g, letrozole or anastrozole).
  • a loading dose may be an initial dose of a drug that may be given at or prior to the beginning of a course of treatment before dropping down to a different, typically lower dose (e.g., a treatment or maintenance dose).
  • a loading dose may be a single dose or short duration regimen of a compound which is administered to the subject to rapidly increase the blood concentration level of the drug.
  • a short duration regimen for use herein will be from: 1 to 14 days; e.g., from 1 to 7 days; e.g., from 1 to 3 days; e.g., for three days; e.g., for two days; e.g., for one day.
  • the “loading dose” can increase the blood concentration of the drug to a therapeutically effective level.
  • the “loading dose” can increase the blood concentration of the drug to a therapeutically effective level in conjunction with a treatment dose of the drug.
  • the “loading dose” can be administered once per day, or more than once per day (e.g., up to 4 times per day).
  • a loading dosage may be used for drug molecules that have a long half-life or slow elimination in vivo.
  • the treatment continues until the patient has no remaining signs and/or symptoms of breast cancer.
  • the treatment continues until the patient has no detectable cancer and/or no signs (e.g., indication) of cancer recurrence.
  • treatment is reinitiated if a patient exhibits one or more signs of cancer recurrence.
  • the treatment continues until the cancer recurs.
  • Signs and/or symptoms of cancer and cancer recurrence may be determined by monitoring the patient over months and years following treatment, using tests such as physical examinations, scans and/or imaging of the site where the cancer was (e.g., x-rays, computed tomography, mammography), and blood tests.
  • tests such as physical examinations, scans and/or imaging of the site where the cancer was (e.g., x-rays, computed tomography, mammography), and blood tests.
  • different modalities for follow up may be PAT059494-WO-PCT mammography, clinical examination, whole body or localized MRI and/or CT scans.
  • a breast cancer patient may have (1) medical history taken and physical exam performed 1–4 times per year as clinically appropriate for 5 years, (2) a mammography every 12 months, and (3) in the absence of clinical signs and symptoms suggestive of recurrent disease, there is no indication for laboratory or imaging studies for metastases screening.
  • patients may be assumed to be treated, but must be observed for recurrence of disease.
  • the treatment as disclosed herein may be administered to patients who no longer have detectable signs and/or symptoms of cancer, but who may remain at risk for recurrence of cancer.
  • the treatment may continue in these patients for a period of time , e.g., ranging from at least about 3 months to at least about 10 years, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years, or any time period in between.
  • the patient may be monitored for recurrence of cancer, for example, according to clinical examination, mammography, scans, imaging, sample collection (e.g., biopsy of tissues), and/or blood tests.
  • sample collection e.g., biopsy of tissues
  • a patient may continue the treatment for an additional period of time.
  • a patient whose cancer recurs may discontinue the treatment, for example, to try another treatment option.
  • Another aspect of the present disclosure relates to a method of treatment for early breast cancer in an adult patient in need thereof, comprising administering to the patient a treatment comprising a cyclin-dependent kinase (CDK) inhibitor, in combination with endocrine therapy, wherein the adult patient is selected or characterized according to one or more criteria.
  • the criteria may relate to patient demographics, features of the patient’s early breast cancer (e.g., type, stage, grade, hormone-receptor status, etc.), previous treatment, and/or other criteria as described herein.
  • the patient is an adult, e.g., 18 years of age or greater. In some embodiments, the patient is about 18 years to about 45 years of age. In some embodiments, the patient is about 45 years of age to about 54 years of age. In some embodiments, the patient is about 55 years of age to about 64 years of age. In some embodiments, the patient is about 64 years of age or older.
  • the patient may belong to an age category that is less than the median PAT059494-WO-PCT age for a given population of EBC patients, or alternatively, the patient may belong to an aged category that is greater than or equal to the median age for a population of EBC patients. II. Gender and menopausal status In some embodiments, the patient is a woman.
  • the patient is a man.
  • the patient’s menopausal status may be premenopausal.
  • the female patient’s menopausal status may be postmenopausal.
  • a patient with postmenopausal status may be defined as (1) a patient who underwent bilateral oophorectomy; (2) a patient having an age more than or equal to 60 years; (3) a patient having an age of less than 60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) and Follicle-stimulating hormone (FSH) and plasma estradiol in the postmenopausal ranges per local normal ranges; or (4) a patient having an age of less than 60 years old and who is taking tamoxifen or toremifene, and has FSH and plasma estradiol level in postmenopausal ranges.
  • FSH Follicle-stimulating hormone
  • Premenopausal status may be defined for patients who do not meet the criteria for postmenopausal status.
  • amenorrhea may not be a reliable indicator of menopausal status as ovarian function may still be intact or resume despite anovulation/amenorrhea.
  • serial measurements of FSH and/or estradiol per local clinical guidelines may be used for a determination of postmenopausal status.
  • Child bearing potential In some embodiments, the patient is a woman of childbearing potential (CBP), defined as physiologically capable of becoming pregnant.
  • Women may be considered of CBP unless they have had 12 months or more than 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks prior to randomization.
  • the woman may be considered not of CBP after confirmation by hormone level assessment.
  • the patient is a woman of CBP who is not pregnant.
  • the patient is not a pregnant or breast-feeding (lactating) woman or a woman who plans to become pregnant or breast-feed during the treatment as described herein.
  • a patient in need of treatment for early breast cancer is a patient who has been diagnosed with early breast cancer.
  • the patient may not have received a prior treatment for the early breast cancer.
  • the patient may have received a prior treatment for the early breast cancer, such as surgery, chemotherapy, radiation therapy, and/or hormone therapy, but may still be in need of a treatment because the early breast cancer did not respond to the prior treatment.
  • the patient received a prior treatment for early breast cancer and has a recurrence of the early breast cancer.
  • the patient received a prior treatment for a cancer, but has been diagnosed with early breast cancer.
  • the patient is at risk for developing early breast cancer and/or at risk for a recurrence of early breast cancer.
  • the patient at risk may not have detectable signs or symptoms or early breast cancer, but may be at risk due to a previous diagnosis of cancer.
  • the patient received a prior treatment for early breast cancer, such as HR+ HER2- stage II or stage III early breast cancer, and has no detectable signs or symptoms of early breast cancer, but remains at risk for recurrence of early breast cancer.
  • Risk factors may relate to the early breast cancer for which the patient received treatment, where a high tumor grade, large tumor size (e.g., greater than 2 mm), and axillary node involvement may correlate with a higher risk for recurrence.
  • the patient has a breast cancer that is diagnosed as and/or confirmed (e.g., histologically confirmed) to be a carcinoma of the breast.
  • the carcinoma may have been diagnosed within 18 months prior to starting treatment.
  • the carcinoma may be a unilateral primary invasive adenocarcinoma.
  • the carcinoma may be a multicentric and/or multifocal tumor.
  • the patient has breast cancer that is hormone receptor positive.
  • the breast cancer may be positive for ER and/or PR.
  • the breast cancer may be ER+/PR-, ER-/PR+, or ER+/PR+.
  • the patient has a breast cancer that is a HER2- breast cancer.
  • the breast cancer may be defined as a cancer with a negative result from an in situ hybridization test and/or an immunohistochemistry (IHC) status of 0 or 1+. If the breast cancer has an IHC of 2+, a negative in situ hybridization (FISH, CISH, or SISH) may be used to confirm HER2- status. PAT059494-WO-PCT VI.
  • the patient has a breast cancer comprising a tumor that belongs to one of the following categories: • Anatomic Stage Group III, or • Anatomic Stage Group IIB, or • Anatomic Stage Group IIA that is either: • N1, or • N0, with: • Grade 3, or • Grade 2.
  • patients having a tumor that Anatomic Stage Group IIA, N0, and Grade 2 may have additional measures to categorize the breast cancer.
  • the tumor may have a Ki67 percentage that is about 20% or greater than about 20%.
  • the tumor may have scores in multiparameter tests that indicate a risk for recurrence and/or spread of cancer, such as a breast recurrence score of ⁇ 26 (on a scale of 0-100) in the Oncotype DX® test, a high risk score in Prosigna®/PAM50 (Prediction Analysis of Microarray 50) test, a high risk score MammaPrint® test, or a high risk score EndoPredict® EPclin test.
  • the patient has a stage IIA tumor.
  • the patient has a stage IIB tumor.
  • the patient has a stage IIIA tumor.
  • the patient has a stage IIIB tumor.
  • the patient has a stage IIIC tumor.
  • the patient does not have a stage IV tumor, e.g., a breast cancer tumor with distant metastases beyond the lymph nodes.
  • the patient has a tumor with a nodal status that is selected from NX, N0, N1, N2, or N3.
  • the patient may have a tumor with N0 status.
  • the patient may have a tumor with N1, N2, or N3 status, or a tumor with a status that is any one of N1, N2, or N3.
  • the patient has a tumor of category T0, category Tis, T1, T2, T3, or a category T4 tumor.
  • the patient has a tumor of category T0.
  • the patient may have a tumor of category T1, T2, or T3 status, or a tumor that is any one of T1, T2, or T3. In some embodiments, the patient has a tumor of category T4. PAT059494-WO-PCT In some embodiments, the patient has a tumor with an M stage of M0. In some embodiments, the patient has a tumor of histological grade GX, G1, G2, or G3 (e.g., Grade X, Grade 1, Grade 2, or Grade 3). The patient may have a tumor of histological grade of Grade 1. The patient may have a tumor of histological Grade 2. The patient may have a tumor of histological Grade 3. In certain embodiments, the patient has a tumor with a Ki67 status of less than or equal to 20%.
  • the Ki67 category may be less than or equal to 14%, or the Ki67 category may be greater than 14%.
  • the patient may have a tumor with a Ki67 status of more than 20%. Ki67 may be measured in archival samples of resected tumors from the patient. Ki67 is a proliferation marker in normal and human cell populations, which may be used as a clinical marker for breast cancers and a predictive marker for success with endocrine therapy.
  • the patient has a tumor that has been evaluated by a genomic test, such as one or more of an Endopredict® test, a Mammaprint® test, an Oncotype DX® test, a Prosigna/PAM50® test, and a Breast Cancer Index® test.
  • the patient may have a risk score from one or more tests that indicates a high risk for cancer recurrence and/or metastasis.
  • the tumor has an EndoPredict EPclin® risk score that indicates high risk.
  • the tumor has an Mammaprint® test result that indicates high risk.
  • the tumor has an Prosigna/PAM50® test result that indicates high risk.
  • the tumor has a Oncotype DX Breast Recurrence Score that is a greater than or equal to about 26. Measures such as histopathological grade, T stage, N stage, M stage, and Ki67 may be determined at the time of initial diagnosis or on a surgical specimen.
  • the patient has a tumor of a ductal subtype.
  • the patient may have a tumor of a lobular subtype.
  • the patient may have a tumor of a subtype that is neither ductal nor lobular.
  • the predominant histology of the tumor is selected from invasive ductal carcinoma, no otherwise specified (NOS), invasive lobular, carcinoma medullary, mucinous, papillary, tubular, ductal carcinoma in situ, and lobular carcinoma in situ.
  • the patient has a tumor comprising a HER2 ISH result comprising an IHC score of 0, 1+, 2+, or 3+.
  • the HER2 ISH result may be obtained prior to surgery or from a surgical specimen.
  • the patient has a positive hormone receptor status.
  • a positive ER status and/or a positive PR status may be obtained prior to surgery or from a surgical specimen.
  • the patient has a tumor with no metastasis in sentinel lymph nodes (e.g., the patient is considered as pN0).
  • the patient may have only micrometastasis in sentinel lymph nodes (e.g., the patient is considered as pN1mi).
  • Patients may have tumors that are T1-2 and no clinically-evident nodes prior to surgery, no neoadjuvant chemotherapy, at least one macrometastasis in 1 or 2 sentinel lymph nodes, and/or no matted nodes or gross extranodal disease at the time of sentinel dissection (e.g., patient is considered as pN1).
  • staging of breast cancer is performed by lymph node dissection, such as axillary lymph node dissection (ALND).
  • staging is performed by sentinel lymph node (SLN) dissection.
  • the tumor is located in only the right breast and not the left breast. Alternatively, the tumor may be located only in the left breast and not in the right breast.
  • the tumor is bilateral, e.g., comprising cancer cells located in both the right breast and the left breast.
  • the patient has a body mass index (BMI) that is more than 25 or equal to 25. In some embodiments, the patient has a BMI that is less than 25.
  • BMI body mass index
  • Prior treatment for cancer the patient has received treatment (which may also be called therapy) for the breast cancer prior to undergoing the methods described herein.
  • the prior treatment may be a primary treatment (also called a primary therapy, main treatment or therapy, induction treatment or therapy, or first-line treatment or therapy) for breast cancer.
  • the patient has completed a primary treatment for breast cancer before the treatment as described herein.
  • the treatment described herein may be an adjuvant treatment following a prior treatment.
  • the prior treatment is not a primary treatment, but follows a primary treatment or other treatments.
  • the treatment described herein may be an adjuvant treatment to a prior treatment, wherein the prior treatment itself followed one or more additional prior treatments for breast cancer.
  • the prior treatment may itself be an adjuvant treatment for a primary treatment.
  • the prior treatment may be a neoadjuvant treatment for a primary treatment.
  • the prior treatment may be PAT059494-WO-PCT a neoadjuvant treatment for the treatment disclosed herein.
  • the patient completes the prior treatment (e.g., adjuvant and/or neoadjuvant treatment) before the treatment disclosed herein.
  • the prior treatment is a neoadjvant treatment for a primary treatment.
  • the prior treatment may be administered to shrink a tumor before the primary treatment.
  • both the prior treatment and the primary treatment for which the prior treatment is a neoadjuvant treatment are completed before the treatment described herein.
  • the prior treatment is neoadjuvant treatment for the treatment described herein.
  • a prior treatment may be radiotherapy (also “radiation therapy”), surgical treatment, or chemotherapy. In some embodiments, the prior treatment is radiotherapy.
  • Radiotherapy may be located at one or more of the following: breast, chest wall, axillary lymph node, supraclavicular lymph node, and internal mammary lymph node.
  • the patient has undergone a surgical treatment.
  • a prior treatment may be surgical resection of the cancer cells (e.g., tumor).
  • the patient may have had one or more of a mastectomy, a breast conserving surgery, an axillary lymph node dissection, or a sentinel lymph node biopsy.
  • the patient has had a mastectomy.
  • the patient has had a lumpectomy.
  • an entire organ or even the surrounding structures may be removed in order to achieve the necessary cancer (e.g., tumor) resection.
  • the prior treatment comprises complete tumor resection.
  • the cancer may be removed completely, with final surgical specimen microscope margins free from tumor.
  • the cancer may be R0 (for example, the surgical margin is microscopically negative for residual tumor).
  • the patient is administered the treatment as described herein as an adjuvant treatment after a prior treatment of surgery.
  • the treatment described herein may start after surgical resection where the tumor was removed completely, with final surgical specimen microscopic margins free from tumor.
  • the prior treatment may be chemotherapy.
  • the patient has received a prior treatment that is a chemotherapy.
  • the chemotherapy may be a neoadjuvant chemotherapy.
  • the neoadjuvant chemotherapy may have been administered PAT059494-WO-PCT before another treatment such as a surgical procedure, radiation therapy, or administration of another medication.
  • the chemotherapy may be an adjuvant chemotherapy.
  • the prior treatment may be a chemotherapy that was administered after another treatment such as a surgical procedure, radiation therapy, or administration of another medication.
  • the chemotherapy may be a neo-/adjuvant chemotherapy.
  • the prior treatment e.g., neoadjuvant chemotherapy and/or adjuvant chemotherapy
  • the patient has received a prior anti-neoplastic chemotherapy, for example, an anthracylcine or a taxane.
  • the patient has received endocrine therapy (ET).
  • the ET may be, for example, a neoadjuvant and/or adjuvant ET.
  • the patient may have received ET within 12 months of beginning the present methods.
  • the patient has received tamoxifen or toremifene as an adjuvant ET, wherein the patient undergoes a washout period of 5 half-lives (e.g., 35 days) prior to beginning the present methods.
  • the patient may receive aromatase inhibitors during the washout period.
  • the patient has received an endocrine therapy selected from an aromatase inhibitor, an anti-estrogens, a gonadotropin-releasing hormone analogues, or and a biologic/targeted therapy.
  • the patient has undergone previous treatment, but the breast cancer did not respond to treatment, for example, due to resistance of the breast cancer cells to a drug.
  • the patient has undergone previous treatment, but the breast cancer has recurred (or “relapsed”).
  • the patient has received treatment (which may also be called therapy) for the breast cancer prior to undergoing the treatment described herein, and is in remission.
  • the patient may be in remission from early breast cancer, for example, HR+/HER2- early breast cancer.
  • the HR+/HER2- early breast cancer may be stage II or stage III cancer.
  • a cancer may be in remission.
  • a patient who had cancer may be in remission.
  • remission may refer to a decrease in or a disappearance of signs of cancer in a patient, following a treatment for cancer.
  • Remission may be partial remission, in which a cancer (e.g., cancer cells and/or a tumor) has decreased in size or in the extent of spread in the body.
  • partial remission may reflect a 50% reduction in measurable parameters for cancer such as growth, size, or spread of cancer cells and/or a tumor.
  • Remission may be complete remission, where signs of cancer (e.g., cancer cells and/or a tumor) are no longer detectable.
  • PAT059494-WO-PCT In complete remission, there may be no evidence of disease. PAT059494-WO-PCT In complete remission, there may be no detectable signs or symptoms of cancer. Remission may be related to the period of time since the patient had detectable signs or symptoms of cancer. For example, after about 1 month without detectable signs or symptoms of cancer, the patient may be described as being in remission.
  • the period of time is about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, about 36 months, or longer.
  • the period of time is about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, or longer.
  • the treatment as described herein may be administered to patients who are in remission.
  • the patients are in complete remission.
  • the patients are in partial remission.
  • the patient is in full remission at the time that the treatment described herein begins.
  • the patient may not have detectable cancer cells and/or a tumor.
  • the patient may have been diagnosed with early breast cancer at a previous time and may have been treated with a prior treatment, with the result that cancer is no longer detectable.
  • a patient who does not have symptoms of cancer may be administered with the treatment described herein.
  • the patient may have been diagnosed with a HR+/HER2- early breast cancer and treated with surgery to remove the cancer, and HR+/HER2- early breast cancer may no longer be detectable.
  • the patient may be at risk for developing HR+/HER2- breast cancer based on the presence of a HR+/HER2- breast cancer diagnosed previously.
  • the patient may be at risk for recurrence of HR+/HER2- breast cancer based on a previous diagnosis of HR+/HER2- early breast cancer.
  • the patient is in partial remission and shows detectable signs of cancer at the time that the treatment described herein begins.
  • the patient was diagnosed with a HR+/HER2- early breast cancer and treated with a prior treatment, but the cancer was not fully removed and/or the cancer recurred.
  • the patient in partial remission may be at risk for regrowth and/or spread of HR+/HER2- breast cancer based on a previous diagnosis of HR+/HER2- early breast cancer.
  • the treatment described herein prevents growth of HR+/HER2- breast cancer cells in the patient, for example, a patient who is in remission (e.g., in full remission or in partial remission).
  • the treatment described herein maintains the patient in remission (e.g., in full remission or in partial remission).
  • the treatment may maintain the remission for at least about 3 months, at least about 6 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, at least about 72 months, at least about 78 months, at least about 84 months, at least about 90 months, at least about 96 months, at least about 102 months, at least about 108 months, at least about 114 months, at least about 120 months, or longer.
  • the treatment reduces recurrence of breast cancer (e.g., an early breast cancer such as a HR+/HER2- early breast cancer).
  • the treatment may reduce recurrence for at least about 3 months, at least about 6 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, at least about 72 months, at least about 78 months, at least about 84 months, at least about 90 months, at least about 96 months, at least about 102 months, at least about 108 months, at least about 114 months, at least about 120 months, or longer.
  • Recurrence of breast cancer may be an ipsilateral breast tumor recurrence (IBTR), defined herein as the reappearance of breast tumor in the same (i.e., ipsilateral) breast or chest wall.
  • Recurrence of breast cancer may be a contralateral breast cancer, defined herein as a primary breast cancer that occurs in the opposite (i.e., contralateral) breast at least three months after the first breast cancer.
  • the method described herein comprises maintaining in remission an adult patient who had previously been diagnosed with HR+/HER2- stage II or stage III early breast cancer, comprising administering to the patient a treatment comprising a dose of ribociclib, a freebase form thereof or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor.
  • the treatment described herein is an adjuvant therapy (also called an adjuvant treatment) to a prior treatment.
  • the adjuvant therapy may follow any prior treatment, for example, the prior treatments described herein.
  • the adjuvant therapy may follow more than one prior treatment.
  • one prior treatment may have been a neoadjuvant treatment preceding a primary treatment (e.g., first-line treatment) such as surgery with subsequent PAT059494-WO-PCT chemotherapy, radiation therapy and/or endocrine therapy, after which the treatment described herein is administered as an adjuvant therapy.
  • a primary treatment e.g., first-line treatment
  • PAT059494-WO-PCT chemotherapy e.g., surgery with subsequent PAT059494-WO-PCT chemotherapy, radiation therapy and/or endocrine therapy, after which the treatment described herein is administered as an adjuvant therapy.
  • the method described herein comprises preventing breast cancer recurrence in an adult patient, comprising providing adjuvant treatment to a patient who has received a prior treatment for HR+/HER2- stage II or III early breast cancer, wherein the adjuvant treatment comprises administering to the patient 400 mg ribociclib or a pharmaceutically acceptable salt thereof on days 1 to 21 of a 28-day cycle for at least 36 months, in combination with an aromatase inhibitor as defined herein on every day of the 28- day cycle.
  • the method described herein comprises maintaining remission an adult patient who had previously been diagnosed with an HR+/HER2- stage II or stage III early breast cancer, comprising providing adjuvant treatment to a patient who has received a prior treatment for HR+/HER2- stage II or III early breast cancer, wherein the adjuvant treatment comprises administering to the patient 400 mg ribociclib or a pharmaceutically acceptable salt thereof on days 1 to 21 of a 28-day cycle for at least 36 months, in combination with an aromatase inhibitor as defined herein administered on every day of the 28-day cycle.
  • the adjuvant treatment does not include administration of a 600 mg/day dose of ribocicilib.
  • a further aspect of the present disclosure relates to a method of treating an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle, wherein the method results in an improvement in the patient in one or more of their overall survival (OS), distant disease-free survival (DDFS), or recurrence free survival (RFS).
  • OS overall survival
  • DDFS distant disease-free survival
  • RFS recurrence free survival
  • the early breast cancer may no longer be in stage II or stage III when the treatment described herein begins.
  • the patient may have received at least one prior treatment, for which the treatment described herein is an adjuvant treatment.
  • Another aspect of the present disclosure relates to a method for improving one or more of overall survival (OS), distant disease-free survival (DDFS), or recurrence free survival (RFS) in a patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, (ii) an aromatase inhibitor administered on every day of the 28-day cycle.
  • OS overall survival
  • DDFS distant disease-free survival
  • RFS recurrence free survival
  • a further aspect of the present disclosure relates to ribociclib for use in a method of improving one or more of overall survival (OS), distant disease-free survival (DDFS), or recurrence free survival (RFS) in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, wherein the method comprises administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle.
  • the methods described herein may prevent local and/or regional invasive recurrence of early breast cancer.
  • an aspect of the present disclosure relates to a method for reducing the risk of local or regional invasive recurrence of early breast cancer in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle.
  • An aspect of the present disclosure relates to ribociclib for use in a method of reducing the risk of local or regional invasive recurrence of early breast cancer in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, wherein the method comprises administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle
  • an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle
  • the method described herein may prevent recurrence of cancer in tissues outside of the breast, such as bone, liver, and lung or pleura.
  • a further aspect of the present disclosure relates to a method for reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, and lung or pleura of an adult patient, who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle.
  • an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle.
  • a further aspect of the present disclosure relates to ribociclib for use in a method of reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, and lung or pleura of an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, wherein the method comprises administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days PAT059494-WO-PCT 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle. Treatment may be administered irrespective of the nodal status of the breast cancer.
  • Another aspect of the present disclosure relates to a method for reducing the risk of recurrence of early breast cancer in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, comprising administering an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle and (ii) an aromatase inhibitor administered on every day of the 28-day cycle, wherein the treatment is administered irrespective of the nodal status of the breast cancer.
  • an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle and (ii) an aromatase inhibitor administered on every day of the 28-day cycle, wherein the treatment is administered irrespective of the nodal status of the breast cancer.
  • An aspect of the present disclosure relates to ribociclib for use in a method of reducing the risk of recurrence of early breast cancer in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle, wherein the treatment is administered irrespective of the nodal status of the breast cancer.
  • the breast cancer may have a nodal status of N0, N1, N2 or N3.
  • the breast cancer may have a nodal status of N0.
  • the early breast cancer is stage II, for example stage IIA. In some embodiments, the early breast cancer is stage III, for example stage IIIB or IIIC. In certain embodiments, the breast cancer is of the ductal subtype. In some embodiments, the patient is Asian. An adjuvant treatment may be needed after a patient has received at least one prior treatment for breast cancer. In some embodiments, the method described herein is an adjuvant treatment because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiation therapy. In some embodiments, the patient has not had a mastectomy. In some embodiments, the dose of ribociclib is 400 mg/day.
  • the ribociclib may be administered in the form of a salt, preferably as ribociclib succinate.
  • the aromatase inhibitor is letrozole or anastrozole.
  • the aromatase inhibitor may be letrozole, preferably administered in a dose of 2.5 mg/day.
  • the aromatase inhibitor may be anastrozole, preferably administered in a dose of 1 mg/day.
  • the dose of ribociclib is 400 mg/day
  • the ribociclib is administered in the form of ribociclib succinate
  • the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg/day of letrozole or 1 mg/day anastrozole.
  • the improvement in OS, DDFS and/or RFS, or the reduction in the risk of recurrence of the breast cancer are achieved in the patient for at least 36 months.
  • the patient has not previously received a CDK4/6 inhibitor.
  • the patient has not received tamoxifen, raloxifene, or aromatase inhibitors for reduction in risk (“chemoprevention”) of breast cancer and/or treatment for osteoporosis within the last 2 years prior to undergoing the present methods.
  • the patient has not received treatment with anthracyclines at cumulative doses of 450 mg/m2 or more for doxorubicin, or 900 mg/m2 or more for epirubicin prior to undergoing the present methods.
  • the patient does not have a known hypersensitivity to any of the excipients of ribociclib and/or ET (e.g., the patient does not have rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption, or a soy allergy).
  • the patient does not receive other anti-neoplastic therapy, except for adjuvant ET as described herein.
  • the patient has not undergone major surgery, chemotherapy, or radiotherapy within 14 days of undergoing the present methods.
  • the patient has not recovered from clinical and laboratory acute toxicities related to prior anti-cancer therapies to a NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03 Grade ⁇ 1 at day of randomization. Exceptions are patients with any grade of alopecia, amenorrhea, grade 2 neuropathy, or other toxicities not considered a safety risk for the patient.
  • the patient does not have a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 2 years before randomization. Patients may have been adequately treated for basal or squamous cell skin carcinoma or had a curatively resected cervical cancer in situ.
  • the patient does not have a known history of human immunodeficiency virus (HIV) infection.
  • the patient does not have a known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is not mandatory, unless required by local regulation).
  • HBV active hepatitis B virus
  • HCV hepatitis C virus
  • the patient does not have clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following: • History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to undergoing the present methods. • Documented cardiomyopathy.
  • LVEF Left Ventricular Ejection Fraction
  • MUGA Multiple Gated acquisition
  • ECHO echocardiogram
  • TdP Torsades de Pointes
  • Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication e.g. within 5 half-lives or 7 days prior to undergoing the present methods.
  • the patient does not to consume grapefruit (or grapefruit juice). In some embodiments, the patient does not consume pummellos, starfruit, and seville oranges (and their PAT059494-WO-PCT juices). In certain embodiments, the patient is not concomitantly using any of boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, and voriconazole.
  • the patient is not currently receiving or has received systemic corticosteroids ⁇ 2 weeks prior to undergoing the present methods, or has not fully recovered from side effects of such treatment.
  • a patient may use corticosteroids for the following: a short duration ( ⁇ 5 days) of systemic corticosteroids; any duration of topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airways diseases), eye drops or local injections (e.g. intra-articular).
  • the patient does not have an impairment of GI function or GI disease that may significantly alter the absorption of the oral trial treatments (e.g.
  • the patient is not suffering from a concurrent severe and/or uncontrolled medical condition that may cause unacceptable safety risks, contraindicate patient treatment or compromise compliance with the methods (e.g. chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease, active untreated or uncontrolled fungal, bacterial or viral infections, active infection requiring systemic anti-bacterial therapy, etc.) or limit life expectancy to ⁇ 5 years.
  • the patient has not been involved in treatment involving investigational drug(s) within 30 days prior to undergoing the present methods or within 5 half-lives of the investigational drug(s) (whichever is longer).
  • the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • the patient has bone marrow and organ function as defined by the following values: • Absolute neutrophil count (ANC) ⁇ 1.5 ⁇ 10 9 /L. • Platelets ⁇ 100 ⁇ 10 9 /L. • Hemoglobin ⁇ 9.0 g/dL. PAT059494-WO-PCT • Estimated glomerular filtration rate (eGFR) ⁇ 30 mL/min/1.73m 2 according to the Modification of Diet in Renal Disease (MDRD) formula. • Alanine transaminase (ALT) ⁇ 2.5 ⁇ Upper Limit Normal (ULN).
  • ANC Absolute neutrophil count
  • HR Absolute neutrophil count
  • Platelets ⁇ 100 ⁇ 10 9 /L.
  • Hemoglobin ⁇ 9.0 g/dL.
  • PAT059494-WO-PCT • Estimated glomerular filtration rate (eGFR) ⁇ 30 mL/
  • AST Aspartate transaminase
  • AST Aspartate transaminase
  • the patient has standard 12-lead ECG values of QTcF interval (QT interval using Fridericia’s correction) at screening ⁇ 450 msec, and a resting heart rate 50-90 beats per minute (determined from the ECG).
  • QTcF interval QT interval using Fridericia’s correction
  • a resting heart rate 50-90 beats per minute (determined from the ECG).
  • X. Region and race/ethnicity In some embodiments, the patient is located in North America. The patient may be located in Europe, for example, Western Europe. The patient may be located in Oceania, for example, in Australia. In some embodiments, the patient is located in Asia.
  • the patient is located in Africa. In some embodiments, the patient is located in Latin America. In some embodiments, the patient may be American Indian. In some embodiments, the patient may be Alaska Native. In some embodiments, the patient may be Asian. In some embodiments, the patient may be Black or African American. In some embodiments, the patient may be Native Hawaiian or Other Pacific Islander. In some embodiments, the patient may be White. In some embodiments, the patient may be a mixed race. In some embodiments, the patient may be non- Asian. In some embodiments, the patient may be Hispanic or Latino. In some embodiments, the patient is not Hispanic or Latino. PAT059494-WO-PCT E.
  • An present disclosure relates to a method of treatment for early breast cancer in an adult patient in need thereof, comprising administering to the patient a treatment comprising a cyclin-dependent kinase (CDK) inhibitor in combination with endocrine therapy (ET), wherein the treatment is characterized by an improvement in the patient’s condition, as compared to a patient not receiving the treatment or as compared to the patient prior to treatment.
  • treatment regimens e.g., the selection of a dose of ribociclib and/or aromatase inhibitor is chosen to achieve certain improvement in the patient’s condition, as compared to a patient not receiving the treatment or as compared to the patient prior to treatment.
  • a patient not receiving the treatment described herein may comprise a patient who does not receive ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate).
  • the patient not receiving the treatment described herein may comprise a patient who does not receive a combination of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) and endocrine therapy.
  • the patient may receive only endocrine therapy alone, without ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate).
  • the patient may receive letrozole alone without ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate).
  • the patient may receive anastrozole alone without ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate).
  • the patient not receiving the treatment described herein may receive another cancer treatment, wherein the other cancer treatment is not a combination of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) and endocrine therapy.
  • the patient not receiving the treatment described herein may be a patient who does not receive any cancer treatment.
  • the improvement in the patient’s condition may relate to a reduction in signs and/or symptoms of breast cancer.
  • the improvement may comprise a reduction in breast cancer progression and/or breast cancer recurrence.
  • the improvement may comprise prevention of breast cancer progression, early breast cancer recurrence, and/or death from the breast cancer.
  • the improvement may comprise a reduction in the risk for cancer progression, cancer recurrence, and/or risk of (or avoidance of) death from the cancer.
  • the improvement in the patient’s condition is the maintenance of the existing signs and/or symptoms of breast cancer.
  • the breast cancer may have about the same characteristics as before treatment, but no further progression of the breast cancer or worsening of the characteristics.
  • PAT059494-WO-PCT In some embodiments, the improvement in the patient’s condition is an improvement as compared to a patient not receiving the treatment. In some embodiments, the patient not receiving the treatment receives another treatment for early breast cancer.
  • the patient not receiving the treatment receives only endocrine therapy alone.
  • the improvement in the patient’s condition may comprise one or more of a reduction in tumor size, prevention of spread of the tumor, prevention or reduction in recurrence of breast cancer, prevention of a second primary malignancy, and increased survival.
  • the improvement in the patient’s condition may comprises an absence of (or a reduction in) locoregional relapse, distant relapse, ipsilateral and contralateral invasive breast cancers and second primary non-breast invasive cancer.
  • the improvement in the patient’s condition relates to measurements such as disease-free survival (DFS), invasive disease-free survival (iDFS), overall survival (OS), distant disease-free survival (DDFS), recurrence-free survival (RFS), and loco-regional recurrence-free survival (LLRFS).
  • Disease-free survival (DFS) may relate to the length of time that a patient survives without local recurrence, contralateral recurrence, distant disease, secondary cancers, or new primary cancers.
  • DFS may be defined as the time from a first date (e.g., a date when the treatment for cancer begins or, alternatively, a date when the treatment for cancer ends) to a date that the patient shows recurrence of a cancer or death.
  • iDFS Invasive disease-free survival
  • OS Overall survival
  • OS may be defined as the time from a first date (e.g., a date when the treatment for cancer begins or, alternatively, a date when the treatment for cancer ends) to a date of death due to any cause.
  • DDFS Distant disease-free survival
  • DDFS may relate to the length of time during which a patient remains free of the cancer recurring at a distant site, e.g., not in the original breast.
  • DDFS may be defined as the time from a first date (e.g., a date when the treatment for cancer begins or, alternatively, a date when the treatment for cancer ends) to a date of first event of distant recurrence, death (any cause), or second primary non-breast invasive cancer (excluding basal and squamous cell carcinomas of the skin).
  • Recurrence free survival may relate to any recurrence (local, regional, or distant) of the original breast cancer, but does not include new cancer(s).
  • RFS may be defined as the time PAT059494-WO-PCT from a first date (e.g., a date when the treatment for cancer begins or, alternatively, a date when the treatment for cancer ends) to a date of first event of local invasive breast recurrence, regional invasive recurrence, distant recurrence, or death (any cause).
  • Loco-regional recurrence-free survival may be defined as the time from a first date (e.g., a date when the treatment for cancer begins or, alternatively, a date when the treatment for cancer ends) to a date of first event of local (ipsilateral) invasive breast recurrence, regional invasive recurrence, or death due to any cause.
  • the present methods improve one or more of DFS, iDFS, OS, DDFS, RFS, and LLRFS in a patient who receives the treatment as compared to a patient who does not receive the treatment.
  • the improvement in the patient’s condition may be a prolongation of the time period between a first date (e.g., a date when the treatment for cancer begins or, alternatively, a date when the treatment for cancer ends) and a date of occurrence of an event as defined in any of DFS, iDFS, OS, DDFS, RFS, and LLRFS.
  • the improvement in the patient’s condition is a decrease in the incidence (or decrease in the time until occurrence) of one or more of invasive ipsilateral breast tumor (IBTR) recurrence, local-regional invasive recurrence, distant recurrence (e.g., presence of metastasis), death from breast cancer, death from a non-breast cancer cause, death from an unknown cause, presence of invasive contralateral breast cancer, and presence of a second primary invasive cancer.
  • the treatment may decrease the incidence (or the time until occurrence) of death from breast cancer, death from a non-breast cancer cause, and death from an unknown cause.
  • the improvement in the patient’s condition is a decrease in the incidence (or decrease in the time until occurrence) of distant recurrence (e.g., presence of metastasis), death from breast cancer, death from a non-breast cancer cause, death from an unknown cause, and presence of a second primary invasive cancer.
  • the improvement in the patient’s condition is a decrease in the incidence (or decrease in the time until occurrence) of invasive ipsilateral breast tumor (IBTR) recurrence, local-regional invasive recurrence, distant recurrence (e.g., presence of metastasis), death from breast cancer, death from a non-breast cancer cause, and death from an unknown cause.
  • IBTR invasive ipsilateral breast tumor
  • the improvement in the patient’s condition is a decrease in the incidence (or decrease in the time until occurrence) of one or more of invasive ipsilateral breast tumor (IBTR) recurrence, local-regional invasive recurrence, death from breast cancer, death from a non-breast cancer cause, and death from an unknown cause.
  • IBTR invasive ipsilateral breast tumor
  • the risk may be determined using different measures.
  • the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 1 when the risk is calculated relative to patients not receiving the treatment.
  • the hazard ratio may be less than about 0.9, about 0.8, about 0.7, about 0.6, about 0.5, about 0.4, about 0.3, about 0.2, or about 0.1)
  • the hazard ratio for iDFS may be calculated using model such as an unstratified and covariate unadjusted Cox model or a stratified and covariate adjusted Cox model, as described in Appendix A.
  • the hazard ratio may be less than or equal to about 0.78.
  • the hazard ratio may be less than or equal to about 0.72.
  • the patient has HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to about 0.74 when the risk is calculated relative to patients not receiving the treatment.
  • the hazard ratio may be less than or equal to about 0.76.
  • the treatment yields at least a 25% reduction in the risk of invasive disease corresponding to a hazard ratio of 0.75 when the risk is calculated relative to patients not receiving the treatment.
  • the treatment reduces the risk of invasive disease to a similar level for patient subgroups comprising patients with stage II early breast cancer, stage III early breast cancer, patients who are premenopausal women or men, and patients who are postmenopausal women.
  • treatment as disclosed herein may achieve the following hazard ratios for particular patients with HR+/HER2- early breast cancer.
  • the patient is a woman and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to patients not receiving the treatment.
  • the patient is a pre-menopausal woman or a man and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.72 when the risk is calculated relative to patients not receiving the treatment.
  • the patient is a post-menopausal woman and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.78 when the risk is calculated relative to patients not receiving the treatment.
  • the patient received a prior neo-/adjuvant chemotherapy and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.73 when the risk is calculated relative to patients not receiving the treatment.
  • PAT059494-WO-PCT In some embodiments, the patient is located in North America, Western Europe or Oceania, and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to patients not receiving the treatment.
  • the patient is not located in North America, Western Europe or Oceania, and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has stage II cancer and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has stage III cancer and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.74 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has stage IIA cancer and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.5 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has stage IIB cancer and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.93 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has stage IIIA cancer and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.79 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has stage IIIB cancer and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.68 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has stage IIIC cancer and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.69 when the risk is calculated relative to patients not receiving the treatment.
  • the patient received prior adjuvant chemotherapy and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.67 when the risk is calculated relative to patients not receiving the treatment.
  • the patient did not receive prior adjuvant chemotherapy and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.81 when the risk is calculated relative to patients not receiving the treatment.
  • PAT059494-WO-PCT the patient received prior neoadjuvant chemotherapy and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.79 when the risk is calculated relative to patients not receiving the treatment.
  • the patient did not receive prior neoadjuvant chemotherapy and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.72 when the risk is calculated relative to patients not receiving the treatment.
  • the patient received prior radiation therapy and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.74 when the risk is calculated relative to patients not receiving the treatment.
  • the patient did not receive prior radiation therapy and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.98 when the risk is calculated relative to patients not receiving the treatment.
  • the patient received prior endocrine therapy and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to patients not receiving the treatment.
  • the patient did not receive endocrine therapy and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.77 when the risk is calculated relative to patients not receiving the treatment.
  • the patient had a prior mastectomy and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.85 when the risk is calculated relative to patients not receiving the treatment.
  • the patient did not have a prior mastectomy and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.55 when the risk is calculated relative to patients not receiving the treatment.
  • the patient is Asian and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.52 when the risk is calculated relative to patients not receiving the treatment.
  • the patient is not Asian and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.81 when the risk is calculated relative to patients not receiving the treatment.
  • the patient is located in Europe and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.88 when the risk is calculated relative to patients not receiving the treatment.
  • the patient is located in North America or Australia and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.70 when the risk is calculated relative to patients not receiving the treatment.
  • the patient is located in Asia and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.34 when the risk is calculated relative to patients not receiving the treatment.
  • the patient is located in Latin America and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.69 when the risk is calculated relative to patients not receiving the treatment.
  • the patient is less than 45 years old and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.68 when the risk is calculated relative to patients not receiving the treatment.
  • the patient is 45 to 54 years old and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.75 when the risk is calculated relative to patients not receiving the treatment.
  • the patient is 55 to 64 and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.84 when the risk is calculated relative to patients not receiving the treatment.
  • the patient is 65 years old or older and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.72 when the risk is calculated relative to patients not receiving the treatment.
  • the patient receives letrozole and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.79 when the risk is calculated relative to patients not receiving the treatment.
  • the patient receives anastrozole and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.70 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has ER+/PR+ cancer and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.73 when the risk is calculated relative to patients not receiving the treatment. In some embodiments, the patient has ER+/PR- cancer and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.91 when the risk is calculated relative to patients not receiving the treatment. PAT059494-WO-PCT In some embodiments, the patient has a tumor with nodal status 0 and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.63 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has a tumor with nodal status N1-N3 and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.77 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has a tumor of category T1-T3 and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.74 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has a tumor of a category greater than T3 (e.g., T4) and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.83 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has a tumor with a histological grade 1 and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.78 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has a tumor with a histological grade 1 and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.78 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has a tumor with a histological grade 2 and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.75 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has a tumor with a histological grade 3 and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.78 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has a tumor with Ki67 status that is 20% or lower and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.80 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has a tumor with Ki67 status that is greater than 20% and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.75 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has a tumor of a ductal subtype and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.68 when the risk is calculated relative to patients not receiving the treatment.
  • PAT059494-WO-PCT the patient has a tumor that is not a ductal subtype or a lobular subtype and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.89 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has a BMI of 25 or greater and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.85 when the risk is calculated relative to patients not receiving the treatment.
  • the patient has a BMI of less than 25 and the treatment may reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.64 when the risk is calculated relative to patients not receiving the treatment.
  • the treatment may yield no deterioration in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to patients not receiving the treatment.
  • the treatment does not cause or worsen events such as pneumonia, pulmonary embolism, dyspnoea, increased alanine aminotransferase, increased aspartate aminotransferase, arthralgia, fatigue, neutropenia, decreased neutrophil count, and/or nausea.
  • the treatment does not cause or worsen conditions related to hepatobiliary toxicity, for example, as measured by increases in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, blood alkaline phosphatase, and/or blood bilirubin.
  • the treatment does not cause or worsen conditions related to myelosuppression (e.g., anemia and/or leukopenia).
  • myelosuppression e.g., anemia and/or leukopenia
  • the treatment does not cause of worsen leukopenia, or lead to decreased white blood cell count, lymphopenia, or decreased lymphocyte count.
  • the treatment does not cause or worsen conditions related to myelosuppression (e.g., neutropenia, decreased neutrophil count, thrombocytopenia, decreased platelet count). In some embodiments, the treatment does not prolong the QT interval in an electrocardiogram. In some embodiments, the treatment does not cause or worsen conditions related to renal toxicity (e.g., increased blood creatinine, decreased glomerular filtration rate, increased blood urea). In some embodiments, the treatment does not cause or worsen conditions related to reproductive toxicity, such as mastitis. PAT059494-WO-PCT F.
  • a method for treatment of HR+/HER2- early breast cancer relates a method of treatment for HR+/HER2- stage II or III early breast cancer in an adult patient in need thereof, comprising administering to the patient a treatment comprising a dose of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle in combination with an endocrine therapy (such as an aromatase inhibitor, preferably letrozole or anastrozole) administered on every day (e.g., days 1-28) of the 28-day cycle.
  • ribociclib or a pharmaceutically acceptable salt thereof, such as ribociclib succinate
  • an endocrine therapy such as an aromatase inhibitor, preferably letrozole or anastrozole
  • a further aspect of the present disclosure relates to a method of preventing or reducing signs or symptoms of early stage breast cancer, comprising administering to the patient a treatment comprising a dose of ribociclib, a freebase form thereof or a pharmaceutically acceptable salt thereof, ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor, preferably letrozole or anastrozole, administered on every day of the 28-day cycle.
  • a treatment comprising a dose of ribociclib, a freebase form thereof or a pharmaceutically acceptable salt thereof, ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor, preferably letrozole or anastrozole, administered on every day of the 28-day cycle.
  • Another aspect of the present disclosure relates to a method of maintaining in remission an adult patient who had previously been diagnosed with HR+/HER2- stage II or stage III early breast cancer, comprising administering to the patient a treatment comprising administering to the patient a treatment comprising a dose of ribociclib, a freebase form thereof or a pharmaceutically acceptable salt thereof, ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor, preferably letrozole or anastrozole, administered on every day of the 28-day cycle.
  • an aromatase inhibitor preferably letrozole or anastrozole
  • Still another aspect of the present disclosure relates to a method of preventing breast cancer recurrence in an adult patient, comprising providing adjuvant treatment to a patient who has received a prior treatment for HR+/HER2- stage II or III early breast cancer, wherein the adjuvant treatment comprises administering to the patient 400 mg ribociclib or a pharmaceutically acceptable salt thereof on days 1 to 21 of a 28-day cycle for at least 36 months, in combination with an aromatase inhibitor as defined in any one of embodiments 23 to 28 administered on every day of the 28-day cycle.
  • the treatment comprises comprising administering to the patient a treatment comprising a dose of about 400 mg/day (or a dose of about 200 mg/day) ribociclib or a pharmaceutically acceptable salt thereof, such as ribociclib succinate, on days 1 to 21 of a 28- day cycle for 36 months, in combination with an endocrine therapy comprising a dose of letrozole ranging from about 1 mg/day to about 4 mg/day or a dose of anastrozole ranging from about 0.5 mg/day to about 1.5 mg/day administered on every day (e.g., days 1-28) of the 28-day cycle.
  • a treatment comprising a dose of about 400 mg/day (or a dose of about 200 mg/day) ribociclib or a pharmaceutically acceptable salt thereof, such as ribociclib succinate, on days 1 to 21 of a 28- day cycle for 36 months, in combination with an endocrine therapy comprising a dose of letrozole ranging from about 1 mg/day to about 4 mg/
  • the treatment comprises administering to the patient a treatment comprising a dose of about 400 mg/day (or a dose of about 200 mg/day) ribociclib or a pharmaceutically acceptable salt thereof, such as ribociclib succinate, on days 1 to 21 of a 28- day cycle for 36 months, in combination with an endocrine therapy, wherein the endocrine therapy comprises a dose of letrozole of about 2.5 mg/day or a dose of anastrozole of about 1 mg/day administered on days 1-28 of the 28-day cycle.
  • a treatment comprising a dose of about 400 mg/day (or a dose of about 200 mg/day) ribociclib or a pharmaceutically acceptable salt thereof, such as ribociclib succinate, on days 1 to 21 of a 28- day cycle for 36 months, in combination with an endocrine therapy, wherein the endocrine therapy comprises a dose of letrozole of about 2.5 mg/day or a dose of anastrozole of about 1 mg/day administered on days 1-
  • the treatment reduces one or more of invasive ipsilateral breast tumor (IBTR) recurrence, local-regional invasive recurrence, distant recurrence (e.g., presence of metastasis), death from breast cancer, death from a non-breast cancer cause, death from an unknown cause, presence of invasive contralateral breast cancer, and presence of a second primary invasive cancer.
  • the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 1 when the risk is calculated relative to patients not receiving the treatment.
  • the hazard ratio for iDFS may be calculated using model such as an unstratified and covariate unadjusted Cox model or a stratified and covariate adjusted Cox model, as described in Appendix A.
  • the hazard ratio may be less than or equal to about 0.78.
  • the hazard ratio may be less than or equal to about 0.72.
  • the patient has HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to about 0.74 when the risk is calculated relative to patients not receiving the treatment.
  • the hazard ratio may be less than or equal to about 0.76.
  • the treatment yields at least a 25% reduction in the risk of invasive disease corresponding to a hazard ratio of 0.75 when the risk is calculated relative to patients not receiving the treatment.
  • the treatment reduces the risk of invasive disease to a similar level for patient subgroups comprising patients with stage II early breast cancer, stage III early breast cancer, patients who are premenopausal women or men, and patients who are postmenopausal women.
  • the treatment may yield no deterioration in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to patients not receiving the treatment.
  • the patient is a postmenopausal woman.
  • the patient is a premenopausal woman or a man.
  • the early breast cancer comprises a tumor of stage II.
  • the tumor may have an anatomic stage IIA.
  • the tumor PAT059494-WO-PCT may have an anatomic stage IIB.
  • the early breast cancer comprises a tumor of stage III.
  • the tumor may have an anatomic stage IIIA.
  • the tumor may have an anatomic stage IIIB.
  • the tumor may have an anatomic stage IIIC.
  • the patient has received prior neo-adjuvant chemotherapy. In some embodiments, the patient has received prior adjuvant chemotherapy.
  • the patient has received prior radiation therapy. In some embodiments, the patient has undergone a mastectomy. In some embodiments, the patient has not undergone a mastectomy. In some embodiments, the patient is located in North America. In some embodiments, the patient is located in Europe, for example, in Western Europe. In some embodiments, the patient is located in Oceania, for example, in Australia. In some embodiments, the patient is located in Latin America. In some embodiments, the patient is located in Asia. In some embodiments, the patient is Asian. In some embodiments, the patient is non-Asian. In some embodiments, the patient may be American Indian. In some embodiments, the patient may be Alaska Native. In some embodiments, the patient may be Black or African American.
  • the patient may be Native Hawaiian or Other Pacific Islander. In some embodiments, the patient may be White. In some embodiments, the patient may be a mixed race. In some embodiments, the patient may be non-Asian. In some embodiments, the patient may be Hispanic or Latino. In some embodiments, the patient is not Hispanic or Latino. In some embodiments, the patient is 18 years or older. The patient may be 18-44 years old. The patient may be 45-54 years old. The patient may be 55 to 64 years old. The patient may be 65 years or older. In some embodiments, the endocrine therapy is a non-steroidal aromatase inhibitor (NSAI). In some embodiments, the NSAI may be letrozole.
  • NSAI non-steroidal aromatase inhibitor
  • the NSAI may be anastrozole.
  • the early breast cancer is selected from a ER+/PR+, a ER-/PR+, and a ER+/PR- breast cancer.
  • the treatment is administered irrespective of the nodal status of the breast cancer.
  • the early breast cancer has a nodal status of N0, N1, N2, or N3.
  • PAT059494-WO-PCT In some embodiments, the early breast cancer comprises a tumor of category T0, category T1, T2, T3, or T3. In some embodiments, the early breast cancer has a histological grade at time of surgery of G1, G2, or G3.
  • the early breast cancer has a Ki67 status (e.g., from an archival tumor) of 20 or less than 20.
  • the early breast cancer may have a Ki67 status of greater than 20.
  • the early breast cancer has a ductal histological subtype or a lobular histological subtype.
  • An aspect of the present disclosure relates to a method of preventing recurrence of breast cancer in an adult patient who has received a prior treatment for HR+/HER2- stage II or stage III early breast cancer, comprising administering to the patient (i) a dose of ribociclib, a freebase form thereof, or a pharmaceutically acceptable salt thereof, and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.
  • a further aspect of the present disclosure relates to a method of treating an adult patient in remission from HR+/HER2- stage II or stage III early breast cancer, comprising administering to the patient (i) a dose of ribociclib, a freebase form thereof, or a pharmaceutically acceptable salt thereof, and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.
  • Another aspect of the present disclosure relates to a method of treating HR+/HER2- stage II or stage III early breast cancer in an adult patient in need thereof, comprising administering to the patient (i) a dose of ribociclib, a freebase form thereof, or a pharmaceutically acceptable salt thereof, ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle and (ii) an aromatase inhibitor, preferably letrozole or anastrozole, administered on every day of the 28-day cycle.
  • One aspect of the present disclosure relates to a method of treating breast cancer recurrence in an adult patient who has received at least one prior treatment for HR+/HER2- stage II or III early breast cancer and who has no detectable signs or symptoms of breast cancer, comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib succinate at a total dose of ribociclib of 400 mg/day administered on days 1 to 21 of a 28-day cycle, and (ii) a dose of either 2.5 mg/day letrozole or 1 mg/day anastrozole administered on every day of the 28-day cycle.
  • an adjuvant treatment comprising (i) a dose of ribociclib succinate at a total dose of ribociclib of 400 mg/day administered on days 1 to 21 of a 28-day cycle, and (ii) a dose of either 2.5 mg/day letrozole or 1 mg/day anastrozole administered on every day of the 28-day cycle.
  • An additional aspect of the present disclosure relates to a method of treating an adult patient who is in remission from HR+/HER2- stage II or stage III early breast cancer and in need of adjuvant treatment, comprising administering to the patient an adjuvant treatment comprising (i) PAT059494-WO-PCT a dose of ribociclib succinate at a total dose of ribociclib of 400 mg/day administered on days 1- 21 of a 28-day cycle and (ii) a dose of either 2.5 mg/day letrozole or 1 mg/day anastrozole administered on every day of the 28-day cycle.
  • the patient has a BMI of 25 or greater. In some embodiments, the patient has a BMI of less than 25.
  • a further aspect of the present disclosure relates to a method of preventing or reducing signs or symptoms of early stage breast cancer, comprising administering to the patient a treatment comprising ribociclib, a freebase form thereof or a pharmaceutically acceptable salt thereof in combination with an aromatase inhibitor, preferably letrozole or anastrozole.
  • the ribociclib is a freebase form thereof or a pharmaceutically acceptable salt thereof, and is administered to the patient in a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle.
  • the aromatase inhibitor is administered on every day of the 28-day cycle.
  • a patient in remission relates a method of treating HR+/HER2- stage II or stage III early breast cancer in an adult patient in remission, comprising administering to the adult patient ribociclib in combination with an aromatase inhibitor whereby the administration maintains the adult patient in remission for at least about 3 months.
  • a further aspect relates to a method of treating HR+/HER2- stage II or stage III early breast cancer in an adult patient, comprising providing adjuvant treatment by administering ribociclib in combination with aromatase inhibitor, wherein the patient at start of the adjuvant treatment is in complete remission, and the administration of ribociclib in combination with an aromatase inhibitor maintains the adult patient in complete remission for at least about 3 months.
  • the administration of ribociclib in combination with an aromatase inhibitor may maintain the adult patient in remission (e.g., complete remission) for a period of time that is at least about 3 months. In some embodiments, the administration maintains the adult patient in remission for at least about 6 months.
  • the administration maintains the adult patient in remission for at least about 9 months. In some embodiments, the administration maintains the adult patient in remission for at least about 12 months. In some embodiments, the administration maintains the adult patient in remission for at least about 15 months. In some embodiments, the administration maintains the adult patient in remission for at least about 18 months. In some embodiments, the administration maintains the adult patient in remission for at least about 21 months. In some embodiments, the administration maintains the adult patient in PAT059494-WO-PCT remission for at least about 24 months. In some embodiments, the administration maintains the adult patient in remission for at least about 27 months.
  • the administration maintains the adult patient in remission for at least about 30 months. In some embodiments, the administration maintains the adult patient in remission for at least about 33 months. In some embodiments, the administration maintains the adult patient in remission for at least about 36 months.
  • ribociclib and an aromatase inhibitor are administered for a treatment duration, and the administration maintains the adult patient in remission for at least the treatment duration.
  • the dose and treatment schedule for the combination of ribociclib and an aromatase inhibitor may follow the exemplary embodiments as follows.
  • a dose of 400 mg ribociclib is orally administered once daily on days 1-21 of a 28-day cycle and aromatase inhibitor is administered once daily on each day of the 28-day cycle.
  • a dose of 400 mg ribociclib is orally administered once daily on days 1-21 of a 28-day cycle for a treatment duration of up to three years and aromatase inhibitor is administered once daily on each day of the 28-day cycle for the up to three years.
  • a dose of 400 mg ribociclib may be orally administered once daily on days 1-21 of a 28-day cycle for a treatment duration of up to five years and aromatase inhibitor is administered once daily on each day of the 28-day cycle for the up to five years.
  • a pharmaceutically acceptable salt of ribociclib is orally administered in an amount corresponding to 400 mg ribociclib.
  • the pharmaceutically acceptable salt may be ribociclib succinate.
  • the adult patient was never treated with a 600 mg dose of ribociclib.
  • the adult patient has never been diagnosed with HR+/HER2- advanced or metastatic breast cancer.
  • Ribociclib and aromatase inhibitor may be administered as adjuvant therapy.
  • the ribociclib is not administered at a dose of 600 mg/day.
  • the dose of ribociclib may be administered in tablet form.
  • two tablets may be orally administered to the adult patient once daily on days 1-21 of a 28-day cycle repeating for a treatment duration, and each tablet contains an amount of a pharmaceutically acceptable ribociclib salt corresponding to 200 mg ribociclib.
  • the ribociclib salt is PAT059494-WO-PCT ribociclib succinate.
  • the aromatase inhibitor is letrozole.
  • the aromatase inhibitor is anastrazole.
  • the aromatase inhibitor is letrozole, and the letrozole is administered in a dose ranging from 1 mg to 4 mg once daily.
  • the aromatase inhibitor may be letrozole, and the letrozole may be administered in a dose of 2.5 mg once daily.
  • the aromatase inhibitor is anastrozole, and the anastrozole is administered in a dose ranging from 0.5 mg once daily to 1.5 mg once daily.
  • anastrozole may be administered in a dose of 1 mg once daily.
  • the patient is a premenopausal woman or man, further comprise administering to the adult patient a gonadotropin-releasing hormone agonist.
  • the gonadotropin-releasing hormone agonist is goserelin.
  • the goserelin is administered in a dose ranging from 2 mg to 5 mg.
  • the dose of goserelin may be 3.6 mg.
  • the goserelin is administered subcutaneously.
  • the goserelin is administered once every 4 weeks.
  • the breast cancer has a histological subtype that is ductal or a histological subtype that is lobular.
  • the breast cancer is a stage IIA cancer or a stage IIB cancer.
  • the breast cancer may be a stage IIA cancer.
  • the breast cancer may be a stage IIB cancer.
  • the breast cancer is a stage IIIA cancer, a stage IIIB cancer, or a stage IIIC cancer.
  • the breast cancer may be a stage IIIA cancer.
  • the breast cancer may be a stage IIIB cancer.
  • the breast cancer may be a stage IIIC cancer.
  • the treatment is administered irrespective of the nodal status of the breast cancer.
  • treatment with ribociclib and aromatase inhibitor is not adjusted on the basis of the nodal status of the early breast cancer.
  • the breast cancer has a nodal status selected from N0, N1, N2, and N3.
  • the breast cancer may have a nodal status of N0.
  • the breast cancer may have a nodal status of N1-N3.
  • the breast cancer may have a nodal status of N1.
  • the breast cancer may have a nodal status of N2.
  • the breast cancer may have a nodal status of N3.
  • PAT059494-WO-PCT In some embodiments, the breast cancer comprises one or more cells having a histological grade selected from G1, G2, or G3.
  • the breast cancer may comprise one or more cells having the histological grade G1.
  • the breast cancer may comprise one or more cells having the histological grade G2.
  • the breast cancer may comprise one or more cells having the histological grade G3.
  • the breast cancer comprises a tumor of category T0, T1, T2, T3, or T4.
  • the breast cancer may comprise a tumor of category T1, T2, or T3.
  • the breast cancer may comprise a tumor of category T0.
  • the breast cancer may comprise a tumor of category T1.
  • the breast cancer may comprise a tumor of category T2.
  • the breast cancer may comprise a tumor of category T3.
  • the breast cancer may comprise a tumor of category T4.
  • the breast cancer has a Ki67 status of 20 or lower. In some embodiments, the breast cancer has a Ki67 status of greater than 20.
  • the patient prior to administering ribociclib and aromatase inhibitor to the adult patient, the patient had surgery for the early breast cancer. In some embodiments, prior to administering ribociclib and aromatase inhibitor to the adult patient, the patient had (1) surgery for the early breast cancer, followed by (2) chemotherapy. In some embodiments, prior to administering ribociclib and aromatase inhibitor to the adult patient, the patient had (1) surgery for the early breast cancer, followed by (2) chemotherapy and/or endocrine therapy. In some embodiments, the endocrine therapy was therapy with a prior aromatase inhibitor. The prior aromatase inhibitor may have been letrozole or anastrozole.
  • the patient immediately prior to administering ribociclib and aromatase inhibitor to the adult patient, the patient had surgery for the early breast cancer. In some embodiments, wherein the surgery comprised a complete surgical resection of the cancer. In some embodiments, the surgery was a mastectomy. In some embodiments, the patient received neoadjuvant therapy. For example, the neoadjuvant therapy may have been chemotherapy. In some embodiments, the adult patient is located in a geographic region selected from North America, Western Europe, or Oceania. In some embodiments, the patient is Asian. PAT059494-WO-PCT In some embodiments, the patient is 18 to 45 years of age. In some embodiments, the patient is 45 to 54 years of age.
  • the patient is 54 to 64 years of age. In some embodiments, the patient is greater than 64 years of age. In some embodiments, wherein the patient has a BMI of 25 or higher. In some embodiments, the patient has a BMI lower than 25.
  • the treatment improves a condition of the patient relative to a patient not receiving the treatment and/or relative to the condition in the patient prior to treatment. In some embodiments, the treatment reduces the risk of invasive disease. For example, The treatment may reduces the risk of invasive disease in the adult patient corresponding to a hazard ratio of less than 1 when the risk is calculated relative to other patients having received the same treatment as the adult patient except that the other patients did not receive the ribociclib.
  • the treatment reduces the risk of invasive disease in the adult patient corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to other patients having received the same treatment as the adult patient except that the other patients did not receive the ribociclib.
  • the adult patient is a premenopausal woman or a man and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to other premenopausal women or men, respectively, having received the same treatment as the premenopausal woman or man, respectively, except that the other premenopausal women or men did not receive the ribociclib.
  • the adult patient was diagnosed with HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease in the adult patient corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to other patients having received the same treatment as the adult patient except that the other patients did not receive the ribociclib.
  • the adult patient was diagnosed with HR+/HER2- stage II early breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to other patients having received the same treatment as the adult patient except that the other patients did not receive the ribociclib.
  • the adult patient was diagnosed with HR+/HER2- stage III early breast cancer, and the treatment yields at least a 25% reduction in the risk of invasive disease corresponding to a hazard ratio of 0.75 when the risk is calculated relative to other patients having PAT059494-WO-PCT received the same treatment as the adult patient except that the other patients did not receive the ribociclib.
  • the treatment reduces the risk of invasive disease to a similar level for patient subgroups comprising patients with stage II early breast cancer, stage III early breast cancer, patients who are premenopausal women or men, and patients who are postmenopausal women.
  • the treatment yields no deterioration in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to other patients having received the same treatment as the adult patient except that the other patients did not receive the ribociclib.
  • the treatment reduces and/or prevents one or more of recurrence of the cancer, spread of the cancer, development and/or growth of an additional cancer, and risk of death from the cancer.
  • the treatment reduces the recurrence of cancer, wherein the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, local-regional invasive recurrence, and distant recurrence.
  • IBTR invasive ipsilateral breast tumor
  • the treatment reduces the spread of cancer, wherein the spread of cancer is an invasive contralateral breast cancer or an additional primary invasive cancer.
  • a further aspect of the present disclosure relates to ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor for use in a method of treatment for HR+/HER2- stage II or III early breast cancer in an adult patient, wherein the method is any one of the methods described herein.
  • Another aspect of the present disclosure relates to the use of ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor in the manufacture of a medicament for treating HR+/HER2- stage II or III early breast cancer in an adult patient, wherein the medicament is administered by any one of the methods described herein.
  • kits for performing a method of treating HR+/HER2- stage II or stage III early breast cancer in an adult patient according to any one of the methods described herein.
  • PAT059494-WO-PCT H A kit for uses and methods
  • One aspect of the present disclosure provides a kit for performing the methods disclosed herein, for example, a kit for performing a method of treating HR+/HER2- stage II or stage III early breast cancer in an adult patient.
  • the kit may be promoted, distributed, or sold as a unit for performing the methods of the present invention.
  • the kit comprises a dose of ribiciclib, a freebase form thereof or a pharmaceutically acceptable salt thereof, and a dose of an aromatase inhibitor such as letrozole or anastrozole.
  • the kit may comprise guidance and/or instructions, e.g., a schedule for administration of the ribociclib and/or the aromatase inhibitor.
  • the kit comprises a dose of ribociclib ranging from about 150 mg/day to 450, and guidance and/or instructions to administer the ribociclib on days 1-21 of a 28-day cycle.
  • the kit may further comprise a dose of an aromatase inhibitor such as letrozole or anastrozole, for example, a dose of about 2.5 mg/day letrozole or about 1 mg/day anastrozole, and may further comprise guidance and/or instructions to administer the aromatase inhibitor on every day of the 28-day cycle.
  • the kit comprises a dose of ribociclib succinate at a total dose of ribociclib of 400 mg/day and a dose of either 2.5 mg/day letrozole or 1 mg/day anastrozole.
  • the kit may further comprise guidance and/or instructions to administer the dose of ribociclib succinate on days 1 to 21 of a 28-day cycle, and to administer the dose of letrozole or anastrozole administered on every day of the 28-day cycle.
  • Exemplary kits may comprise more than 1 daily dose, for example, a kit may comprise 21 doses of the ribociclib, or freebase form thereof or a pharmaceutically acceptable salt thereof, and 28 doses of the aromatase inhibitor (e.g., letrozole or anastrozole), for administration over the whole 28-day cycle.
  • kits may comprise doses of ribociclib, or freebase form thereof or a pharmaceutically acceptable salt thereof, and the aromatase inhibitor (letrozole or anastrozole) for multiple 28-day cycles.
  • aromatase inhibitor letrozole or anastrozole
  • a method of treating HR+/HER2- stage II or stage III early breast cancer in an adult patient in need thereof comprising administering to the patient a treatment comprising a dose of ribociclib, a freebase form thereof or a pharmaceutically acceptable salt thereof, PAT059494-WO-PCT ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor, preferably letrozole or anastrozole, administered on every day of the 28-day cycle.
  • a method of preventing or reducing signs or symptoms of early stage breast cancer comprising administering to the patient a treatment comprising ribociclib, a freebase form thereof or a pharmaceutically acceptable salt thereof in combination with an aromatase inhibitor, preferably letrozole or anastrozole. 3.
  • a treatment comprising ribociclib, a freebase form thereof or a pharmaceutically acceptable salt thereof in combination with an aromatase inhibitor, preferably letrozole or anastrozole.
  • an aromatase inhibitor preferably letrozole or anastrozole.
  • a method of preventing or reducing signs or symptoms of early breast cancer comprising administering to the patient a treatment comprising a dose of ribociclib, a freebase form thereof or a pharmaceutically acceptable salt thereof, ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor, preferably letrozole or anastrozole, administered on every day of the 28-day cycle.
  • a treatment comprising a dose of ribociclib, a freebase form thereof or a pharmaceutically acceptable salt thereof, ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor, preferably letrozole or anastrozole, administered on every day of the 28-day cycle.
  • a method of maintaining remission in an adult patient who had previously been diagnosed with HR+/HER2- stage II or stage III early breast cancer comprising administering to the patient a treatment comprising a dose of ribociclib, a freebase form thereof or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor, preferably letrozole or anastrozole.
  • a treatment comprising a dose of ribociclib, a freebase form thereof or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor, preferably letrozole or anastrozole.
  • ribociclib salt is ribociclib succinate. 19. The method of any one of embodiments 1 to 18, wherein the dose of ribociclib is 200 mg/day or 400 mg/day. 20. The method of any one of embodiments 1 to 18, wherein the ribociclib is not administered at a dose of 600 mg/day. 21. The method of any one of embodiments 1 to 19, wherein ribociclib is administered as ribociclib succinate, and the total dose of ribociclib is 200 mg/day. 22. The method of any one of embodiments 1 to 19, wherein ribociclib is administered as ribociclib succinate, and the total dose of ribociclib is 400 mg/day. 23.
  • the method of embodiment 33 wherein the goserelin is administered in a dose ranging from 2 mg to 5 mg. 35.
  • 38. The method of any one of embodiments 1 to 31, wherein the patient is a postmenopausal woman.
  • any one of embodiments 1 to 39 wherein the treatment is administered to the patient for at least 12 months. 41.
  • the method of embodiment 40, wherein the treatment is administered to the patient for at least 24 months. 42.
  • the method of embodiment 40 or embodiment 41 wherein the treatment is administered to the patient for at least 36 months. 43.
  • the method of any one of embodiments 40 to 41, wherein the treatment is administered to the patient for at least 48 months. 44.
  • the method of any one of embodiments 40 to 41, wherein the treatment is administered to the patient for at least 60 months. 45.
  • the method of any one of embodiments 1 to 44, wherein the treatment continues until the patient has no detectable cancer. 46.
  • the method of any one of embodiments 1 to 45, wherein the breast cancer is ER+ and PR+. 47.
  • the method of any one of embodiments 1 to 45, wherein the breast cancer is ER- and PR+.
  • 48. The method of any one of embodiments 1 to 45, wherein the breast cancer is ER+ and PR-.
  • 49. The method of any one of embodiments 1 to 48, wherein the breast cancer has a histological subtype that is ductal or a histological subtype that is lobular.
  • 50. The method of any one of embodiments 1 to 49, wherein the breast cancer is a stage IIA cancer or a stage IIB cancer. 51.
  • the method of embodiment 50, wherein the breast cancer is a stage IIA cancer.
  • 52. The method of embodiment 50, wherein the breast cancer is a stage IIB cancer. 53.
  • the method of any one of embodiments 1 to 56, wherein the treatment is administered irrespective of the nodal status of the breast cancer.
  • the method of any one of embodiments 1 to 57, wherein the breast cancer has a nodal status selected from N0, N1, N2, and N3. 59.
  • the method of embodiment 57 or 58, wherein the breast cancer has a nodal status of N0. 60. The method of embodiment 57 or 58, wherein the breast cancer has a nodal status of N1 to N3. 61. The method of embodiment 57 or 58, wherein the breast cancer has a nodal status of N1. 62. The method of embodiment 57 or 58, wherein the breast cancer has a nodal status of N2. 63. The method of embodiment 57 or 58, wherein the breast cancer has a nodal status of N3. 64. The method of any one of embodiments 1 to 63, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2, or G3. 65.
  • the method of embodiment 64, wherein the breast cancer comprises one or more cells having the histological grade G1.
  • the method of embodiment 64, wherein the breast cancer comprises one or more cells having the histological grade G2.
  • the method of embodiment 64, wherein the breast cancer comprises one or more cells having the histological grade G3.
  • the method of any one of embodiments 1 to 67, wherein the breast cancer comprises a tumor of category T0, T1, T2, T3, or T4.
  • PAT059494-WO-PCT 69 The method of embodiment 68, wherein the breast cancer comprises a tumor of category T1, T2, or T3.
  • the method of embodiment 68, wherein the breast cancer comprises a tumor of category T0. 71.
  • the method of embodiment 68 or 69, wherein the breast cancer comprises a tumor of category T1.
  • the method of embodiment 68 or 69, wherein the breast cancer comprises a tumor of category T2.
  • the method of embodiment 68 or 69, wherein the breast cancer comprises a tumor of category T3.
  • the method of embodiment 68, wherein the breast cancer comprises a tumor of category T4.
  • the method of any one of embodiments 1 to 74, wherein the breast cancer has a Ki67 status of 20 or lower.
  • the method of any one of embodiments 1 to 74, wherein the breast cancer has a Ki67 status of greater than 20. 77.
  • any one of embodiments 1 to 76 wherein prior to the administration, the patient has received a loading dose of (i) ribociclib and/or (ii) an endocrine therapy.
  • 78. The method of any one of embodiments 1 to 77, wherein the patient has received at least one prior treatment for cancer.
  • 79. The method of embodiment 78, wherein the prior treatment is an adjuvant treatment after another prior treatment.
  • 80. The method of embodiment 78 or 79, wherein the prior treatment is surgery.
  • the method of embodiment 80, wherein the surgery comprises a complete surgical resection of the cancer.
  • 82. The method of embodiment 80 or 81, wherein the surgery is a mastectomy. 83.
  • the method of embodiment 80 or 81, wherein the prior treatment is a chemotherapy.
  • the method of embodiment 83, wherein the prior treatment is an adjuvant chemotherapy.
  • the method of embodiment 83, wherein the prior treatment is a neoadjuvant chemotherapy.
  • the method of embodiment 78 or 79, wherein the prior treatment is an endocrine therapy.
  • the method of embodiment 78 or 79, wherein the prior treatment is radiation therapy.
  • the method of embodiment 98 wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than 1 when the risk is calculated relative to patients not receiving the treatment.
  • 100 The method of embodiment 99, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to patients not receiving the treatment.
  • 101 The method of any one of embodiments 1 to 37 and 39 to 100, wherein the patient is a premenopausal woman or a man and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to patients receiving the treatment.
  • 102 The method of any one of embodiments 1 to 37 and 39 to 100, wherein the patient is a premenopausal woman or a man and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to patients receiving the treatment.
  • any one of embodiments 98 to 100 wherein the patient has HR+/HER2- stage III early breast cancer, and the treatment yields at least a 25% reduction in the risk of invasive disease corresponding to a hazard ratio of 0.75 when the risk is calculated relative to patients not receiving the treatment.
  • the treatment reduces the risk of invasive disease to a similar level for patient subgroups comprising patients with stage II early breast cancer, stage III early breast cancer, patients who are premenopausal women or men, and patients who are postmenopausal women.
  • any one of embodiments 1 to 105 wherein the treatment yields no deterioration in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to patients not receiving the treatment.
  • the treatment reduces and/or prevents one or more of recurrence of the cancer, spread of the cancer, development and/or growth of an additional cancer, and risk of death from the cancer.
  • PAT059494-WO-PCT 108 wherein the treatment yields no deterioration in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to patients not receiving the treatment.
  • the treatment reduces the recurrence of cancer, wherein the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, local-regional invasive recurrence, and distant recurrence.
  • IBTR invasive ipsilateral breast tumor
  • the treatment reduces the spread of cancer, wherein the spread of cancer is an invasive contralateral breast cancer or an additional primary invasive cancer.
  • 110 The method of any one of embodiments 1 to 109, wherein the treatment prevents death from cancer. 111.
  • a method of maintaining in remission an adult patient who had previously been diagnosed with HR+/HER2- stage II or stage III early breast cancer comprising administering to the patient a treatment comprising administering to the patient a treatment comprising a dose of ribociclib, a freebase form thereof or a pharmaceutically acceptable salt thereof, ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28- day cycle in combination with an aromatase inhibitor, preferably letrozole or anastrozole, administered on every day of the 28-day cycle. 112.
  • a method of preventing breast cancer recurrence in an adult patient comprising providing adjuvant treatment to a patient who has received a prior treatment for HR+/HER2- stage II or III early breast cancer, wherein the adjuvant treatment comprises administering to the patient 400 mg ribociclib or a pharmaceutically acceptable salt thereof on days 1 to 21 of a 28-day cycle for at least 36 months, in combination with an aromatase inhibitor as defined in any one of embodiments 26 to 31 administered on every day of the 28-day cycle.
  • the prior treatment is surgical resection of the cancer.
  • Ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor for use in a method of treatment for HR+/HER2- stage II or III early breast cancer in an adult patient, wherein the method is the method of any one of embodiments 1 to 112.
  • a method of treating HR+/HER2- stage II or stage III early breast cancer in an adult patient in remission comprising administering to the adult patient ribociclib in combination with an aromatase inhibitor whereby the administration maintains the adult patient in remission for at least 3 months.
  • a method of treating HR+/HER2- stage II or stage III early breast cancer in an adult patient comprising providing adjuvant treatment by administering ribociclib in combination with aromatase inhibitor, wherein the patient at start of the adjuvant treatment is in complete remission, and the administration of ribociclib in combination with aromatase inhibitor maintains the adult patient in complete remission for at least 3 months.
  • ribociclib and aromatase inhibitor are administered for a treatment duration, and the administration maintains the adult patient in remission (e.g., complete remission) for at least the treatment duration.
  • a dose of 400 mg ribociclib is orally administered once daily on days 1-21 of a 28-day cycle and aromatase inhibitor is administered once daily on each day of the 28-day cycle.
  • any one of embodiments 117 to 129 wherein a dose of 400 mg ribociclib is orally administered once daily on days 1-21 of a 28-day cycle for a treatment duration of up to three years and aromatase inhibitor is administered once daily on each day of the 28-day cycle for the up to three years.
  • a dose of 400 mg ribociclib is orally administered once daily on days 1-21 of a 28-day cycle for a treatment duration of up to five years and aromatase inhibitor is administered once daily on each day of the 28-day cycle for the up to five years.
  • the method of embodiment 150 wherein the goserelin is administered in a dose ranging from 2 mg to 5 mg. 152.
  • the method of embodiment 151, wherein the dose of goserelin is 3.6 mg. 153.
  • the method of any one of embodiments 150 to 153, wherein the goserelin is administered once every 4 weeks.
  • PAT059494-WO-PCT 155 The method of any one of embodiments 117 to 148, wherein the patient is a postmenopausal woman. 156.
  • the method of any one of embodiments 117 to 156, wherein the breast cancer is a stage IIIA cancer, a stage IIIB cancer, or a stage IIIC cancer. 162.
  • the method of any one of embodiments 117 to 156, wherein the breast cancer is a stage IIIA cancer. 163.
  • the method of any one of embodiments 117 to 156, wherein the breast cancer is a stage IIIC cancer.
  • the method of any one of embodiments 117 to 156, wherein the treatment is administered irrespective of the nodal status of the breast cancer. 166.
  • the method of any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2, or G3. 174.
  • the method of any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having the histological grade G1. 175.
  • the method of any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having the histological grade G2. 176. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having the histological grade G3. 177. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises a tumor of category T0, T1, T2, T3, or T4. 178. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises a tumor of category T1, T2, or T3. 179. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises a tumor of category T0. 180.
  • the method of any one of embodiments 117 to 156, wherein the breast cancer comprises a tumor of category T1. 181.
  • the method of any one of embodiments 117 to 156, wherein the breast cancer comprises a tumor of category T4.
  • the method of any one of embodiments 117 to 156, wherein the breast cancer has a Ki67 status of 20 or lower.
  • the method of any one of embodiments 117 to 156, wherein the breast cancer has a Ki67 status of greater than 20.
  • any one of embodiments 117 to 203 wherein the treatment reduces the risk of invasive disease.
  • the treatment reduces the risk of invasive disease in the adult patient corresponding to a hazard ratio of less than 1 when the risk is calculated relative to other patients having received the same treatment as the adult patient except that the other patients did not receive the ribociclib.
  • 207. The method any one of embodiments 117 to 203, wherein the treatment reduces the risk of invasive disease in the adult patient corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to other patients having received the same treatment as the adult patient except that the other patients did not receive the ribociclib.
  • PAT059494-WO-PCT The method of any one of embodiments 117 to 203, wherein the adult patient is a premenopausal woman or a man and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to other premenopausal women or men, respectively, having received the same treatment as the premenopausal woman or man, respectively, except that the other premenopausal women or men did not receive the ribociclib.
  • any one of embodiments 117 to 203 wherein the adult patient was diagnosed with HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease in the adult patient corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to other patients having received the same treatment as the adult patient except that the other patients did not receive the ribociclib.
  • any one of embodiments 117 to 203 wherein the adult patient was diagnosed with HR+/HER2- stage III early breast cancer, and the treatment yields at least a 25% reduction in the risk of invasive disease corresponding to a hazard ratio of 0.75 when the risk is calculated relative to other patients having received the same treatment as the adult patient except that the other patients did not receive the ribociclib.
  • any one of embodiments 117 to 203 wherein the treatment yields no deterioration in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to other patients having received the same treatment as the adult patient except that the other patients did not receive the ribociclib.
  • IBTR invasive ipsilateral breast tumor
  • the treatment reduces the spread of cancer, wherein the spread of cancer is an invasive contralateral breast cancer or an additional primary invasive cancer.
  • Ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor for use in a method of treatment for HR+/HER2- stage II or III early breast cancer in an adult patient, wherein the method is the method of any one of embodiments 117 to 216. 218.
  • a method of treating an adult patient who has been diagnosed with HER+/HER2- stage II or stage III early breast cancer comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle, wherein the method results in an improvement in the patient in one or more of their overall survival (OS), distant disease- free survival (DDFS), or recurrence free survival (RFS). 221.
  • OS overall survival
  • DDFS distant disease- free survival
  • RFS recurrence free survival
  • a method for improving one or more of overall survival (OS), distant disease-free survival (DDFS), or recurrence free survival (RFS) in a patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle. 222.
  • a method for reducing the risk of local or regional invasive recurrence of early breast cancer in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered PAT059494-WO-PCT on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle. 223.
  • a method for reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, and lung or pleura of an adult patient, who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle.
  • an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle.
  • a method for reducing the risk of recurrence of early breast cancer in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle and (ii) an aromatase inhibitor administered on every day of the 28-day cycle, wherein the treatment is administered irrespective of the nodal status of the breast cancer.
  • an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle and (ii) an aromatase inhibitor administered on every day of the 28-day cycle, wherein the treatment is administered irrespective of the nodal status of the breast cancer.
  • any of embodiments 220 to 235, wherein the aromatase inhibitor is letrozole or anastrozole. 237.
  • Ribociclib for use in a method of improving one or more of overall survival (OS), distant disease-free survival (DDFS), or recurrence free survival (RFS) in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, wherein the method comprises administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle. 242.
  • OS overall survival
  • DDFS distant disease-free survival
  • RFS recurrence free survival
  • Ribociclib for use in a method of reducing the risk of local or regional invasive recurrence of early breast cancer in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, wherein the method comprises administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle. 243.
  • Ribociclib for use in a method of reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, and lung or pleura of an adult patient who has PAT059494-WO-PCT been diagnosed with HR+/HER2- stage II or stage III early breast cancer, wherein the method comprises administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle. 244.
  • Ribociclib for use in accordance with any of embodiments 241 to 243, wherein the treatment is administered irrespective of the nodal status of the breast cancer.
  • Ribociclib for use in a method of reducing the risk of recurrence of early breast cancer in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1- 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28- day cycle, wherein the treatment is administered irrespective of the nodal status of the breast cancer. 246.
  • Ribociclib for use according to any of embodiments 241 to 245, wherein the breast cancer has a nodal status of N0, N1, N2 or N3. 247. Ribociclib for use according to embodiment 246, wherein the breast cancer has a nodal status of N0. 248. Ribociclib for use according to any of embodiments 241 to 247, wherein the early breast cancer is stage II, such as stage IIA. 249. Ribociclib for use according to any of embodiments 241 to 247, wherein the early breast cancer is stage III, such as stage IIIB or IIIC. 250. Ribociclib for use according to any of embodiments 241 to 249, wherein the breast cancer is of the ductal subtype. 251.
  • Ribociclib for use according to any of embodiments 241 to 250, wherein the patient is Asian. 252. Ribociclib for use according to any of embodiments 241 to 251, wherein the method is an adjuvant treatment because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiation therapy. PAT059494-WO-PCT 253. Ribociclib for use according to embodiment 252, wherein the patient has not had a mastectomy. 254. Ribociclib for use according to any of embodiments 241 to 253, wherein the dose of ribociclib is 400 mg/day. 255.
  • Ribociclib for use according to any of embodiments 241 to 258, wherein the dose of ribociclib is 400 mg/day, the ribociclib is administered in the form of ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg/day of letrozole or 1 mg/day anastrozole.
  • Ribociclib for use according to any of embodiments 241 to 259, wherein the improvement in OS, DDFS and/or RFS, or the reduction in the risk of recurrence of the breast cancer, are achieved in the patient for at least 36 months. 261.
  • Ribociclib succinate for use in a method of treatment of HR+/HER2- stage II or stage III early breast cancer in an adult patient who has received at least one prior treatment for early breast cancer and has no signs or symptoms of cancer, wherein the method comprises administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib succinate at a total dose of ribociclib of 400 mg/day administered on days 1 to 21 of a 28-day cycle, and (ii) a dose of either 2.5 mg/day letrozole or 1 mg/day anastrozole administered on every day of the 28-day cycle. 262.
  • Ribociclib succinate for use according to embodiment 261, wherein the adjuvant treatment comprises a dose of 1 mg/day anastrozole. PAT059494-WO-PCT 264. Ribociclib succinate for use according to any one of embodiments 261 to 263, wherein the breast cancer has a nodal status of N0, N1, N2 or N3. 265. Ribociclib succinate for use according to embodiment 264, wherein the breast cancer has a nodal status of N0. 266. Ribociclib succinate for use according to any one of embodiments 261 to 265, wherein the early breast cancer is stage II, such as stage IIA. 267.
  • Ribociclib succinate for use according to any one of embodiments 261 to 265, wherein the early breast cancer is stage III, such as stage IIIB. 268.
  • Ribociclib succinate for use according to any one of embodiments 261 to 265, wherein the early breast cancer is stage III, such as IIIC. 269.
  • Ribociclib succinate for use according to any one of embodiments 261 to 268, wherein the breast cancer is of the ductal subtype.
  • Ribociclib succinate for use according to any one of embodiments 261 to 269, wherein the patient is Asian. 271.
  • Ribociclib succinate for use according to any one of embodiments 261 to 270, wherein the method is an adjuvant treatment because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, endocrine therapy, and radiation therapy. 272. Ribociclib succinate for use according to embodiment 271, wherein the patient has not had a mastectomy. 273. Ribociclib succinate for use according to any one of embodiments 261 to 272, wherein the method improves overall survival (OS), distant disease-free survival (DDFS), and/or recurrence free survival (RFS) of the breast cancer in the patient for at least 36 months; or the method reduces the risk of recurrence of the breast cancer in the patient for at least 36 months. 274.
  • OS overall survival
  • DDFS distant disease-free survival
  • RFS recurrence free survival
  • a method of preventing recurrence of breast cancer in an adult patient who has received a prior treatment for HR+/HER2- stage II or stage III early breast cancer comprising administering to the patient (i) a dose of ribociclib, a freebase form thereof, or a pharmaceutically acceptable salt thereof, and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.
  • a dose of ribociclib a freebase form thereof, or a pharmaceutically acceptable salt thereof
  • an aromatase inhibitor preferably letrozole or anastrozole.
  • a method of treating an adult patient in remission from HR+/HER2- stage II or stage III early breast cancer comprising administering to the patient (i) a dose of ribociclib, a freebase form thereof, or a pharmaceutically acceptable salt thereof, and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole. 276.
  • a method of treating HR+/HER2- stage II or stage III early breast cancer in an adult patient in need thereof comprising administering to the patient (i) a dose of ribociclib, a freebase form thereof, or a pharmaceutically acceptable salt thereof, ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle and (ii) an aromatase inhibitor, preferably letrozole or anastrozole, administered on every day of the 28-day cycle.
  • ribociclib is a pharmaceutically acceptable ribociclib salt.
  • the ribociclib salt is ribociclib succinate.
  • a method of treating breast cancer recurrence in an adult patient who has received at least one prior treatment for HR+/HER2- stage II or III early breast cancer and who has no detectable signs or symptoms of breast cancer comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib succinate at a total dose of ribociclib of 400 mg/day administered on days 1 to 21 of a 28-day cycle, and (ii) a dose of either 2.5 mg/day letrozole or 1 mg/day anastrozole administered on every day of the 28-day cycle. 293.
  • a method of treating an adult patient who is in remission from HR+/HER2- stage II or stage III early breast cancer and in need of adjuvant treatment comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib succinate at a total dose of ribociclib of 400 mg/day administered on days 1-21 of a 28-day cycle and (ii) a dose of either 2.5 mg/day letrozole or 1 mg/day anastrozole administered on every day of the 28-day cycle. 294.
  • the gonadotropin-releasing hormone agonist is goserelin.
  • the method of any one of embodiments 302 to 304, wherein the treatment is administered to the patient for at least 48 months. 306.
  • the method of any one of embodiments 274 to 306, wherein the breast cancer is ER+ and PR+. 308.
  • the method of any one of embodiments 274 to 306, wherein the breast cancer is ER- and PR+. 309.
  • the method of any one of embodiments 274 to 306, wherein the breast cancer is ER+ and PR-. 310.
  • the method of any one of embodiments 274 to 309, wherein the breast cancer has a histological subtype that is ductal. 311.
  • the method of any one of embodiments 274 to 310, wherein the breast cancer has a histological subtype that is lobular. 312.
  • the method of any one of embodiments 274 to 311, wherein the breast cancer is a stage IIA cancer or a stage IIB cancer. 313.
  • the method of embodiment 312, wherein the breast cancer is a stage IIA cancer. 314.
  • the method of embodiment 312, wherein the breast cancer is a stage IIB cancer. 315.
  • PAT059494-WO-PCT 316 The method of embodiment 315, wherein the breast cancer is a stage IIIA cancer. 317.
  • the method of embodiment 315, wherein the breast cancer is a stage IIIB cancer. 318.
  • the method of embodiment 315, wherein the breast cancer is a stage IIIC cancer. 319.
  • the method of embodiment 326, wherein the breast cancer comprises one or more cells having the histological grade G2. 329.
  • the method of embodiment 326, wherein the breast cancer comprises one or more cells having the histological grade G3. 330.
  • the method of any one of embodiments 274 to 329, wherein the breast cancer comprises a tumor of category T0, T1, T2, T3, or T4.
  • 340 The method of any one of embodiments 274 to 291 and 293 to 339, wherein the patient has received at least one prior treatment for cancer. 341.
  • the method of embodiment 292 or embodiment 340, wherein the prior treatment is an adjuvant treatment after another prior treatment. 342.
  • the method of embodiment 340 or 341, wherein the prior treatment is surgery. 343.
  • the method of embodiment 342, wherein the surgery comprises a complete surgical resection of the cancer. 344.
  • the method of embodiment 340 or embodiment 341, wherein the prior treatment is a chemotherapy.
  • the method of embodiment 345, wherein the prior treatment is an adjuvant chemotherapy. 347.
  • the method of embodiment 345, wherein the prior treatment is a neoadjuvant chemotherapy.
  • PAT059494-WO-PCT 348 The method of embodiment 340 or embodiment 341, wherein the prior treatment is an endocrine therapy. 349.
  • the method of embodiment 340 or embodiment 341, wherein the prior treatment is radiation therapy. 350.
  • the method of any one of embodiments 274 to 352, wherein the patient is 18 to 45 years of age.
  • the method of any one of embodiments 274 to 352, wherein the patient is 45 to 54 years of age. 355.
  • the method of embodiment 360 wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than 1 when the risk is calculated relative to patients not receiving the treatment.
  • PAT059494-WO-PCT 362. The method of embodiment 361, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to patients not receiving the treatment.
  • 363. The method of any one of embodiments 274 to 299 and 301 to 362, wherein the patient is a premenopausal woman or a man and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to patients receiving the treatment. 364.
  • the cancer is HR+/HER2- stage II early breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to patients not receiving the treatment.
  • the treatment reduces the risk of invasive disease to a similar level for patient subgroups comprising patients with stage II early breast cancer, stage III early breast cancer, patients who are premenopausal women or men, and patients who are postmenopausal women. 368.
  • any one of embodiments 274 to 367 wherein the treatment yields no deterioration in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to patients not receiving the treatment.
  • the treatment reduces and/or prevents one or more of recurrence of the cancer, spread of the cancer, development and/or growth of an additional cancer, and risk of death from the cancer. 370.
  • PAT059494-WO-PCT 371.
  • a method of treating an adult patient who has been diagnosed with HER+/HER2- stage II or stage III early breast cancer comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle, wherein the method results in an improvement in the patient in one or more of their overall survival (OS), distant disease-free survival (DDFS), or recurrence free survival (RFS).
  • OS overall survival
  • DDFS distant disease-free survival
  • RFS recurrence free survival
  • a method for improving one or more of overall survival (OS), distant disease-free survival (DDFS), or recurrence free survival (RFS) in a patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, (ii) an aromatase inhibitor administered on every day of the 28-day cycle. 3.
  • OS overall survival
  • DDFS distant disease-free survival
  • RFS recurrence free survival
  • a method for reducing the risk of local or regional invasive recurrence of early breast cancer in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycleand (ii) an aromatase inhibitor administered on every day of the 28-day cycle. 4.
  • a method for reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, and lung or pleura of an adult patient, who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle.
  • an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle.
  • PAT059494-WO-PCT 5 The method of any of claims 1 to 4, wherein the treatment is administered irrespective of the nodal status of the breast cancer. 6.
  • a method for reducing the risk of recurrence of early breast cancer in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer comprising administering an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle and (ii) an aromatase inhibitor administered on every day of the 28-day cycle, wherein the treatment is administered irrespective of the nodal status of the breast cancer.
  • an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle and (ii) an aromatase inhibitor administered on every day of the 28-day cycle, wherein the treatment is administered irrespective of the nodal status of the breast cancer.
  • the method of any of claims 1 to 8, wherein the early breast cancer is stage II, for example stage IIA. 10. The method of any of claims 1 to 8, wherein the early breast cancer is stage III, for example stage IIIB or IIIC. 11. The method of any of claims 1 to 10, wherein the breast cancer is of the ductal subtype. 12. The method of any of claims 1 to 11, wherein the patient is Asian. 13. The method of any of claims 1 to 12, wherein the method is an adjuvant treatment because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiation therapy. 14. The method of claim 13, wherein the patient has not had a mastectomy. 15. The method of any of claims 1 to 14, wherein the dose of ribociclib is 400 mg/day. 16.
  • the aromatase inhibitor is letrozole or anastrozole. 18.
  • the aromatase inhibitor is letrozole, preferably administered in a dose of 2.5 mg/day.
  • PAT059494-WO-PCT 19 The method of claim 17, wherein the aromatase inhibitor is anastrozole, preferably administered in a dose of 1 mg/day. 20.
  • Ribociclib for use in a method of improving one or more of overall survival (OS), distant disease-free survival (DDFS), or recurrence free survival (RFS) in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle.
  • OS overall survival
  • DDFS distant disease-free survival
  • RFS recurrence free survival
  • Ribociclib for use in a method of reducing the risk of local or regional invasive recurrence of early breast cancer in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, comprising g administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle. 24.
  • Ribociclib for use in a method of reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, and lung or pleura of an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer and the method is an adjuvant treatment comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle.
  • Ribociclib for use in accordance with any of claims 22 to 24, wherein the treatment is administered irrespective of the nodal status of the breast cancer. 26.
  • Ribociclib for use in a method of reducing the risk of recurrence of early breast cancer in an adult patient who has been diagnosed with HR+/HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a PAT059494-WO-PCT 28-day cycle, and (ii) an aromatase inhibitor administered on every day of the 28-day cycle, wherein the treatment is administered irrespective of the nodal status of the breast cancer.
  • Ribociclib for use according to any of claims 22 to 26, wherein the breast cancer has a nodal status of N0, N1, N2 or N3.
  • Ribociclib for use according to any of claims 22 to 32, wherein the method is an adjuvant treatment because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiation therapy.
  • Ribociclib for use according to claim 33 wherein the patient has not had a mastectomy.
  • Ribociclib for use according to any of claims 22 to 36, wherein the aromatase inhibitor is letrozole or anastrozole. 38. Ribociclib for use according to claim 37, wherein the aromatase inhibitor is letrozole, preferably administered in a dose of 2.5 mg/day. 39. Ribociclib for use according to claim 37, wherein the aromatase inhibitor is anastrozole, preferably administered in a dose of 1 mg/day. PAT059494-WO-PCT 40.
  • Ribociclib for use according to any of claims 22 to 39, wherein the dose of ribociclib is 400 mg/day, the ribociclib is administered in the form of ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg/day of letrozole or 1 mg/day anastrozole.
  • K. More exemplary embodiments More methods of treatment and uses of ribociclib are provided in the following embodiments. 1.
  • Ribociclib succinate for use in a method of treatment of HR+/HER2- stage II or stage III early breast cancer in an adult patient who has received at least one prior treatment for early breast cancer and has no signs or symptoms of cancer, wherein the method comprises administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib succinate at a total dose of ribociclib of 400 mg/day administered on days 1 to 21 of a 28-day cycle, and (ii) a dose of either 2.5 mg/day letrozole or 1 mg/day anastrozole administered on every day of the 28-day cycle.
  • Ribociclib succinate for use according to embodiment 1, wherein the adjuvant treatment comprises a dose of 1 mg/day anastrozole. 4. Ribociclib succinate for use according to any one of embodiments 1 to 3, wherein the breast cancer has a nodal status of N0, N1, N2 or N3. 5. Ribociclib succinate for use according to embodiment 4, wherein the breast cancer has a nodal status of N0. 6. Ribociclib succinate for use according to any one of embodiments 1 to 5, wherein the early breast cancer is stage II, such as stage IIA. 7. Ribociclib succinate for use according to any one of embodiments 1 to 5, wherein the early breast cancer is stage III, such as stage IIIB. 8.
  • Ribociclib succinate for use according to any one of embodiments 1 to 5, wherein the early breast cancer is stage III, such as IIIC. PAT059494-WO-PCT 9. Ribociclib succinate for use according to any one of embodiments 1 to 8, wherein the breast cancer is of the ductal subtype. 10. Ribociclib succinate for use according to any one of embodiments 1 to 9, wherein the patient is Asian. 11. Ribociclib succinate for use according to any one of embodiments 1 to 10, wherein the method is an adjuvant treatment because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, endocrine therapy, and radiation therapy. 12. Ribociclib succinate for use according to embodiment 11, wherein the patient has not had a mastectomy. 13.
  • Ribociclib succinate for use according to any one of embodiments 1 to 12, wherein the method improves overall survival (OS), distant disease-free survival (DDFS), and/or recurrence free survival (RFS) of the breast cancer in the patient for at least 36 months; or the method reduces the risk of recurrence of the breast cancer in the patient for at least 36 months.
  • OS overall survival
  • DDFS distant disease-free survival
  • RFS recurrence free survival
  • a method of preventing recurrence of breast cancer in an adult patient who has received a prior treatment for HR+/HER2- stage II or stage III early breast cancer comprising administering to the patient (i) a dose of ribociclib, a freebase form thereof, or a pharmaceutically acceptable salt thereof, and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole. .
  • a method of treating an adult patient in remission from HR+/HER2- stage II or stage III early breast cancer comprising administering to the patient (i) a dose of ribociclib, a freebase form thereof, or a pharmaceutically acceptable salt thereof, and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole. .
  • a method of treating HR+/HER2- stage II or stage III early breast cancer in an adult patient in need thereof comprising administering to the patient (i) a dose of ribociclib, a freebase form thereof, or a pharmaceutically acceptable salt thereof, ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle and (ii) an aromatase inhibitor, preferably letrozole or anastrozole, administered on every day of the 28-day cycle.
  • PAT059494-WO-PCT 4 The method of any one of embodiments 1 to 3, wherein the ribociclib is a pharmaceutically acceptable ribociclib salt. 5. The method of embodiment 4, wherein the ribociclib salt is ribociclib succinate. 6.
  • a method of treating breast cancer recurrence in an adult patient who has received at least one prior treatment for HR+/HER2- stage II or III early breast cancer and who has PAT059494-WO-PCT no detectable signs or symptoms of breast cancer comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib succinate at a total dose of ribociclib of 400 mg/day administered on days 1 to 21 of a 28-day cycle, and (ii) a dose of either 2.5 mg/day letrozole or 1 mg/day anastrozole administered on every day of the 28-day cycle.
  • a method of treating an adult patient who is in remission from HR+/HER2- stage II or stage III early breast cancer and in need of adjuvant treatment comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib succinate at a total dose of ribociclib of 400 mg/day administered on days 1-21 of a 28-day cycle and (ii) a dose of either 2.5 mg/day letrozole or 1 mg/day anastrozole administered on every day of the 28-day cycle.
  • 21. The method of any one of embodiments 1 to 20, wherein the treatment comprises administering a gonadotropin-releasing hormone agonist. 22. The method of embodiment 21, wherein the gonadotropin-releasing hormone agonist is goserelin. 23.
  • 27. The method of any one of embodiments 1 to 20, wherein the patient is a postmenopausal woman.
  • 28. The method of any one of embodiments 1 to 26 wherein the patient is a premenopausal woman or a man. 29.
  • the method of any one of embodiments 1 to 33, wherein the breast cancer is ER- and PR+. 36. The method of any one of embodiments 1 to 33, wherein the breast cancer is ER+ and PR-. 37. The method of any one of embodiments 1 to 36, wherein the breast cancer has a histological subtype that is ductal. 38. The method of any one of embodiments 1 to 37, wherein the breast cancer has a histological subtype that is lobular. 39. The method of any one of embodiments 1 to 38, wherein the breast cancer is a stage IIA cancer or a stage IIB cancer. 40. The method of embodiment 39, wherein the breast cancer is a stage IIA cancer. 41.
  • the method of embodiment 39, wherein the breast cancer is a stage IIB cancer. 42. The method of any one of embodiments 1 to 38, wherein the breast cancer is a stage IIIA cancer, a stage IIIB cancer, or a stage IIIC cancer. 43. The method of embodiment 42, wherein the breast cancer is a stage IIIA cancer. 44. The method of embodiment 42, wherein the breast cancer is a stage IIIB cancer. 45. The method of embodiment 42, wherein the breast cancer is a stage IIIC cancer. 46. The method of any one of embodiments 1 to 45, wherein the treatment is administered irrespective of the nodal status of the breast cancer. 47.
  • the method of embodiment 46 or 47, wherein the breast cancer has a nodal status of N1.
  • the breast cancer comprises one or more cells having a histological grade selected from G1, G2, or G3.
  • the method of embodiment 53, wherein the breast cancer comprises one or more cells having the histological grade G1.
  • the method of embodiment 53, wherein the breast cancer comprises one or more cells having the histological grade G2.
  • the method of embodiment 53, wherein the breast cancer comprises one or more cells having the histological grade G3.
  • the method of any one of embodiments 1 to 56, wherein the breast cancer comprises a tumor of category T0, T1, T2, T3, or T4.
  • the method of embodiment 57, wherein the breast cancer comprises a tumor of category T1, T2, or T3. 59.
  • the method of embodiment 57, wherein the breast cancer comprises a tumor of category T0. 60. The method of embodiment 57 or 58, wherein the breast cancer comprises a tumor of category T1. 61. The method of embodiment 57 or 58, wherein the breast cancer comprises a tumor of category T2. 62. The method of embodiment 57 or 58, wherein the breast cancer comprises a tumor of category T3. 63. The method of embodiment 57, wherein the breast cancer comprises a tumor of category T4. PAT059494-WO-PCT 64. The method of any one of embodiments 1 to 63, wherein the breast cancer has a Ki67 status of 20 or lower. 65.
  • 66. The method of any one of embodiments 1 to 65, wherein prior to the administration, the patient has received a loading dose of (i) ribociclib and/or (ii) an endocrine therapy.
  • 67. The method of any one of embodiments 1 to 18 and 20 to 66, wherein the patient has received at least one prior treatment for cancer.
  • the method of embodiment 19 or 67, wherein the prior treatment is an adjuvant treatment after another prior treatment.
  • 69. The method of embodiment 67 or 68, wherein the prior treatment is surgery.
  • 70. The method of embodiment 69, wherein the surgery comprises a complete surgical resection of the cancer.
  • the method of any one of embodiments 1 to 79, wherein the patient is 45 to 54 years of age.
  • any one of embodiments 87 to 89 wherein the cancer is HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to patients not receiving the treatment.
  • 92 The method of any one of embodiments 87 to 89, wherein the cancer is HR+/HER2- stage II early breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to patients not receiving the treatment.
  • PAT059494-WO-PCT 93 PAT059494-WO-PCT 93.
  • any one of embodiments 87 to 89 wherein the cancer is HR+/HER2- stage III early breast cancer, and the treatment yields at least a 25% reduction in the risk of invasive disease corresponding to a hazard ratio of 0.75 when the risk is calculated relative to patients not receiving the treatment.
  • the treatment reduces the risk of invasive disease to a similar level for patient subgroups comprising patients with stage II early breast cancer, stage III early breast cancer, patients who are premenopausal women or men, and patients who are postmenopausal women. 95.
  • any one of embodiments 1 to 94 wherein the treatment yields no deterioration in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to patients not receiving the treatment.
  • the treatment reduces and/or prevents one or more of recurrence of the cancer, spread of the cancer, development and/or growth of an additional cancer, and risk of death from the cancer.
  • the treatment reduces the recurrence of cancer, wherein the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, local-regional invasive recurrence, and distant recurrence.
  • IBTR invasive ipsilateral breast tumor
  • adjuvant therapy refers to a treatment given after a primary treatment, e.g., in order to lower the risk that the disease will recur.
  • an adjuvant therapy may be administered, inter alia, to lower the risk of cancer recurrence, for example, by destroying cancer cells that remain after a primary treatment.
  • a treatment comprising a dose PAT059494-WO-PCT of ribociclib in combination with an aromatase inhibitor may be administered as an adjuvant after a primary treatment, e.g., comprising surgery, radiation therapy, and/or chemotherapy.
  • Neoadjuvant therapy refers to a treatment delivered before a primary treatment.
  • a neoadjuvant therapy may, inter alia, reduce the size of a tumor or kill cancer cells that have spread.
  • “Co-administer,” “co-administration,” or “combined administration” or the like are meant to encompass administration of the selected therapeutic agents to a single patient, and encompass treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • Combination refers to either a fixed combination of two or more agents (also referred to as co- agents or combination partners), e.g., in one dosage unit form, or a nonfixed combination (or kit of parts) for the combined administration where a first agent (also referred to as a first therapeutic agent) and a second agent (also referred to as a second therapeutic agent) may be administered independently at the same time or separately within time intervals, e.g., where these time intervals allow the combination partners to provide a cooperative, e.g. synergistic effect.
  • combined administration or the like as utilized herein is meant to encompass administration of the selected combination partners to a single subject in need thereof (e.g.
  • fixed combination means that the active ingredients, e.g. combination partners, are both administered to a patient simultaneously in the form of a single dosage.
  • non-fixed combination or “kit of parts” mean that the active ingredients, e.g. combination partners, are provided separately, e.g., within a kit, and/or are both administered to a patient as separate dosage forms either concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • Dose range refers to an upper and a lower limit of an acceptable variation of the amount of therapeutic agent specified.
  • a dose of the agent in any amount within the specified range can be administered to patients undergoing treatment.
  • a “loading dose” may be an initial dose of a drug that may be given at or prior to the beginning of a course of treatment before dropping down to a different, typically lower dose (e.g., a treatment or maintenance dose).
  • a loading dose may be a single dose or short duration regimen of a compound which is administered to the subject to rapidly increase the blood concentration level of the drug.
  • a short duration regimen for use herein will be from: 1 to 14 days; e.g., from 1 to 7 days; e.g., from 1 to 3 days; e.g., for three days; e.g., for two days; e.g., for one PAT059494-WO-PCT day.
  • the “loading dose” can increase the blood concentration of the drug to a therapeutically effective level.
  • the “loading dose” can increase the blood concentration of the drug to a therapeutically effective level in conjunction with a treatment dose of the drug.
  • the “loading dose” can be administered once per day, or more than once per day (e.g., up to 4 times per day).
  • a loading dosage may be used for drug molecules that have a long half-life or slow elimination in vivo.
  • “Pharmaceutical preparation” or “pharmaceutical composition” refers to a mixture or solution containing at least one therapeutic agent suitable to be administered to a warm-blooded animal, e.g., a human.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
  • Subject “patient,” or “warm-blooded animal” is intended to include animals.
  • subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the subject is a human.
  • "Therapeutically effective" preferably relates to an amount of a therapeutic agent that is capable of providing a therapeutic response in a subject or prophylactically effective against the progression of a cancer.
  • a therapeutically effective treatment or amount of treatment need not completely treat a subject, but may partially or completely delay, ameliorate, reverse, or reduce at least one or more signs, symptoms, or manifestations of a disease.
  • Treatment can be prophylactic and/or therapeutic (including but not limited to palliative, symptom-alleviating, symptom-reducing) as well as the delay of progression of a disease or disorder such as cancer.
  • prophylactic means the prevention or delay of the onset or recurrence of a disease such as cancer.
  • delay of progression means administration of the combination to patients being in a pre-stage or in an early phase of the cancer to be treated, a pre-form of the corresponding cancer is diagnosed and/or in a patient diagnosed with a condition under which it is likely that a corresponding cancer will develop.
  • Tumor refers to an abnormal mass of tissue. Tumors may comprise cancer cells. Tumors may be described as benign if they do not spread into or invade nearby tissues or other parts of the body. Tumors may be described as malignant if they spread into other tissues or parts of the body.
  • PK Ctrough and pharmacokinetics
  • the trial will include pre and postmenopausal women and men with HR- positive, HER2-negative EBC, with an Anatomic Stage Group III, IIB or a subset of Stage IIA cases (as defined in Inclusion Criterion #8, see below), after adequate surgical resection, radiotherapy (if indicated), adjuvant or neoadjuvant chemotherapy (if indicated), and who are deemed to be eligible for adjuvant ET for at least 60 months of duration. See FIG.1.
  • Duration of ET in the trial will be 60 months from the randomization date.
  • Control arm • ET: Same as in the Investigational arm. In both arms, ET will be administered according to the local clinical guidelines and current local prescribing information. Subsequent ET (or any other anti-cancer treatment) given after the protocol-required 60 months of ET (or after premature discontinuation of ET in the trial) will be administered according to the Investigator’s clinical judgment and is not considered a trial treatment. Randomization will be stratified by the following factors: • Menopausal status: premenopausal women and men vs. postmenopausal women • AJCC 8 th edition Anatomic Stage Group: Anatomic Stage Group II vs.
  • Anatomic Stage Group III Prior neoadjuvant/adjuvant chemotherapy: yes vs. no • Geographical region: North America/Western Europe/Oceania vs. rest of the world Enrollment of patients with Anatomic Stage Group II is capped at approximately 2,000 patients.
  • the trial will include screening, treatment, and follow up phases.
  • the trial includes an exploratory component that requires collection of tumor and blood samples (except for patients enrolled in China).
  • Eligibility Inclusion Criteria Criteria Patients eligible for inclusion in this trial must meet all of the following criteria: PAT059494-WO-PCT Signed and dated Patient Informed Consent Form (PICF) obtained prior to any trial-specific screening procedure. Patient is ⁇ 18 years-old at the time of PICF signature.
  • PICF Patient Informed Consent Form
  • Postmenopausal status is defined as: • Patient underwent bilateral oophorectomy, or • Age ⁇ 60 years, or • Age ⁇ 60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) and Follicle-stimulating hormone (FSH) and plasma estradiol are in the postmenopausal ranges per local normal ranges. • If taking tamoxifen or toremifene and age ⁇ 60 years, then FSH and plasma estradiol level in postmenopausal ranges.
  • Patient PAT059494-WO-PCT with a multicentric and/or multifocal tumor is eligible if all histopathologically examined lesions meet the pathologic criteria in inclusion criteria 5 and 6.
  • Patient has breast cancer that is positive for ER and/or PgR according to the local laboratory as determined on the most recently analyzed tissue sample.
  • Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0 or 1+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required to confirm the HER2-negative status (based on the most recently analyzed tissue sample tested by a local laboratory).
  • IHC immunohistochemistry
  • Patient after surgical resection where tumor was removed completely, with the final surgical specimen microscopic margins free from tumor, and belongs to one of the following categories: • Anatomic Stage Group III, or • Anatomic Stage Group IIB, or • Anatomic Stage Group IIA that is either: • N1, or • N0, with: • Grade 3, or • Grade 2, with any of the following criteria: • Ki67 ⁇ 20%, or • Oncotype DX Breast Recurrence Score ⁇ 26, or • Prosigna/PAM50 categorized as high risk, or PAT059494-WO-PCT • MammaPrint categorized as high risk, or • EndoPredict EPclin Risk Score categorized as high risk Notes: • For patients whose tumors are Anatomic Stage IIA, N0: • If Grade is 1 or unknown (Gx), patient is not eligible.
  • ALND is the preferred method for axillary lymph node staging, however SLN dissection can be used to determine the N category in the following cases: • No metastasis in SLN (patient is considered as pN0). • Only micrometastasis in SLN (patient is considered as pN1mi). • Patients with T1-2 and no clinically-evident nodes prior to surgery, no neoadjuvant chemotherapy, at least one macrometastasis in 1 or 2 SLNs, no matted nodes or gross extranodal disease at the time of SLN dissection (patient is considered as pN1). In all other cases, ALND is required to determine the N category.
  • patient has completed adjuvant and/or neoadjuvant chemotherapy according to the institutional guidelines, prior to screening. If indicated, patient has completed adjuvant radiotherapy according to the institutional guidelines, prior to screening.
  • Patient has no contraindication for the adjuvant ET in the trial and is planned to be treated with ET for 5 years (since randomization date) or more.
  • Patient may have already received any standard neoadjuvant and/or adjuvant ET at the time of PICF signature, but randomization should occur within 12 months of the initial start date of ET. Ovarian suppression or short term ET for fertility preservation is not considered neoadjuvant/adjuvant ET.
  • Patient has adequate bone marrow and organ function as defined by the following local laboratory values: • Absolute neutrophil count (ANC) ⁇ 1.5 ⁇ 10 9 /L • Platelets ⁇ 100 ⁇ 10 9 /L • Hemoglobin ⁇ 9.0 g/dL • Estimated glomerular filtration rate (eGFR) ⁇ 30 mL/min/1.73m 2 according to the Modification of Diet in Renal Disease (MDRD) formula • Alanine transaminase (ALT) ⁇ 2.5 ⁇ Upper Limit Normal (ULN) • Aspartate transaminase (AST) ⁇ 2.5 ⁇ ULN • Total serum bilirubin ⁇ ULN; or total bilirubin ⁇ 3.0 ⁇ ULN or direct bilirubin ⁇ 1.5 ⁇ ULN in patients with well documented Gilbert’s Syndrome PAT059494-WO-PCT • International normalized ratio (INR) ⁇ 1.5 (unless the patient is receiving anticoagulants and the INR is within the therapeutic range of intended use for
  • CBP Women of childbearing potential
  • ⁇ -hCG negative serum pregnancy test
  • Women of CBP must be willing to use highly effective methods of contraception. Contraception must continue during the trial treatment and for 21 days after stopping the treatment.
  • Highly effective contraception methods include: • Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
  • PAT059494-WO-PCT Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking trial treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. • Male partner sterilization (at least 6 months prior to randomization). For female patients on the trial the vasectomized male partner should be the sole partner for that patient. If vasectomy of the male partner is the highly effective method of contraception chosen, the success of the vasectomy should be medically confirmed according to local practice. • Placement of an intrauterine device (IUD).
  • IUD intrauterine device
  • Atient with a known hypersensitivity to any of the excipients of ribociclib and/or ET e.g. rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption, and soy allergy.
  • atient is concurrently using other anti-neoplastic therapy with the exception of adjuvant ET (see Inclusion Criterion #12). atient has had major surgery, chemotherapy or radiotherapy within 14 days prior to randomization.
  • Atient has not recovered from clinical and laboratory acute toxicities related to prior anti-cancer therapies to a NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03 Grade ⁇ 1 at day of randomization. Exceptions to this criterion: patients with any grade of alopecia, amenorrhea, grade 2 neuropathy are allowed to enter the trial or other toxicities not considered a safety risk for the patient as per Investigator’s discretion, are allowed to enter the trial. atient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 2 years before randomization. Note: Patients with adequately treated, basal or squamous cell skin carcinoma or curatively resected cervical cancer in situ are eligible.
  • PAT059494-WO-PCT atient has known history of human immunodeficiency virus (HIV) infection (testing is not mandatory, unless required by local regulation). atient has known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is not mandatory, unless required by local regulation). linically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following: • History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to trial entry. • Documented cardiomyopathy.
  • MI myocardial infarction
  • angina pectoris symptomatic pericarditis
  • coronary artery bypass graft within 6 months prior to trial entry.
  • LVEF Left Ventricular Ejection Fraction
  • MUGA Multiple Gated acquisition
  • ECHO echocardiogram
  • TdP Risk factors for Torsades de Pointes
  • Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication e.g. within 5 half-lives or 7 days prior to starting trial treatment.
  • corticosteroids are permitted: a short duration ( ⁇ 5 days) of systemic corticosteroids; any duration of topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airways diseases), eye drops or local injections (e.g. intra-articular).
  • Atient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the oral trial treatments (e.g. uncontrolled ulcerative diseases, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, or small bowel resection). atient has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease, active untreated or uncontrolled fungal, bacterial or viral infections, active infection requiring systemic anti- bacterial therapy, etc.) or limit life expectancy to ⁇ 5 years.
  • GI gastrointestinal
  • Efficacy assessments Efficacy assessment for the primary endpoint of iDFS will include detection of locoregional relapse, distant relapse, ipsilateral and contralateral invasive BC, second primary invasive non-BCs and deaths. Assessments for events of recurrence will be done clinically every 12 weeks ( ⁇ 2 weeks) for the first 24 months from randomization and every 24 weeks ( ⁇ 3 weeks) thereafter. Mammography will be done annually.
  • PAT059494-WO-PCT Use of subsequent anti-cancer therapy, time to first subsequent anti- cancer therapy and healthcare resources utilization will be evaluated for each arm.
  • PK assessments Approximately 130 patients from the Investigational arm will be part of the PK subset. Plasma samples for ribociclib determination will be obtained pre- and post-dose on C1D15.
  • Statistical The primary efficacy analysis will be the comparison of the distribution of Methods iDFS between the two treatment arms using a stratified log-rank test at one-sided 2.5% level of significance, using strata information at the time of randomization.
  • iDFS Distribution of iDFS will be estimated using the Kaplan- Meier method.
  • the iDFS at the end of each year along with 95% confidence intervals will be presented for each of the two treatment arms.
  • the stratified Cox regression will be used to estimate the hazard ratio of iDFS, along with 95% confidence interval, using strata information as per IRT at the time of randomization.
  • RESULTS Overview of results Results from an interim analysis of the NATALEE trial: Kisqali plus endocrine therapy (ET) significantly reduced the risk of disease recurrence compared to standard ET alone in the adjuvant setting.
  • NATALEE is the first and only positive Phase III study of a CDK4/6 inhibitor demonstrating consistent benefit in a broad population of patients with stage II and III HR+/HER2- early breast cancer (EBC) at risk of recurrence, including those with no nodal involvement.
  • the primary endpoint of invasive disease-free survival (iDFS) has been met. Kisqali plus ET significantly reduced the risk of disease recurrence, compared to standard adjuvant ET alone, with consistent benefit in patients with stage II and stage III EBC regardless of nodal involvement.
  • the 400mg ribociclib dose demonstrated an improved profile with less overall toxicity, particularly dose- dependent adverse events (cardiac QT interval & neutropenia).
  • dose-dependent adverse events cardiac QT interval & neutropenia
  • the iDFS benefit was consistent across stratification factors and other subgroups. Secondary endpoints of overall survival, recurrence-free survival, and distant disease-free survival were consistently in favor of the RIB+ET arm.
  • addition of RIB had a favorable safety profile with no new signals.
  • addition of RIB to the standard-of-care ET demonstrated a statistically significant and clinically meaningful improvement in iDFS, with a well-tolerated safety profile.
  • the combined therapy can therefore be seen as suitable for use in a broad population of patients who have stage II or stage III HR+/HRE2- early breast cancer, including N0 patients whose cancer has not spread to nearby lymph nodes. This is unexpected based on the results of other parallel studies.
  • Assessment of Health-Related Quality of Life (HRQOL) in NATALEE QoL was analyzed after a median follow-up of 34 months. About 20% of patients had completed 3 years of ribociclib plus endocrine therapy.
  • HRQOL The prespecified analysis of HRQOL was based on patient-reported outcomes based on a number of survey instruments: the EORTC QLQ-C30 (European Organisation for Research and PAT059494-WO-PCT Treatment of Cancer Quality-of-Life questionnaire) for function (physical, social, and emotional) and global health status; EORTC QLQ-BR23 for breast cancer symptoms; the EQ-VAS (Euro- QoL visual analog scale) of the EQ-5D-5L; and the Hamilton Anxiety and Depression Scale (See also FIGS.5-8 for exemplary questionaires).
  • the HRQOL of patients with HR+/HER2 ⁇ EBC was maintained with the addition of ribociclib to standard-of-care adjuvant NSAI vs NSAI alone.
  • Kisqali iDFS benefit across pre-specified subgroups PAT059494-WO-PCT Kisqali data across all secondary efficacy endpoints was also consistent, including distant disease-free survival (DDFS) (25.1% risk reduction) and recurrence-free survival (RFS) (27.3% risk reduction). With fewer than 4% of events in both treatment arms (3.3% in the Kisqali-ET arm and 3.4% in the ET only arm), overall survival (OS) results will continue to evolve in the longer term. The safety profile of Kisqali at the 400 mg dose remained consistent with previously reported results, with generally low-grade adverse events (AEs), other than laboratory abnormalities.
  • AEs adverse events
  • AEs of special interest were neutropenia (44.3%), liver-related AEs (e.g., elevated transaminases) (8.6%), and QT interval prolongation (1.0%)1,2. No new safety signals were identified.
  • BC Approximately 1.7 million new cases of BC and 522,000 deaths attributed to BC were estimated to occur in 2012 worldwide. In the United States, BC was projected to be the most common cancer diagnosed in 2018 with an estimated incidence of 268,670 new cases and 41,400 deaths. Based on Surveillance, Epidemiology, and End Results Program (SEER) data collected between years 1975 and 2012, 93% of cases of BC diagnosed were EBC, with 62% limited to the breast tissue and 31% localized within the breast tissue and regional lymph nodes. Although many patients with EBC may be rendered disease-free with local treatments, distant recurrence due to micro-metastatic disease is common and is the primary cause of death in patients with EBC.
  • SEER End Results Program
  • BC BC express receptors for steroid hormones (estrogen receptor [ER] and/or progesterone receptor [PgR]), and therefore may benefit from adjuvant endocrine therapy (ET) with tamoxifen or aromatase inhibitors (AI) (letrozole, anastrozole or exemestane). ET, independent of chemotherapy, reduces the risk of recurrence and BC deaths in HR-positive EBC.
  • ER estrogen receptor
  • PgR progesterone receptor
  • ET adjuvant endocrine therapy
  • AI aromatase inhibitors
  • ET independent of chemotherapy, reduces the risk of recurrence and BC deaths in HR-positive EBC.
  • the ET should be combined with a luteinizing hormone-releasing hormone agonist. Rationale for conducting the trial and for trial design While adjuvant ET for HR-positive EBC is effective in reducing risk of recurrence and improving survival, recurrences are still common, especially in patients with features indicative of an intermediate or high risk of recurrence, like those with Anatomic Stage Groups II and III, among other features.
  • the addition of the CDK4/6 inhibitor ribociclib to ET has proven clinical efficacy with tolerable toxicity profile in HR-positive, HER2-negative advanced BC; therefore, the addition of ribociclib in the adjuvant setting may prolong invasive disease-free survival (iDFS) in patients with HR- positive, HER2-negative EBC with intermediate and high risk for recurrence, by enhancing primary endocrine responsiveness and preventing or delaying the development of acquired resistance for ET.
  • iDFS invasive disease-free survival
  • ribociclib will be administered at a dose of 400 mg once daily for 3 weeks on/1 week off.
  • the 400 mg ribociclib dose has consistent efficacy (based on post hoc exploratory analyses) and a potentially improved safety profile in terms of QTc prolongation and hematologic toxicity, as compared with the standard 600 mg dose, so it is expected to be well tolerated for the proposed 3 year treatment duration.
  • neoplastic therapy To explore use of subsequent anti- Incidence of subsequent anti- neoplastic therapy neoplastic therapy and time to first subsequent anti-neoplastic therapy 3. To explore healthcare resource Number of patients hospitalized, utilization total number of hospitalizations, and length of stay in hospitals, number of patients with Emergency Room and additional visits 4. To explore prognostic and Assessment of expression and predictive biomarkers of treatment alterations of genes related but not with ribociclib and ET limited to CDK and ER pathways in baseline tumor and circulating tumor (ct) DNA and ctRNA samples, and their correlation with efficacy endpoints Expression of markers such as Ki67 by immunochemistry may be evaluated 5.
  • iDFS is the primary endpoint of the trial, as defined per the STEEP System.
  • the trial will include pre and postmenopausal women and men with HR- positive, HER2-negative EBC, with an Anatomic Stage Group III, IIB or a subset of Stage IIA cases (as defined in Inclusion Criterion #8), after adequate surgical resection, radiotherapy (if indicated), adjuvant or neoadjuvant chemotherapy (if indicated), and who are deemed to be eligible for adjuvant ET for at least 60 months of duration. See FIG.1.
  • Control arm • ET: Same as in the Investigational arm. In both arms, ET will be administered according to the local clinical guidelines and current local prescribing information. Subsequent ET (or any other anti-cancer treatment) given after the protocol-required 60 months of ET (or after premature discontinuation of ET in the trial) will be administered according to the Investigator’s clinical judgment and is not considered a trial treatment. Randomization will be stratified by the following factors: • Menopausal status: premenopausal women and men vs. postmenopausal women • AJCC 8 th edition Anatomic Stage Group: Anatomic Stage Group II vs. Anatomic Stage Group III • Prior neoadjuvant/adjuvant chemotherapy: yes vs.
  • PAT059494-WO-PCT Enrollment of patients with Anatomic Stage Group II is capped at approximately 2,000 patients.
  • the trial will include screening, treatment, and follow up phases.
  • the trial includes an exploratory component that requires collection of tumor and blood samples (except for patients enrolled in China).
  • Eligibility Inclusion Criteria Criteria Patients eligible for inclusion in this trial must meet all of the following criteria: 1. Signed and dated Patient Informed Consent Form (PICF) obtained prior to any trial-specific screening procedure. 2.
  • Patient is ⁇ 18 years-old at the time of PICF signature. 3.
  • Postmenopausal status is defined as: • Patient underwent bilateral oophorectomy, or • Age ⁇ 60 years, or • Age ⁇ 60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) and Follicle-stimulating hormone (FSH) and plasma estradiol are in the postmenopausal ranges per local normal ranges. • If taking tamoxifen or toremifene and age ⁇ 60 years, then FSH and plasma estradiol level in postmenopausal ranges.
  • Patient PAT059494-WO-PCT with a multicentric and/or multifocal tumor is eligible if all histopathologically examined lesions meet the pathologic criteria in inclusion criteria 5 and 6.
  • Patient has breast cancer that is positive for ER and/or PgR according to the local laboratory as determined on the most recently analyzed tissue sample.
  • Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0 or 1+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required to confirm the HER2-negative status (based on the most recently analyzed tissue sample tested by a local laboratory).
  • IHC immunohistochemistry
  • Patient after surgical resection where tumor was removed completely, with the final surgical specimen microscopic margins free from tumor, and belongs to one of the following categories: • Anatomic Stage Group III, or • Anatomic Stage Group IIB, or • Anatomic Stage Group IIA that is either: • N1, or • N0, with: • Grade 3, or • Grade 2, with any of the following criteria: • Ki67 ⁇ 20%, or • Oncotype DX Breast Recurrence Score ⁇ 26, or • Prosigna/PAM50 categorized as high risk, or • MammaPrint categorized as high risk, or • EndoPredict EPclin Risk Score categorized as high risk Notes: • For patients whose tumors are Anatomic Stage IIA, N0: • If Grade is 1 or unknown (Gx), patient is not eligible.
  • ALND is the preferred method for axillary lymph node staging, however SLN dissection can be used to determine the N category in the following cases: • No metastasis in SLN (patient is considered as pN0). • Only micrometastasis in SLN (patient is considered as pN1mi). • Patients with T1-2 and no clinically-evident nodes prior to surgery, no neoadjuvant chemotherapy, at least one macrometastasis in 1 or 2 SLNs, no matted nodes or gross extranodal disease at the time of SLN dissection (patient is considered as pN1). In all other cases, ALND is required to determine the N category.
  • patient has completed adjuvant and/or neoadjuvant chemotherapy according to the institutional guidelines, prior to screening. If indicated, patient has completed adjuvant radiotherapy according to the institutional guidelines, prior to screening.
  • Patient has no contraindication for the adjuvant ET in the trial and is planned to be treated with ET for 5 years (since randomization date) or more.
  • Patient may have already received any standard neoadjuvant and/or adjuvant ET at the time of PICF signature, but randomization should occur within 12 months of the initial start date of ET. Ovarian suppression or short term ET for fertility preservation is not considered neoadjuvant/adjuvant ET.
  • CBP Women of childbearing potential
  • ⁇ -hCG negative serum pregnancy test
  • Women of CBP must be willing to use highly effective methods of contraception. Contraception must continue during the trial treatment and for 21 days after stopping the treatment.
  • Highly effective contraception methods include: • Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
  • Patients eligible for this trial must not meet any of the following criteria: 1. Patient has received any CDK4/6 inhibitor. 2. Patient has received prior treatment with tamoxifen, raloxifene or AIs for reduction in risk (“chemoprevention”) of breast cancer and/or treatment for osteoporosis within the last 2 years prior to randomization. Patient is concurrently using hormone replacement therapy. 3. Patient has received prior treatment with anthracyclines at cumulative doses of 450 mg/m2 or more for doxorubicin, or 900 mg/m2 or more for epirubicin. 4.
  • Patient has known history of human immunodeficiency virus (HIV) infection (testing is not mandatory, unless required by local regulation).
  • Patient has known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is not mandatory, unless required by local regulation).
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality including any of the following: • History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to trial entry. • Documented cardiomyopathy.
  • LVEF Left Ventricular Ejection Fraction
  • MUGA Multiple Gated acquisition
  • ECHO echocardiogram
  • TdP Risk factors for Torsades de Pointes
  • Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication e.g. within 5 half-lives or 7 days prior to starting trial treatment.
  • PAT059494-WO-PCT Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade Atrioventricular (AV) block (e.g. bifascicular block, Mobitz type II and third degree AV block).
  • AV Atrioventricular
  • Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the oral trial treatments (e.g. uncontrolled ulcerative diseases, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, or small bowel resection).
  • GI gastrointestinal
  • Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease, active untreated or uncontrolled fungal, bacterial or viral infections, active infection requiring systemic anti- bacterial therapy, etc.) or limit life expectancy to ⁇ 5 years.
  • GI gastrointestinal
  • Efficacy assessments Efficacy assessment for the primary endpoint of iDFS will include detection of locoregional relapse, distant relapse, ipsilateral and contralateral invasive BC, second primary invasive non-BCs and deaths. Assessments for events of recurrence will be done clinically every 12 weeks ( ⁇ 2 weeks) for the first 24 months from randomization and every 24 weeks ( ⁇ 3 weeks) thereafter. Mammography will be done annually.
  • Use of subsequent anti-cancer therapy, time to first subsequent anti- cancer therapy and healthcare resources utilization will be evaluated for each arm.
  • PK assessments Approximately 130 patients from the Investigational arm will be part of the PK subset. Plasma samples for ribociclib determination will be obtained pre- and post-dose on C1D15. Exploratory biomarkers assessment PAT059494-WO-PCT Tumor tissue samples will be collected (except for patients enrolled in China) to identify biomarkers that may be predictive of benefit from ribociclib and to assess molecular alterations of genes shown to be associated with HR-positive BC and the cell cycle.
  • a mandatory archival paraffin tumor tissue from the curative surgery specimen is required from all patients (except for patients enrolled in China). If available, an additional tumor tissue sample collection is requested from the biopsy specimen of the tumor at the time of the initial diagnosis or before the administration of neoadjuvant chemotherapy (if administered). An additional tumor biopsy collection is mandatory at the time of recurrence (unless unsafe for the patient per Investigator’s discretion), for identifying potential biomarkers and exploring mechanisms underlying disease recurrence (except for patients enrolled in China).
  • Mandatory blood samples for ctDNA/ctRNA will be collected at baseline, at regular intervals until distant recurrence and at time of recurrence (except for patients enrolled in China).
  • Optional blood samples for pharmacogenetic analysis will be collected in patients that consent to this (except for patients enrolled in China).
  • additional biomarker analyses are planned.
  • Statistical The primary efficacy analysis will be the comparison of the distribution of Methods iDFS between the two treatment arms using a stratified log-rank test at one-sided 2.5% level of significance, using strata information at the time of randomization. Distribution of iDFS will be estimated using the Kaplan- Meier method. The iDFS at the end of each year along with 95% confidence intervals will be presented for each of the two treatment arms.
  • the stratified Cox regression will be used to estimate the hazard ratio of iDFS, along with 95% confidence interval, using strata information as per IRT at the time of randomization.
  • Three interim efficacy analyses are planned.
  • the first interim analysis that allows the trial to stop for futility (non-binding), is planned after approximately 40% iDFS events (approximately 200 events) are documented. No efficacy will be declared in the first interim analysis.
  • the second and third interim analyses, that allow the trial to stop for superior efficacy are planned after all patients have been randomized and PAT059494-WO-PCT approximately 70% and 85% iDFS events (approximately 350 and 425 events) are documented, respectively.
  • the Final Analysis for iDFS will be performed after approximately 500 iDFS events have been documented, if the trial fails to stop at the interim analyses.
  • the sample size calculation is based on the primary variable, iDFS.
  • the 5-year iDFS rate for the patients with Anatomic Stage II (excluding low risk patients) is assumed to be approximately 79% (based on data from a retrospective study assessing the prognostic effect of Ki67 and other disease characteristics in HR-positive, HER2-negative EBC) and 72% for patients with Anatomic Stage III (based on data for patients with ⁇ 4 lymph nodes treated with AIs in the EBC Trialists’ Collaborative Group meta-analysis).
  • the overall 5-year iDFS of the control arm is expected to be approximately 74.8%. It is expected that treatment with ribociclib in addition to standard ET will result in a 27% reduction in the hazard rate for iDFS, i.e. an expected hazard ratio of 0.73. 500 iDFS events will provide a power of approximately 93% and 85% when the overall hazard ratio is 0.73 and 0.76, respectively. Assuming a 15% dropout rate by the time of the final iDFS analysis (i.e. dropout hazard rate of 0.00629 per month), a total of 5,000 patients will need to be randomized including approximately 3,000 Anatomic Stage III patients.
  • BC Breast cancer
  • 1 BC incidence varies between individuals of different ethnicities and in different geographic locations around the world, with rates ranging from 27 per 100,000 in Middle Africa and Eastern Asia to 92 in Northern America.
  • 3 Estimated incidence of BC in European countries in 2012 was 458,337. 4 BC in men is not common, with a reported frequency of approximately 1% of all BC but its incidence is continuously rising.
  • EBC early breast cancers
  • SEER Epidemiology and End Results
  • EBC Trialists Collaborative Group (EBCTCG) meta-analysis of almost 150,000 women in 200 randomized clinical trials, approximately 36% and 20% of patients with EBC without any adjuvant systemic therapy will experience recurrence and death due to BC, respectively, during 5 years of follow-up.
  • EBCTCG Collaborative Group
  • recurrences and BC-related deaths in patients with hormone receptor (HR)-positive EBC continue to occur after 5 years from surgery, with only 45% of patients reported to be recurrence-free at 15 years of follow-up.
  • HR hormone receptor
  • Adjuvant systemic treatments that comprise cytotoxic, biological and endocrine therapies in patients with EBC decrease locoregional and distant recurrences, decrease BC-specific mortality and improve overall survival (OS). 8
  • the need and selection of systemic adjuvant therapies is based on individual risk of recurrence and is guided by several clinical, pathological and genomic predictive and prognostic factors of tumor and patient such as tumor stage, histopathological grade, tumor HR status, human epidermal growth factor receptor-2 (HER2) PAT059494-WO-PCT status, multi-gene testing recurrence scores, proliferation markers like Ki67, menopausal status, patient’s comorbidities, age, and others.
  • EBC can be classified as having low, intermediate/moderate or high risk for recurrence after surgery. 7 While there is no consensus on the definition of these risk groups, generally, patients with smaller tumors, no metastasis in regional lymph nodes, low tumor grade, HR-positive and HER2-negative status, and low recurrence genomic score have low risk of recurrence (i.e.5-10% recurrences at 5- years). These patients are usually considered for adjuvant endocrine therapy (ET), without chemotherapy, due to a lower clinical benefit of latter versus the former.
  • ETD adjuvant endocrine therapy
  • Luminal A subtype tumors also have loss of CDKN2A, which encodes p16 INK4A , a CDK inhibitor.
  • the luminal subtypes also maintain expression of Rb, which is essential for benefit from treatment with a CDK4/6 inhibitor.
  • Dysregulation of cell cycle checkpoints may have clinical and therapeutic significance. For example, patients with HR-positive BC exhibiting a gene expression signature of Rb loss had a shorter recurrence-free survival (RFS) following adjuvant tamoxifen.
  • RFS recurrence-free survival
  • a tumor gene expression signature of E2F activation is also associated with higher residual tumor cell proliferation following neoadjuvant AI therapy.
  • CDK4/6-Rb-E2F pathway promotes endocrine resistance
  • treatment with a CDK4/6 inhibitor or knockdown of CDK4 expression leads to reactivation of Rb, binding back of E2F and subsequent cell cycle arrest, thus abrogating endocrine-resistant cell proliferation.
  • CDK4/6 selective inhibitors of CDK4/6, such as palbociclib, abemaciclib and ribociclib, demonstrated synergy with ET in preclinical studies and efficacy in clinical studies and have been approved as initial therapy (in combination with an AI) or after disease progression following prior ET (in combination with fulvestrant) in patients with HR-positive, HER2-negative advanced BC 21–26 (refer to the most recent ribociclib Investigator’s Brochure (IB) for more information about the efficacy of ribociclib).
  • IB Brochure
  • ribociclib is absorbed with median T max of 4.00 h (range: 0.58 to 4.20 h). Following repeated daily oral administration, steady-state of ribociclib was achieved by approximately Day 8. At the steady state, geometric mean of ribociclib plasma C max was 1040 ng/mL (geometric coefficient of variation [CV] 49.3%) and AUC 0-24h was 11400 ng*h/mL (geometric CV 57.8%). The geometric mean of effective T 1/2 of ribociclib was 31.6 h (geometric CV 33.2%) and accumulation ratio was 2.46 (geometric CV 24.6%).
  • LEQ803 an active metabolite of ribociclib, has similar PK characteristics as parent drug. Neither ribociclib nor LEQ803 accumulate substantially following repeated daily administration. Ribociclib undergoes extensive hepatic metabolism via CYP3A in humans based on in vitro and in vivo studies. Ribociclib is mainly eliminated via hepatic clearance, with renal clearance playing a lesser role in humans. The majority of the administered dose was excreted in feces (69.1%), with a minor amount excreted in urine (22.6%). Ribociclib accounted for approximately 23% of the total radioactivity in plasma (CLEE011A2102).
  • the most prominent metabolites in plasma are CCI284 (N-hydroxylation), LEQ803 (N-demethylation), and M1 (secondary glucuronide), each representing ⁇ 10% of total radioactivity.
  • the clinical activity (pharmacological and safety) following ribociclib treatment is primarily due to parent drug, with a negligible contribution from circulating metabolites.
  • Concomitant use of ribociclib with strong CYP3A4 inhibitors or strong CYP3A4 inducers should be avoided as ribociclib exposure may be markedly affected.
  • Co-administration of a strong CYP3A4 inhibitor increased ribociclib AUC inf by 3.2-fold following a single oral dose of 400 mg ribociclib (CLEE011A2101).
  • Co-administration of a strong CYP3A4 inducer decreased ribociclib AUC inf by 89% following a single oral dose of 600 mg ribociclib (CLEE011A2101).
  • Ribociclib is a moderate to strong inhibitor of CYP3A4, but did not have a substantial effect on CYP1A2 substrates in humans (CLEE011A2106).
  • letrozole, anastrozole and steroidal AI i.e. exemestane
  • exemestane i.e. exemestane
  • AIs can be used either as an upfront therapy or after 2-3 or 5 years of prior tamoxifen (see Section 1.1.2).
  • the long-term efficacy of both approaches of AIs administration is similar.
  • 30 Clinical treatment guidelines suggest that there is no compelling evidence showing meaningful clinical efficacy or toxicity differences between letrozole, anastrozole and exemestane, therefore similar precautions and monitoring activities should apply irrespective of type of AI administered.
  • 11 GnRH agonists are used to achieve gonadal suppression in premenopausal women or men. The following sections provide general information on NSAI and goserelin.
  • Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system. Letrozole acts by highly selective inhibition of conversion of androgens (mainly from adrenal glands, the primary source of estrogens in postmenopausal women) to estrogens. Letrozole induces a 75% to 95% decrease of estrogen levels after two weeks of treatment with daily doses of 0.1 to 5 mg, with no significant clinical and laboratory toxicities or changes in levels of other hormones of the endocrine system. 31, 32 Letrozole is administered orally once daily at a dose of 2.5 mg.
  • AE adverse events
  • Anastrozole Anastrozole like letrozole, is a selective NSAI. It significantly lowers serum estradiol concentrations with no detectable effect on formation of adrenal corticosteroids or aldosterone. Anastrozole is administered orally once daily at a dose of 1 mg, taken with or without food. Anastrozole is metabolized by N-dealkylation, hydroxylation and glucuronidation. Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Renal elimination accounts for approximately 10% of total clearance. The major circulating metabolite of anastrozole lacks pharmacologic activity. Anastrozole metabolism occurs mainly via CYP3A4 and UGT1A4 based on in vitro data.
  • GnRH agonists are synthetic analogues of gonadotropin-releasing hormone that by continuous stimulation of the GnRH receptor achieve desensitization of the pituitary gland to GnRH.
  • GnRH agonists differ from the naturally-occurring GnRH by modifications in the decapeptide structure (usually by amino acid substitution in position 6, but also in positions 9 and 10) to decrease degradation of the molecule.
  • Goserelin is the GnRH agonist to be used in this trial.
  • the most common AEs occurring in women treated with goserelin includes hot flushes, headache, sweating, acne, emotional liability, depression, decreased libido, vaginitis, breast atrophy, seborrhea and peripheral edema.
  • goserelin can be associated with hot flushes, sexual dysfunction, decreased erections and lower urinary tract symptoms.
  • ribociclib has proven clinical efficacy with tolerable toxicity profile in HR- positive, HER2-negative advanced BC; therefore, the addition of ribociclib in the adjuvant setting may prolong invasive disease-free survival (iDFS) in patients with HR-positive, HER2- negative EBC with intermediate and high risk for recurrence, by enhancing primary endocrine responsiveness and preventing or delaying the development of acquired resistance to ET.
  • iDFS invasive disease-free survival
  • Adjuvant ET in the trial will be NSAI (letrozole, anastrozole) for postmenopausal women and NSAI combined with goserelin in premenopausal women and men.
  • NSAI letrozole, anastrozole
  • the randomized, stratified, multicenter design of this trial minimizes allocation bias, balancing both known and unknown prognostic factors in the assignment of treatments.
  • Appropriate adjudication of outcomes, especially the primary endpoint is of critical importance to the validity of trial results in this open-label trial.
  • the primary endpoint chosen is objective (iDFS), and a standardized definition will be used (per STEEP System for Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials).
  • iDFS events will not only be based on clinical or radiological assessments but also will be confirmed histologically or cytologically (unless there is an unacceptable risk to the patient due to the procedure), therefore requiring an objective confirmation to consider a recurrence as an iDFS event.
  • assessment for recurrence should continue until distant relapse per STEEP criteria. All these elements support the validity and objectiveness of the underlying recurrence assessment for the iDFS endpoint and ensure that the results of the trial would not be affected by the open-label design.
  • PAT059494-WO-PCT The trial will include pre and postmenopausal women and men with HR-positive, HER2-negative EBC, with an Anatomical Stage Group (according to AJCC 8 th edition) III, IIB or a subset of Stage IIA cases (as defined in Inclusion Criterion #8).
  • Anatomic Stage Groups include (mostly) tumors with metastatic regional lymph nodes and/or large primary lesions, which have increased risk of recurrence despite ET in which the addition of ribociclib could be of higher benefit.
  • Ki67 or gene expression tests will be used (if these are available) to identify patients with node- negative Anatomic Stage IIA and histological grade 2, that are considered of higher risk.
  • Ki67 index suffers from poor reproducibility, it is commonly used globally for the estimation of prognosis and guiding the decision on adjuvant treatment choice in ER-positive, HER2-negative EBC.
  • cut-offs used to define a high Ki67 index, its prognostic or predictive value has been demonstrated in a number of studies. 37 The 20% cut-off has been identified as an appropriated to stratify high-risk patients in ER-positive, HER2-negative EBC.
  • Anatomic Stage Group III Based on emerging data from other CDK4/6 inhibitor EBC trials that suggest an increased treatment benefit in Anatomic Stage Group III patients, the number of patients with Stage II disease is capped at approximately 2,000, out of a total study population of approximately 5,000 patients. Both pre and postmenopausal women will be included since differences in efficacy and safety of ribociclib are not expected in these populations. To mitigate potential differences in clinical outcomes between pre and postmenopausal women, stratification by menopausal status will be employed. Categorization into the AJCC 8 th edition Anatomic Stage Groups requires determination of the T, N and M categories.
  • Axillary lymph node dissection is the preferred method for axillary lymph node staging; however sentinel lymph node (SLN) dissection can be used to determine the N-category in certain patients (see Inclusion Criterion #8). SLN dissection without subsequent ALND in case of positive SLN became acceptable practice in selected patients following the results of the ACOSOG Z0011 clinical trial where patients with metastatic SLN were randomized to either ALND or no additional surgery.
  • Premenopausal women will be combined with men in the same stratum since both men and premenopausal women may have higher recurrence rate compared to postmenopausal women and the number of men expected is too small to make it as a separate stratum.
  • neoadjuvant or adjuvant chemotherapy decreases recurrences in HR- positive EBC (with no significant difference between adjuvant and neoadjuvant chemotherapy regarding recurrence-free survival)
  • randomization will also be stratified according to whether or not the patient has received any prior neoadjuvant/adjuvant chemotherapy.
  • the primary efficacy of the investigational intervention will be evaluated by its effect on the iDFS as it is defined in the STEEP (Standardized Definitions for Efficacy End Points) System. 35
  • the definition of iDFS in the STEEP System is broad, clinically-relevant and includes the most commonly accepted DFS events used in published trials for EBC. 1.3.3. Rationale for Regimen and Dose Selection Ribociclib at a dose of 600 mg daily from Days 1 to 21 of a 28-day cycle has been the regimen shown to be tolerable and efficacious when combined with ET in clinical trials in patients with advanced BC (see Section 1.2.1.2).
  • ribociclib in combination with ET will be administered for 36 months at a dose of 400 mg daily on Days 1-21 of a 28-day cycle. This schedule and duration of ribociclib therapy should be sufficient to detect a meaningful impact of the recurrence rate.
  • PK-QTcF PK-QT Interval in the ECG corrected according to the formula of Fridericia
  • PK- ANC PK-Absolute Neutrophil Count
  • Table A1 Estimated C max and Mean QTcF Change From Baseline at Different Dose Regimens of Ribociclib.
  • R ibociclib dosing regimen Estimated geometric mean Estimated mean ⁇ QTcF (msec) C max (ng/mL) (90% CI) of ribociclib + NSAI a 600 mg QD 3 weeks on/1 week 1870 22.6 (21.06, 24.06) off (approved dosing regimen) 400 mg QD 3 weeks on/1 week 1080 18.9 (17.65, 20.11) off aEstimated by PK-QT model based on the pop-PK model predicted C max,ss .
  • Table A2 Median PFS by Ribociclib Dose Reduction and Placebo Trial Ribociclib 600 mg Ribociclib 600 Ribociclib 600 mg to Placebo mg to 400 mg 400 mg to 200 mg MONALEESA-2 27.7 months 24.9 months 27.6 months 16.0 months MONALEESA-3 18.8 months 22.1 months NE* 12.8 months PAT059494-WO-PCT MONALEESA-7 22.1months 24.7months 27.5 months 13.0 months *NE: Not Estimable Table A3: ORR by Ribociclib Dose Reduction and Placebo Trial Ribociclib 600 mg Ribociclib 600 Ribociclib 600 Placebo mg to 400 mg mg to 400 mg to 200 mg MONALEESA-2 35.1 (27.9, 42.3) 44.0 (34.3, 53.7) 60.3 (48.2, 72.4) 28.7 (23.9, 33.6) MONALEESA-3 29.8 (24.7, 35.0) 33.6 (25.7, 41.5) 41.9 (24.6, 59.3) 21.5
  • a ribociclib 400 mg dose may be associated with less toxicity (e.g. lower ⁇ QTcF, lower incidence of neutropenia and possibly other adverse events) than the 600 mg dose, while having the potential to provide efficacy (in terms of PFS and ORR).
  • the ribociclib 400 mg daily dose (400 mg once-daily 3 weeks on/1 week off), with dose reductions to 200 mg if needed based on severity of toxicity, will be investigated as a starting dose in this trial.
  • 1.3.4. Rationale for Choice of Combination Drugs Ribociclib will be combined with standard ET approved for adjuvant treatment of EBC and will include NSAI, either letrozole or anastrozole. In premenopausal women and men, ET will include gonadal suppression by goserelin that will be administered every 4 weeks subcutaneously.
  • Goserelin will be administered every 4 weeks subcutaneously.
  • One-month depot formulation of goserelin must be used to suppress gonadal function in this trial (both for PAT059494-WO-PCT women and men) as the 3-month depot formulations do not reliably suppress estrogen levels in all female patients.
  • 11 1.3.6. Risks and Benefits Based on preclinical and clinical data, treatment of ribociclib in combination with ET is expected to be tolerable and toxicities of the treatment are expected to be manageable and reversible with treatment interruption, ribociclib dose reduction, or discontinuation. Patients in this trial will be carefully monitored for key toxicities that have been observed with ribociclib (refer to the latest ribociclib IB) or ETs (see Section 1.2.2).
  • LRRFS defined as time from date of arms with respect to loco-regional randomization to date of first event of recurrence-free survival (LRRFS) local invasive breast recurrence, regional invasive recurrence or death due to any cause 2.
  • LRRFS defined as time from date of arms with respect to loco-regional randomization to date of first event of recurrence-free survival (LRRFS) local invasive breast recurrence, regional invasive recurrence or death due to any cause 2.
  • LRRFS defined as time from date of arms with respect to loco-regional randomization to date of first event of recurrence-free survival (LRRFS)
  • LRRFS defined as time from date of arms with respect to loc
  • Trial Design 3.1 Overall Trial Design This is a phase III, multicenter, randomized, open-label trial to evaluate efficacy and safety of ribociclib with ET as an adjuvant treatment in women and men with HR-positive, HER2-negative EBC. iDFS is the primary endpoint of the trial, as defined per the STEEP System.
  • the trial will include pre and postmenopausal women and men with HR-positive, HER2-negative EBC, with an AJCC 8 th edition Anatomic Stage Group III, IIB or a subset of Stage IIA cases (as defined in Inclusion Criterion #8), after adequate surgical resection, radiotherapy (if indicated), adjuvant or neoadjuvant chemotherapy (if indicated), and who are deemed to be eligible for adjuvant ET for at least 60 months from the date of randomization. Patients who previously started any standard neoadjuvant/adjuvant ET are included in the trial provided that the ET was started within 12 months prior to randomization.
  • PAT059494-WO-PCT The trial will include the following phases: • Screening Phase • Treatment Phase • Following-up Phase Refer to 1 for the trial design schema and to Section 6.3 for a detailed description of the trial phases. Approximately 5,000 patients will be randomized at a 1:1 ratio (through an Interactive Response Technology system [IRT]) using the following stratification factors: • Menopausal status: premenopausal women and men vs. postmenopausal women • AJCC 8 th edition Anatomic Stage Group: Anatomic Stage Group II vs. Anatomic Stage Group III • Prior neoadjuvant/adjuvant chemotherapy: yes vs. no • Geographical region: North America/Western Europe/Oceania vs.
  • IRT Interactive Response Technology system
  • Randomized patients will receive, starting from Cycle 1 Day 1 (C1D1) either: • Investigational arm: • Ribociclib 400 mg by mouth once daily on days 1 to 21 of a 28-day cycle, for 36 months since the randomization date (approximately 39 cycles). and • ET consisting of: • For postmenopausal women: letrozole 2.5 mg by mouth once daily continuously or anastrozole 1 mg by mouth once daily continuously. • For premenopausal women and men: letrozole 2.5 mg by mouth once daily continuously or anastrozole 1 mg by mouth once daily continuously, combined with goserelin 3.6 mg subcutaneously once every 4 weeks.
  • Duration of ET in the trial will be 60 months from the randomization date.
  • Control arm • ET: Same as in the Investigational arm. In both arms, ET will be administered according to the local clinical guidelines and current local prescribing information. Subsequent ET (or any other anti-cancer treatment) given after the protocol-required 60 months of ET (or after premature discontinuation of ET in the trial) will be administered according to the Investigator’s clinical judgment and is not considered a trial treatment. Safety will be assessed for each patient (see Sections 6.4.2 and 7.1) and will include routine safety monitoring.
  • CA decision may prematurely terminate the trial within a country, or a change in opinion of the IRB/IEC may lead to its termination at the local level.
  • Patient Selection This trial can fulfill its objectives only if appropriate patients are enrolled. Patients who fail to meet all inclusion criteria or fulfill at least one exclusion criterion must not be randomized in the trial. Novartis or TRIO will not grant any eligibility waivers. See Section 6.1 for additional information on patient screening and randomization.
  • 4.1. Inclusion Criteria Patients eligible for inclusion in this trial must meet all of the following criteria: PAT059494-WO-PCT 1. Signed and dated Patient Informed Consent Form (PICF) obtained prior to any trial-specific screening procedure. 2. Patient is ⁇ 18 years-old at the time of PICF signature. 3.
  • PICF Patient Informed Consent Form
  • Postmenopausal status is defined as: • Patient underwent bilateral oophorectomy, or • Age ⁇ 60 years, or • Age ⁇ 60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) and Follicle-stimulating hormone (FSH) and plasma estradiol are in the postmenopausal ranges per local normal ranges. • If taking tamoxifen or toremifene and age ⁇ 60 years, then FSH and plasma estradiol level in postmenopausal ranges.
  • Patient with a multicentric and/or multifocal tumor is eligible if all the histopathologically examined lesions meet the pathologic criteria in inclusion criteria 5 and 6.
  • Patient has breast cancer that is positive for ER and/or PgR according to the local laboratory as determined on the most recently analyzed tissue sample.
  • Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0 or 1+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required to confirm the HER2-negative status (based on the most recently analyzed tissue sample tested by a local laboratory). 7.
  • IHC immunohistochemistry
  • PAT059494-WO-PCT Patient after surgical resection where tumor was removed completely, with the final surgical specimen microscopic margins free from tumor, and belongs to one of the following categories (see FIG.3): • Anatomic Stage Group III, or • Anatomic Stage Group IIB, or • Anatomic Stage Group IIA that is either: • N1, or • N0, with: • Grade 3, or • Grade 2, with any of the following criteria: • Ki67 ⁇ 20%, or • Oncotype DX Breast Recurrence Score ⁇ 26, or • Prosigna/PAM50 categorized as high risk, or • MammaPrint categorized as high risk, or • EndoPredict EPclin Risk Score categorized as high risk.
  • Patient has no contraindication for the adjuvant ET in the trial and is planned to be treated with ET for 5 years (since randomization date) or more. 12.
  • Patient may have already received any standard neoadjuvant and/or adjuvant ET at the time of PICF signature, but randomization should occur within 12 months of the initial start date of ET. Ovarian suppression or short term ET for fertility preservation is not considered neoadjuvant/adjuvant ET. If patient was receiving tamoxifen or toremifene as adjuvant ET, a washout period of 5 half-lives (i.e.35 days) prior to randomization is required (during that period patient can take AI).
  • Patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
  • Patient has adequate bone marrow and organ function as defined by the following local laboratory values: • Absolute neutrophil count (ANC) ⁇ 1.5 ⁇ 10 9 /L. • Platelets ⁇ 100 ⁇ 10 9 /L. • Hemoglobin ⁇ 9.0 g/dL. • Estimated glomerular filtration rate (eGFR) ⁇ 30 mL/min/1.73m 2 according to the Modification of Diet in Renal Disease (MDRD) formula. • Alanine transaminase (ALT) ⁇ 2.5 ⁇ Upper Limit Normal (ULN). • Aspartate transaminase (AST) ⁇ 2.5 ⁇ ULN.
  • Standard 12-lead ECG values assessed by a central laboratory as: • QTcF interval (QT interval using Fridericia’s correction) at screening ⁇ 450 msec. • Resting heart rate 50-90 beats per minute (determined from the ECG). 16.
  • Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures.
  • Women of childbearing potential (CBP) defined as all women physiologically capable of becoming pregnant (see Inclusion Criterion #18 for additional information), must have confirmed negative serum pregnancy test (for ⁇ -hCG) within 14 days prior to randomization.
  • CBP childbearing potential
  • Women of CBP must be willing to use highly effective methods of contraception. Contraception must continue during the trial treatment and for 21 days after stopping the treatment.
  • Highly effective contraception methods include: • Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking trial treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. • Male partner sterilization (at least 6 months prior to randomization). For female patients on the trial the vasectomized male partner should be the sole partner for that patient.
  • vasectomy of the male partner is the highly effective method of contraception chosen, the success of the vasectomy should be medically confirmed according to local practice.
  • Placement of an intrauterine device IUD.
  • Use of oral (estrogen and progesterone), transdermal, injected, implanted, hormone containing intrauterine system, or any other hormonal methods of contraception is not allowed in this trial.
  • Patient has received prior treatment with tamoxifen, raloxifene or AIs for reduction in risk (“chemoprevention”) of breast cancer and/or treatment for osteoporosis within the last 2 years prior to randomization.
  • chemoprevention a reduction in risk
  • Patient is concurrently using hormone replacement therapy.
  • Patient has received prior treatment with anthracyclines at cumulative doses of 450 mg/m2 or more for doxorubicin, or 900 mg/m2 or more for epirubicin.
  • 4. Patient with a known hypersensitivity to any of the excipients of ribociclib and/or ET (e.g. rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose- galactose malabsorption, and soy allergy). 5.
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality including any of the following: • History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to trial entry. • Documented cardiomyopathy. • Left Ventricular Ejection Fraction (LVEF) ⁇ 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) (testing not mandatory).
  • MI myocardial infarction
  • MUGA Multiple Gated acquisition
  • ECHO echocardiogram
  • TdP Torsades de Pointes
  • PAT059494-WO-PCT Clinically significant cardiac arrhythmias (e.g.
  • ventricular tachycardia e.g. bifascicular block, Mobitz type II and third degree AV block.
  • AV Atrioventricular
  • Patient is currently receiving any of the following substances within 7 days before randomization: • Concomitant medications, herbal supplements, and/or fruits (e.g. grapefruit, pummellos, starfruit, Seville oranges) and their juices that are known as strong inhibitors or inducers of CYP3A4/5. • Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5. 14.
  • corticosteroids are permitted: a short duration ( ⁇ 5 days) of systemic corticosteroids; any duration of topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airways diseases), eye drops or local injections (e.g. intra-articular). 15.
  • Patient has impairment of GI function or GI disease that may significantly alter the absorption of the oral trial treatments (e.g. uncontrolled ulcerative diseases, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, or small bowel resection). 16.
  • Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease, active untreated or uncontrolled fungal, bacterial or viral infections, active infection requiring systemic anti-bacterial therapy, etc.) or limit life expectancy to ⁇ 5 years. 17. Participation in other studies involving investigational drug(s) within 30 days prior to randomization or within 5 half-lives of the investigational drug(s) (whichever is longer), or participation in any other type of medical research judged not to be scientifically or medically compatible with this trial.
  • the protocol e.g. chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease, active untreated or uncontrolled fungal, bacterial or viral infections, active infection requiring systemic anti-bacterial therapy, etc.
  • ET will be procured locally according to local practice and regulation, or supplied by Novartis (or its designee). ET will be administered according to the current local prescribing information and clinical guidelines.
  • “Trial treatment” refers to either the combination of ET with ribociclib in the Investigational arm, or to ET alone in the Control arm (given for 60 months since randomization), or to ET (given for 60 months since randomization) in the Investigational arm after discontinuation of ribociclib.
  • Subsequent ET (or any other anti-cancer treatment) given after the protocol-required 60 months duration (or after premature discontinuation of ET in the trial) will be administered according to the Investigator’s clinical judgment and is not considered a trial treatment.
  • the Reference Safety Information for ribociclib is included in the “Reference Safety Information” section of the ribociclib IB. 5.1.1. Schedule and Administration Randomized patients will receive, starting from C1D1, either: • Investigational arm: • Ribociclib 400 mg (2 x 200 mg tablets by mouth) once daily on days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28). And • ET consisting of: • For postmenopausal women: • Letrozole 2.5 mg by mouth daily continuously or anastrozole 1 mg by mouth daily continuously.
  • Randomization and C1D1 should preferably occur on the same day.
  • a window of up to 7 days between randomization and C1D1 is permitted.
  • C1D1 is defined as the day when the patient takes the first dose of trial treatment after randomization (note: for patients who were receiving ET prior to randomization, C1D1 is considered as the day they receive the first dose of ribociclib [Investigational arm] or the first dose of ET after randomization [Control arm]).
  • a complete cycle of treatment is defined as 28 days. Cycles must occur as per a schedule calculated considering C1D1 as the starting point.
  • a flexibility window of ⁇ 3 day is allowed for the trial assessments (except for ECG when it is required on C1D1), to accommodate any scheduling issue, but treatment schedule remains fixed based on the calculation considering C1D1 as the starting point. Since cycles are fixed, if for any reason ribociclib begins later than D1 of a cycle, intake should nevertheless stop at D21 and then patient should proceed to the 7 days off period. If ribociclib dosing is interrupted for > 28 days due to ribociclib-related toxicity, it must be permanently discontinued. Details and examples are available in the CRF Completion Guidelines.
  • a patient decides to discontinue from the trial treatment, the Investigator must make a reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this decision and record this information in the patient’s chart and on the appropriate page of the Case Report Form (CRF). They will be considered withdrawn if they state an intention to withdraw consent from trial participation.
  • the Investigator should discontinue trial treatment for a given patient if he/she believes that continuation would be detrimental to the patient’s well-being. Trial treatment must also be discontinued under the following circumstances: • Pregnancy. • Lactation. • Any protocol deviation that results in a significant risk to the patient’s safety per Sponsor’s judgment.
  • Ribociclib should be taken as follows: • Ribociclib is dosed for the first 21 days out of the 28-day cycle. Patients should not resume a new cycle of ribociclib until completion of the 7-day off period. • When visits take place on the scheduled D1 of a cycle (or in the allowed + 3 days window) patients must take ribociclib (and ET) in the clinic under the supervision of the Investigator or designee.
  • patients may take ribociclib (and ET) at home.
  • Patients should be instructed to take ribociclib and ET together, with a large glass of water ( ⁇ 250 mL or ⁇ 8 oz.) at the same time each day. Patients can determine if they prefer morning or early afternoon dosing, but they should maintain a consistent time. Evening doses are strongly not recommended.
  • patients in the PK subset (see Section 6.4.3) must take ribociclib and ET in the morning due to PK assessments on C1D15. Afterwards patients can determine if they prefer morning or early afternoon dosing, but should maintain a consistent time.
  • Patients should be instructed to swallow the tablets whole and not to chew or crush them.
  • CYP3A4 inhibitors These foods are known as CYP3A4 inhibitors and have a potential to increase exposure to ribociclib (note: oranges and orange juice are allowed). • Herbal or dietary supplements known as strong inhibitors or inducers of CYP3A4/5 or those with a known risk of QT prolongation are not permitted (see Section 5.4.3.1). Multivitamins are permitted. • Patients should be instructed not to take any medication reported as prohibited in Section 5.4 (see also Appendix 4: Concomitant Medications).
  • Goserelin will be administered subcutaneously on D1 ⁇ 3 of each 28-day cycle, in accordance with the current local prescribing information (Note: 3-month depot formulation of goserelin is not allowed in the trial).
  • PAT059494-WO-PCT prior to randomization
  • Patients receiving 3-monthly goserelin prior to randomization must switch to the monthly formulation.
  • Table A6 Dose Modification Guidelines Ribociclib Dose Number of tablets & strength Starting dose 400 mg 2 x 200 mg tablets Dose level -1 200 mg 1 x 200 mg tablet 5.2.1.2. Ribociclib Dose Adjustments Recommendations for dose interruption, reduction of ribociclib in the management of ribociclib related AEs are summarized in Table A7, Table A8, Table A9, Table A10 and Table A11. Clinical judgment of the treating Investigator should guide the management plan of each patient based on individual benefit/risk assessment. Unscheduled laboratory assessments may be performed if medically indicated to document a (potential) AE for decision making (e.g. dose adjustments).
  • Ribociclib must be discontinued in case of: • Events requiring a discontinuation according to Table A7, Table A8, Table A9, Table A10 and Table A11. PAT059494-WO-PCT • Dosing was interrupted for > 28 days due to ribociclib-related toxicity.
  • Dose Adjustments for Hematological and Hepatic Toxicities Table A7: Ribociclib Dose Adjustment, Management Recommendations and Mandatory Discontinuation for Hematological Adverse Reactions (CTCAE v4.03) Toxicity/Grade Dose Adjustment and Management Recommendations Thrombocytopenia Grade 1 ( ⁇ 75 x 10 9 /L) No dose adjustment required.
  • G rade 2 ( ⁇ 50 x 109/L - ⁇ 75 x 109/L) Dose interruption until recovery to grade ⁇ 1. Re-initiate ribociclib at the same dose level. Grade 3 ( ⁇ 25 x 10 9 /L - ⁇ 50 x 10 9 /L) Dose interruption until recovery to grade ⁇ 1. Re-initiate ribociclib at the same dose level. If toxicity recurs at grade 3: temporary dose interruption until recovery to grade ⁇ 1 and reduce ribociclib to the next lower dose level. G rade 4 ( ⁇ 25 x 109/L) Dose interruption until recovery to grade ⁇ 1. Re-initiate ribociclib at the next lower dose level.
  • toxicity recurs at grade 4 discontinue ribociclib (mandatory). Decreased Absolute Neutrophil Count (ANC) Grade 1 ( ⁇ 1.5 x 10 9 /L) No dose adjustment required. Grade 2 ( ⁇ 1.0 - ⁇ 1.5 x 10 9 /L) No dose adjustment required. Grade 3 ( ⁇ 0.5 - ⁇ 1.0 x 10 9 /L) Dose interruption until recovery to ⁇ 1.0 x 10 9 /L. Re-initiate ribociclib at the same dose level. If toxicity recurs at grade 3: temporary dose interruption until recovery to ⁇ 1.0 x 10 9 /L. • If resolved in ⁇ 7 days, then re-initiate at the same dose level.
  • Bilirubin will be fractionated if elevated. Elevated AST or ALT AST or ALT without bilirubin elevation > 2 x ULN Same grade as baseline or increase from baseline No dose adjustment required, with Liver Function Tests grade 0 to grade 1 (confirmed 48-72 h later) (LFT) monitored per protocol if same grade as baseline or every two weeks in case of increase from baseline grade 0 to 1.
  • Grade 2 (> 3.0 - 5.0 x ULN) Dose interruption of ribociclib. If resolved to ⁇ baseline grade in ⁇ 21 days, then re- initiate at the same dose level. If resolved to ⁇ baseline grade in > 21 days or toxicity recurs, then re-initiate at the next lower dose level. Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after dose resumption. If toxicity recurs after a dose reduction or recovery to ⁇ baseline grade is > 28 days, discontinue ribociclib (mandatory). Grade 3 (> 5.0 - 20.0 x ULN) Dose interruption of ribociclib until resolved to ⁇ baseline grade, re-initiate at the next lower dose level.
  • Grade 4 (> 20.0 x ULN) Discontinue ribociclib (mandatory) AST or ALT and concurrent Bilirubin
  • AST or ALT >3.0 x ULN combined with total bilirubin > 2 x ULN without evidence of cholestasis
  • AST or ALT >3.0 x ULN combined with total bilirubin > 2 x ULN without evidence of cholestasis
  • patient with elevated AST or ALT or total bilirubin at baseline [AST or ALT > 2 x baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN]- whichever is lower- combined with [total bilirubin > 2 x baseline AND > 2.0 x ULN]
  • Confounding factors and/or alternative causes for increased transaminases should be excluded before dose interruption/reduction.
  • QTcF 481-500 msec Perform a repeat ECG within one hour of the first QTcF of ⁇ 481 msec. Repeat ECG as clinically indicated until the QTcF returns to ⁇ 481 msec. Re- initiate at the same dose level. No dose adjustment required for first occurrence. If QTcF ⁇ 481 msec recurs, ribociclib should be reduced by 1 dose level for the second occurrence. If QTcF ⁇ 481 msec recurs (third occurrence), ribociclib must be permanently discontinued.
  • TEN Toxic Epidermal Necrolysis
  • Table A11 Ribociclib Dose Adjustment, Management Recommendation and Mandatory Discontinuation for All Other Adverse Reactions Grade Dose Adjustment and Management Recommendations 1 No dose adjustment recommended. Initiate appropriate medical therapy and monitor. 2 Dose interruption until recovery to grade ⁇ 1. Initiate appropriate medical therapy and monitor.
  • Re-initiate ribociclib at the same dose level If the same toxicity recurs at grade 2, interrupt ribociclib until recovery to grade ⁇ 1. Re-initiate ribociclib at the next lower dose level. 3 Dose interruption until recovery to grade ⁇ 1. Initiate appropriate medical therapy and monitor. Re-initiate ribociclib at the next lower dose level. If toxicity recurs at grade 2 or 3, discontinue ribociclib (mandatory). 4 Discontinue ribociclib (mandatory) and treat with appropriate medical therapy. 5.2.1.3. Follow-up for Toxicities Ongoing AEs or abnormal laboratory values at time of ribociclib discontinuation must be followed closely until resolution to baseline values or stabilization of the event.
  • DILI Drug-Induced Liver Injury
  • the threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL value; patients meeting any of the following criteria will require further follow-up as outlined below: • For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x ULN combined with TBIL > 2.0 x ULN PAT059494-WO-PCT • For patients with elevated AST or ALT or TBIL value at baseline: (AST or ALT > 2 x baseline AND > 3.0 x ULN) OR (AST or ALT > 8.0 x ULN), whichever is lower, combined with (TBIL > 2 x baseline AND > 2.0 x ULN) Medical assessment needs to ensure that liver test elevations are not caused by cholestasis, defined as: Alkaline Phosphatase (ALP) elevation > 2.0 x ULN with R value ⁇ 2 in patients without bone metastasis, or elevation of ALP liver fraction in patients with bone metastasis.
  • ALP Al
  • the R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to cholestatic or hepatocellular liver injury or mixed type injury). In the absence of cholestasis, these patients must be immediately discontinued from ribociclib, and repeat LFT as soon as possible, preferably within 48 hours from the awareness of the abnormal results.
  • the evaluation should include laboratory tests, detailed history, physical assessment and the possibility of liver metastasis or new liver lesions, obstructions/compressions, etc.
  • Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin, direct and indirect bilirubin, ALP (fractionated if ALP is grade 2 or higher), creatine kinase, prothrombin time (PT)/INR and GGT.
  • LFTs albumin, ALT, AST, total bilirubin, direct and indirect bilirubin, ALP (fractionated if ALP is grade 2 or higher), creatine kinase, prothrombin time (PT)/INR and GGT.
  • PT prothrombin time
  • GGT prothrombin time
  • liver metastases • Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections (cytomegalovirus, Epstein-Barr, herpes simples); autoimmune or alcoholic hepatitis; non- alcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease.
  • Compliance will be assessed by the Investigator and/or designated site personnel at each patient visit during the Treatment Phase and information provided by the patient and/or caregiver will be captured in the source documents.
  • the administration of the trial treatment will be recorded in the appropriate sections of the CRF.
  • patients will complete a diary to record their daily intakes. They will be instructed to return all unused ribociclib (and ET if provided by Novartis) (partially used and empty containers) and their diary at each visit during the Treatment Phase.
  • Site staff will perform accountability of the returned drug and will assess compliance with trial treatment.
  • ribociclib and ET if provided by Novartis
  • the Investigator or designee must maintain an accurate record of the receipt and dispensing of the trial treatment in a drug accountability log.
  • PAT059494-WO-PCT Drug accountability will be reviewed by the trial monitor during site visits and at the completion of the trial. 5.3.4. Disposal and Destruction Ribociclib (and ET if provided by Novartis) can be destroyed at the local Novartis facility, Drug Supply group or third party, as appropriate. Destruction at the investigational site of trial treatment provided by Novartis will only be permitted if authorized by Novartis or designee and if permitted by local regulations. 5.4. Concomitant Medications and Treatments 5.4.1. General Considerations The patient must be instructed to notify the investigational site about any new medications she/he takes after signature of the PICF.
  • bisphosphonates, denosumab) are allowed for the treatment of osteoporosis, and when used as adjuvant therapy to reduce bone recurrence and improve BC outcomes, when administered according to the Cancer Care Ontario/American Society of Clinical Oncology Clinical Practice Guideline or the corresponding local guideline. 46 When these are indicated, it is strongly recommended to initiate bone-modifying agents prior to randomization. Patients are not permitted to participate in any additional parallel investigational drug or device study. Participation in other studies involving investigational drug(s) within 30 days prior to randomization or within 5 half-lives of the investigational drug(s) (whichever is longer), or participation in any other type of medical research judged not to be scientifically or medically compatible with this trial, is prohibited.
  • Medications with a known risk for QT prolongation and/or TdP may precipitate QT prolongation and TdP in combination with ribociclib).
  • Concomitant tamoxifen or toremifene use Herbal medications/preparations or dietary supplements that are strong inhibitors or inducers of CYP3A4/5 or those with a known risk of QT prolongation. These include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng.
  • DHEA dehydroepiandrosterone
  • PAT059494-WO-PCT • Moderate inhibitors or inducers of CYP3A4/5 (may increase or decrease ribociclib exposure, respectively). • Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index (ribociclib may increase exposure to these medications). • Based on in vitro data (refer to the most recent ribociclib IB for details), co-administration of ribociclib with strong inhibitors of Bile Salt Export Pump (BSEP) may lead to intrahepatic cholestasis, and co-administration of ribociclib with sensitive substrates of the renal transporters, MATE1 and OCT2 (has a potential to increase exposure to substrates of these transporters, although no animal or clinical data are available to support these statements).
  • BSEP Bile Salt Export Pump
  • Drugs with QT Prolongation As far as possible, avoid co-administering medications with a “Known”, “Possible” or “Conditional” risk of TdP or any other medication with the potential to increase the risk of drug- related QT prolongation (e.g. via a potential DDI increasing the exposure of ribociclib or the exposure of the QT prolonging drug). Medications with a known risk for QT prolongation are prohibited during treatment with ribociclib. If concomitant administration of drugs with a known risk of TdP is required and cannot be avoided, ribociclib must be interrupted.
  • ribociclib may be resumed under close clinical and ECG monitoring to ensure patient safety.
  • a list of drugs associated with QT prolongation and/or TdP is available online (www.qtdrugs.org). Refer to the current ribociclib IB and other drug package insert and Appendix 4: Concomitant Medications, for information on possible interactions with other drugs. 5.4.3.4.
  • Permitted Concomitant Therapy Medications required to treat AEs, manage cancer symptoms, concurrent diseases and supportive care agents, such as pain medications, antiemetics and anti-diarrheals are allowed, with some exceptions as stated in Section 5.4.3.5 and Appendix 4: Concomitant Medications. Potential drug interaction between ribociclib and concomitant medications should always be taken into consideration. PAT059494-WO-PCT 5.4.3.5. Considerations About Other Concomitant Treatments Corticosteroids Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to lead to induction of CYP3A enzymes, thereby potentially reducing ribociclib drug exposure to sub- therapeutic levels.
  • Systemic corticosteroid treatment should not be given during treatment with ribociclib, except for: • Topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airways diseases), eye drops or local injections (e.g. intra-articular); • A short duration ( ⁇ 5 days) of systemic corticosteroids ⁇ to the anti-inflammatory potency of 4 mg dexamethasone (e.g. for chronic obstructive pulmonary disease or as an antiemetic).
  • WBC White Blood Cells
  • Antiemetic Medications Ribociclib has minimal to low emetogenic potential according to the definition of anti-neoplastic agent emetogenicity. 46 Antiemetic therapy can be used according to clinical guidelines for anti-neoplastic medications with low to minimal emetogenic potential for treatment and/or prevention of nausea and vomiting as a result of treatment. 49, 50 Potential drug interaction between ribociclib and antiemetic medications should always be taken into consideration. Example of a prohibited antiemetic medication is ondansetron that in combination with ribociclib may precipitate TdP.
  • PAT059494-WO-PCT 6. Trial Visits and Assessments 6.1. Screening and Randomization 6.1.1. Screening After the patient signs the main PICF, she/he must be recorded in the IRT (on the same date) and this is considered as the start of the Screening Phase (see Section 6.3.1). At this time, a unique Patient Number (Patient No.) will be assigned in the system. This number is retained as the primary identifier for the patient throughout her/his entire participation in the trial, even if the patient is re-screened. The Patient No. consists of the Site Number (Site No.) with a sequential patient number suffixed to it, so that each patient is numbered uniquely across the entire database. 6.1.2.
  • Randomization Patients will be assigned to one of the two treatment arms in a ratio of 1:1. Randomization will be stratified by the factors reported in Section 8.4. Randomization may occur as soon as all screening assessments have been conducted (in the appropriate time window) and eligibility status confirmed by the Investigator. Randomization will be done in the IRT as per instructions provided in the applicable User Manual. 6.1.3. Screen Failures Patients that have signed the PICF but are not randomized for any reason will be considered screen failures and will be recorded as such in the IRT. Limited data will be entered in the CRF for screen failed patients, according to the CRF Completion Guidelines. 6.1.4. Re-Screening Re-screening of patients is only allowed once per patient, if the patient was not randomized before (i.e. IRT randomization).
  • the Patient No. initially assigned will be used and the patient will be identified with this number throughout her/his entire participation to the trial.
  • a new PICF must be signed if the Investigator chooses to re-screen a patient following screen failure. In case re-screening occurs, all evaluations re-assessed should meet the eligibility criteria. For eligibility purposes, the laboratory tests performed closest to the randomization date will be considered and must meet the eligibility criteria. For re-screened patients, there is no need to re-draw a sample for ctDNA/ctRNA, unless the patient was on any ongoing anti-cancer treatment when the sample was taken. PAT059494-WO-PCT 6.2.
  • Schedule of Visits and Assessments Table A12 lists all of the protocol required assessments and indicates with an “X”, the visits when they must be performed. All data obtained from these assessments must be supported in the patient’s source documentation. Allowed visit windows are as follows (unless otherwise specified): • Randomization must occur within 42 days of the date of PICF signature (Note: for patients receiving tamoxifen at time of PICF signature, consider the need of a washout period prior to randomization, according to Inclusion Criterion #12). • All screening assessments must occur within 28 days prior to randomization. • Randomization and C1D1 should preferably occur on the same day. A window of up to 7 days between randomization and C1D1 visit is permitted.
  • Trial Phases and Visits 6.3.1. Screening Phase The Screening Phase starts when the patient signs the main PICF and ends when she/he is randomized or screen failed. No trial-specific procedure may be performed until the main PICF is signed (note: randomization must occur within 42 days of the date of PICF signature).
  • the Investigator must: • Perform all screening procedures within 28 days prior to randomization (see Table A12 for list of assessments to be performed). • Assess the inclusion and exclusion criteria as detailed in Section 4.
  • Treatment Phase The Treatment Phase starts when the patient begins with trial treatment (C1D1) and ends at time of the 30-Day Safety Follow-up visit. 6.3.2.1. Trial Treatment After randomization, trial treatment should be started as soon as possible and no later than 7 days after the randomization. Trial treatment will continue until criteria in Section 5.1.1.1 is met. During trial treatment, visits need to be performed according to the following schedule: • Up to completing 36 months of trial treatment, from randomization date: in the schedule specified in Table A12 (i.e.
  • 30-Day Safety follow-up Visit All patients must have safety evaluations for 30 days after the last dose of all trial treatments.
  • the 30-Day Safety Follow-up visit will take place 30 days ( ⁇ 3 days) from the last dose of all trial treatments.
  • SAEs and non-serious AEs if applicable per Section 7.1
  • subsequent anti-neoplastic therapies and healthcare resource utilization data (if any) will be collected at this visit. No other test or assessment is required. If patients refuse to return for the 30-Day Safety Follow-up visit or are unable to do so, every effort should be made to contact them by telephone to determine if any AE was experienced. Attempts to contact the patient should be documented in the source documents (e.g. dates of telephone calls, registered letters, etc.). 6.3.3.
  • the follow-up Phase starts after the 30-Day Safety Follow-up visit and will continue until death, withdrawal of consent, loss to follow-up or end of trial, whichever is earliest.
  • PAT059494-WO-PCT Patients will be assessed for recurrence and survival according to Sections 6.4.1.1 and 6.4.1.2.
  • evaluations for recurrence will be performed during the Follow-up Phase (according to Sections 6.4.1.1) until documentation of distant disease recurrence, death, withdrawal of consent, loss to follow-up, or end of trial.
  • a final evaluation at the time of the patient’s withdrawal should be made and will be considered the EOT visit (for patients that withdraw prior to completing trial treatment).
  • Novartis will continue to keep and use collected trial information (including any data resulting from the analysis of a patient’s samples until their time of withdrawal) according to applicable law. All biological samples not yet analyzed at the time of withdrawal will no longer be used, unless permitted by applicable law. They will be stored according to applicable legal requirements.
  • PAT059494-WO-PCT 6.3.5 Lost to Follow-up
  • the Investigator should show "due diligence" by contacting the patient, family or family physician and will document in the source documents the steps taken to contact the patient, e.g.
  • Efficacy assessment for the primary endpoint of iDFS will include detection of locoregional relapse, distant relapse, ipsilateral and contralateral invasive BCs and second primary non-breast invasive cancer (see Appendix 2: Guidelines for Standardized Definitions for Efficacy Endpoints in Adjuvant Breast Cancer Trials (based on STEEP) and Appendix 3: Recurrence Detection Guidelines). Efficacy assessments also include evaluation of the survival status done according to Section 6.4.1.2.
  • Efficacy assessments are fixed according to the calendar, taking as a reference the randomization date (not the date of a previous assessment), regardless of treatment interruptions. If a patient discontinues trial treatment for reasons other than distant disease recurrence (or death, lost to follow-up, or withdrawal of consent), recurrence assessments should continue as per the schedule in Table A12 and Table A13 until distant disease recurrence, withdrawal of consent by the patient, patient is lost to follow-up, death or end of trial.
  • follow-up for recurrence will not be discontinued at the event of local or regional recurrence, contralateral invasive BC event or second primary non-breast invasive cancer. 6.4.1.1.
  • Recurrence Assessments will be reported as local, regional, distant, contralateral invasive BC and second primary non-breast invasive cancer (excluding basal or squamous cell carcinomas of the skin) (see Appendix 2: Guidelines for Standardized Definitions for Efficacy Endpoints in Adjuvant Breast Cancer Trials (based on STEEP)).
  • the imaging assessments described in sections 6.4.1.1.1 and 6.4.1.1.2 are aligned with the standard of care imaging assessments done in EBC patients. No additional radiological examinations are required as part of this protocol.
  • Clinical Evaluation and Mammography PAT059494-WO-PCT Detection of recurrence will be done by clinical evaluation that includes medical history and physical examination.
  • Clinical evaluation for recurrence will be done as follows: • At screening within 28 days period prior to randomization. • Subsequently every 12 weeks ( ⁇ 2 weeks) following randomization (using the randomization date as the reference date and not the date of the previous assessment) during the first 24 months and every 24 weeks ( ⁇ 3 weeks) thereafter. Note: The 12-week (or 24 week) interval should be respected regardless of whether trial treatment is temporarily withheld or unscheduled assessments performed. A window of ⁇ 2 or 3 weeks (as detailed above) is permitted to take into account scheduling issues. Scheduled mammography should be done (unless bilateral mastectomy): • At screening (unless done within 12 months prior to screening start).
  • Recurrence that is suspected clinically only but is not confirmed as described in Appendix 3 Recurrence Detection Guidelines, will not be reported as confirmed recurrence in the CRF and will not be considered as an iDFS event per STEEP System. Imaging assessments (excluding scheduled mammography, although mammography can be used to evaluate recurrence suspected during clinical evaluation) will be performed after clinical evaluation, within 4 weeks after clinical suspicion of recurrence. Findings from radiological evaluations (evaluation of suspicion of recurrence or unconfirmed findings) will be recorded in the CRF.
  • Radiological assessments may be used for evaluation after clinical suspicion of recurrence: PAT059494-WO-PCT • Chest, abdomen, pelvis computed tomography (CT) or magnetic resonance imaging (MRI) • Brain CT or MRI • Whole body bone scan (bone scintigraphy) • Localized bone CT, MRI or X-ray, for any lesions identified on the whole body bone scan that are not visible on the chest, abdomen, pelvis CT or MRI • CT or MRI of other sites (e.g.
  • CT with intravenous (i.v.) contrast is a preferred imaging methodology performed after clinical suspicion of recurrence.
  • a patient is known to have a contraindication to i.v. contrast media or develops a contraindication during the trial, a non-contrast spiral CT of chest (MRI is not recommended due to respiratory artifacts) and contrast-enhanced MRI (if possible) of abdomen and pelvis should be performed.
  • a whole body bone scan e.g.
  • Tc-99m bone scan sodium fluoride PET [NaF-PET] bone scan
  • NaF-PET sodium fluoride PET
  • Imaging Collection Plan P rocedure Screening P hase Treatment Phase and Follow-up Phase Any of the following: Not Within 4 weeks of clinical suspicion of recurrence* (including CT or MRI (with mandated local, regional, distant), or contralateral invasive BC or second contrast unless primary non-BC. contraindicated), bone scan, US, Note: In case of skin, subcutaneous or other superficial lesions PET, plain X-ray for which imaging may not be informative, it is acceptable to films, mammography not perform imaging procedures to evaluate such lesions.
  • Mammography Mandatory Every 12 months ( ⁇ 4 weeks) after randomization (if (unless bilateral unless done mammography was done at screening) or every 12 months ( ⁇ mastectomy) within 12 4 weeks) from the date of the latest mammography done prior months prior to screening, if applicable. Mammography should also be done to screening as clinically indicated. start An interval of no more than 12 months (+ 4 weeks) between mammography procedures should be maintained. Mammography should continue until documentation of distant PAT059494-WO-PCT P rocedure Screening P hase Treatment Phase and Follow-up Phase disease recurrence, death, withdrawal of consent, loss to follow-up, or end of trial.
  • Imaging data will be collected and stored in accordance with local regulations. The local Investigator’s assessment will be used for the primary/secondary endpoint analysis and for treatment decision making. In the future, central review of the imaging data may be performed retrospectively from locally stored images, if deemed necessary by the Sponsor.
  • Table A14 Histology/Cytology Collection Plan Procedure Screening Treatment Phase and Post Treatment follow-up Phase Phase Histological or Not Within 4 weeks of clinical suspicion of recurrence* (including cytological mandated local, regional, distant), contralateral invasive BC or second evaluation of primary non-BC.
  • recurrence Clinical evaluations for recurrence with or without radiologic and/or histologic/cytologic confirmation should continue until documentation of distant disease recurrence, death, withdrawal of consent, loss to follow-up, or end of trial.
  • Survival status will be assessed according to the following schedule: PAT059494-WO-PCT • If 30-Day Safety Follow-up takes place during the first 24 months after randomization: every 12 weeks ( ⁇ 2 weeks) until 24 months after date of randomization and every 24 weeks ( ⁇ 3 weeks) thereafter. • If 30-Day Safety Follow-up takes place after the first 24 months after date of randomization: every 24 weeks ( ⁇ 3 weeks). Survival assessments will continue until death, withdrawal of consent, lost to follow-up or end of trial, whichever is earliest. 6.4.2. Safety Assessments Safety of patients will be monitored by assessing physical examinations, ECOG Performance Status, height, weight, vital signs, ECG, laboratory assessments (including hematology, biochemistry, and coagulation), as well as collection of AEs at every applicable visit.
  • Physical Examination is to be performed according to the visit schedule as outlined in Table A12. At screening, the physical examination comprises a total body examination that should include: general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological review. If indicated, rectal, external genitalia, breast and pelvis exams will be performed. Information about the physical examination must be present in the source documentation at the study site. Significant findings that were present prior to the signing of the main PICF consent must be included in the Medical History page on the patient’s CRF. Significant new findings that begin or worsen after informed consent must be recorded on the AE page of the patient’s CRF.
  • a symptom/sign-oriented physical examination is acceptable, in addition to the examination directed to the detection of recurrences (see Section 6.4.1.1.1).
  • Vital Signs Vital signs body temperature, pulse rate, blood pressure
  • Blood pressure systolic and diastolic
  • Pulstolic and diastolic should be measured after the patient has been sitting for approximately five minutes.
  • Height and Weight Height will be measured at screening only. Weight will be measured at screening and at subsequent time points as specified in Table A12.
  • PAT059494-WO-PCT 6.4.2.4. Performance Status The performance status will be assessed according to the ECOG Performance Status Scale 52 as specified in Table A15, following the schedule given in Table A12.
  • Table A15 ECOG Performance Status Score Description 0 Fully active, able to carry on all pre-disease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature e.g. light house work, office work 2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 5 Dead 6.4.2.5. Laboratory Evaluations Clinical laboratory analyses (hematology, biochemistry, coagulation, and other required tests) are performed by the local laboratory (see Table A16).
  • TRIO home pregnancy tests, which may be done according to Section 6.4.2.5.4 from C7.
  • the Investigator is responsible for reviewing all laboratory reports for patients in the trial and evaluating any abnormalities for clinical significance.
  • TRIO must be provided with a copy of the laboratory’s certification and a tabulation of the normal ranges and units of each parameter collected in the CRF. Additionally, if at any time a patient has laboratory parameters obtained from a different (outside) laboratory, TRIO must be provided with a copy of the certification and a tabulation of the normal ranges and units for this laboratory as well.
  • Unscheduled local laboratory assessments may be performed if medically indicated to document a (potential) AE for decision making (e.g. dose modifications).
  • FSH estradiol for confirmation of menopausal status (pre/post).
  • Biochemistry Biochemistry tests are to be performed according to the schedule in Table A12. For details of the biochemistry panel, see Table A16. Coagulation INR and aPTT are to be performed according to the schedule outlined in Table A12. Pregnancy Tests and Assessments of Menopausal Status/Fertility When applicable, FSH and estradiol are to be performed according to Table A12 and Table A16. If applicable, FSH and estradiol will be done at screening for eligibility and for confirmation of the menopausal status (see Inclusion Criterion #3). A serum pregnancy test must be performed for all women of CBP at screening. During the Treatment Phase, pregnancy test will be done as follows: • Every cycle from C1 thru C6: urine or serum pregnancy test, according to Table A12.
  • ECGs collected during the trial will be transmitted to a central laboratory and will be centrally reviewed by an independent reviewer.
  • an ECG report will be sent from the central laboratory to the site.
  • the central laboratory ECG assessment will be used to define patient’s eligibility according to Inclusion Criterion #15. Note: In order to ensure the ECG evaluation is received by the site from the central laboratory for eligibility assessment, it is advisable to perform the ECG at least 3 business days prior to the scheduled randomization date.
  • the Investigator (or other site’s qualified physician) will assess the ECGs and will determine the QTcF duration and any potential ribociclib dose adjustment (see Section 5.2.1.2.2). If an ECG report from the central laboratory shows a QTcF ⁇ 481 msec, ribociclib dosing should be interrupted (if not previously done) and patient should be managed according to Section 5.2.1.2.2. Interpretation of the tracing must be made by a site’s qualified physician and documented on the CRF. Local cardiologist ECG assessment may be performed at any time during the trial at the discretion of the Investigator. When a pre-dose ECG is to be collected, then the ECG measurement must occur before dosing of the trial treatment.
  • PK sample is to be obtained on the same day as ECG, then the sample should be collected after the ECG and before dosing of the trial treatment. See FIG.4 and Section 5.1.2.1.1 for additional guidance on the timing of ECG in relation to ribociclib dosing and PK sampling, at C1D15.
  • Table A17 ECG Collection Plan Cycle Patients Day Time ECG Type Screening All -28 to -1 Anytime Single 12 Lead 1 All Day 1 Pre-dose 1 Single 12 Lead All Day 15 2 Pre-dose 1 Single 12 Lead All 2h post-dose ( ⁇ 15 min) Single 12 Lead All 4 h post-dose ( ⁇ 15 min) Single 12 Lead 2 All Day 1 Pre-dose 1 Single 12 Lead All Day 15 Pre-dose 1 Single 12 Lead 2h post-dose ( ⁇ 15 min) Single 12 Lead 3 All Day 1 Pre-dose 1 Single 12 Lead 6 All Day 1 Pre-dose 1 Single 12 Lead PAT059494-WO-PCT Cycle Patients Day Time ECG Type 7 and thereafter Patients with Day 1 Pre-dose Single 12 Lead every 3 rd cycle QTcF ⁇ 481 (i.e.7, 10, 13 msec at any etc.) until 36 time prior to months from cycle 7 randomization 3 EOT Anytime Single 12 Lead Unscheduled ECG Anytime Single 12 Lead 1 The exact date and time of dosing must be recorded on the appropriate CRF.
  • ECG assessment is to be done prior to PK sampling. 3 Or until ribociclib discontinuation (in Investigational arm) or ET discontinuation (in Control arm), in cases where treatment is discontinued prior to completing 36 months.
  • the QTcF values using Fridericia’s correction will be reviewed centrally. If any of the ECG reading after randomization includes a new clinically-relevant abnormal ECG finding or a QTcF value of ⁇ 481 msec, ribociclib must be interrupted, ECG must be repeated and management guidelines detailed in Table A9 must be followed. An unscheduled ECG may be repeated at the discretion of the Investigator at any time during the trial and as clinically indicated.
  • ECG tracing should be labeled with the trial number, patient number, date, and kept in the source documents at the trial site.
  • Clinically significant ECG abnormalities present at screening when the patient signed PICF should be reported on the Medical History CRF page. New or worsened clinically significant findings occurring after informed consent must be recorded on the AE CRF page. 6.4.3.
  • Pharmacokinetics Assessments Approximately 130 patients from the Investigational arm will be considered as the PK subset. Plasma samples for ribociclib determination will be obtained from these patients at the time points indicated in Table A18.
  • Table A18 PK Blood Collection Schedule in Patients in the PK Subset C ycle Day Scheduled Time Point Relative to Dosing (Sampling W indow) Blood Volume (mL) 1 15 Pre-dose (0 h) a 2 1 15 2 h post-dose ( ⁇ 15 min) 2 1 15 4 h post-dose ( ⁇ 30 min) 2 a Collect PK sample immediately before drug administration.
  • PK samples 1 15 Pre-dose (0 h) a 2 1 15 2 h post-dose ( ⁇ 15 min) 2 1 15 4 h post-dose ( ⁇ 30 min) 2 a Collect PK sample immediately before drug administration.
  • Sections 5.1.2.1.1 and 6.4.2.6 for additional guidance on the timing of collection of PK samples in relation to ribociclib dosing and ECG at C1D15.
  • PAT059494-WO-PCT All efforts will be made to obtain the PK samples at the scheduled nominal time relative to dosing.
  • PK samples will be analyzed using a liquid chromatography-tandem mass spectrometry (LC- MS/MS) method with a lower limit of quantification (LLOQ) of approximate 1.00 ng/mL. Any results below the LLOQ and any missing samples will be recorded accordingly.
  • LLOQ liquid chromatography-tandem mass spectrometry
  • Leftover plasma from analysis may be used for exploratory metabolite assessments or other bioanalytical purposes (e.g. cross check between different sites, stability assessment). Instructions for collection, preparation and shipment can be found in the applicable Laboratory Manual. 6.4.4. Biomarkers Genetic aberrations that lead to an upregulation in the CDK signaling are observed frequently in BC.
  • Biomarkers indicative of resistance to treatment and mechanisms underlying disease recurrence will also be investigated. While the goal of the biomarkers analysis is to provide supportive data for the clinical trial, there may be circumstances when a decision is made to stop a collection, or not perform or discontinue an analysis due to either practical or strategic reasons. For example, there may be inadequate sample number, issues related to the quality of the sample or issues related to the assay that preclude analysis. Alternatively, there may be insufficient efficacy to allow for correlative analyses due to a limited number of samples.
  • Table A19 Biomarker Sample Collection Plan Sample Type Requirement Visit Time point Volume Tumor samples (from all patients, except those enrolled in China) Archival paraffin tumor Mandatory tissue from surgical specimen (or, in patients who underwent neoadjuvant therapy and had a pathological complete response, at the time of the initial At screening: diagnosis or before the confirmation of istration of sam NA N/A admin ple’s neoadjuvant therapy) availability for (Tumor block [preferred] submission to OR 20 unstained slides [15 central for patients who received laboratory neoadjuvant therapy]).
  • Tumor tissue samples will be collected for identifying biomarkers that may be predictive of benefit from ribociclib and exploring mechanisms underlying disease recurrence. Tumor tissue will be used to assess molecular alterations of several genes shown to be associated with HR- positive BC and cell cycle such as, but not limited, to CDK4, CDK6, CCND1, CCNE1, p53, PIK3CA, RB1. 17 Protein (e.g.
  • Ki67, pRb by IHC) and/or gene expression will also be assessed in tumor material. Broad panels or whole exome sequencing may be used in order to detect any additional mutation and assess their potential impact on clinical outcome.
  • Required tumor samples are (see also Table A19): • Mandatory archival paraffin tumor tissue from curative surgical specimen (see Inclusion Criterion #7): this may be a tumor block (preferred) or 20 unstained slides (15 slides for patients who received neoadjuvant therapy). Since archival samples may not be located at the institution where diagnosis was rendered, the investigational sites will be responsible for locating them and preparing the blocks or unstained slides (or having them prepared), if necessary.
  • tumor tissue sample from the tumor biopsy specimen at the time of the initial diagnosis, or before the administration of neoadjuvant therapy. This sample is mandatory for patients who underwent neoadjuvant therapy and had a pathological complete response (see Inclusion Criterion #7).
  • Mandatory unless unsafe for the patient per Investigator’s discretion
  • tumor biopsy at the time of recurrence and before start of new anti-neoplastic therapy.
  • a sample from both the local/regional recurrence and a distant site is required.
  • This tumor biopsy will be sent to a designated laboratory who will review the biopsy to assure quality and sufficient tumor tissue quantity before the initiation of new anti- neoplastic therapy. If the quality or quantity of the biopsy will not be satisfactory, the Investigator will receive notification, and another biopsy attempt will be made (if safe for the patient) before the start of new anti-neoplastic therapy.
  • PAT059494-WO-PCT Assessments in Blood (mandatory) Mandatory blood samples (4 x 10 mL) for plasma ctDNA/ctRNA will be collected as per Table A19. ctDNA/ctRNA plasma samples will be used to assess mutations, copy number variations and expression of genes that are relevant to HR-positive BC (e.g.
  • PIK3CA, ESR1 and the CDK4/6 pathway and/or cancer using the most sensitive and advanced technology at the time of testing Use of ctDNA/ctRNA in plasma samples offers a unique opportunity to monitor mutations and gene expressions in a non-invasive manner during the course of treatment, allowing for the detection of changes in tumor burden and monitoring response to treatment and disease recurrence. 53–56 . Evaluation of mutations at time of recurrence may provide information regarding potential mechanisms of resistance to hormone and/or CDK4/6 targeted therapy. 6.4.4.2. Additional Biomarker Assessments (optional) This trial includes optional biomarker components that are hypothesis generating (i.e. discovery based research) and/or supported by an exploratory objective.
  • samples When remaining samples are available (tumor, blood, DNA, RNA) in sufficient quantity and quality and if allowed per local regulation, samples may be stored for up to 15 years from end of the trial and further analyzed to address scientific questions related to ribociclib or cancer, including research to help develop ways to detect, monitor or treat cancer.
  • a decision to perform such exploratory biomarker research trials would be based on outcome data from this trial or from new scientific findings related to the drug class or disease, as well as reagent and assay availability. These studies will only be performed in patients giving consent to this optional part of the trial. 6.4.4.3.
  • GWAS genome-wide association studies
  • HLA human leukocyte antigen
  • CYP3A4 CYP3A4 polymorphism
  • PAT059494-WO-PCT Healthcare resource utilization data should be captured throughout the Treatment and Follow- up Phases, as described in Table A12. Every effort should be made to collect data around health care utilization post-recurrence. These data will be collected for 12 months following distant recurrence and should follow the same schedule as for post-recurrence PRO collection (see Table A20). Hospitalization data of interest will focus on those hospitalizations reported as SAEs, as required in Section 7.3.1. Hospitalizations as a result of the following reasons are not to be reported: • Routine treatment or monitoring of the studied indication not associated with any deterioration in condition.
  • the EORTC QLQ-C30, version 3.0, EORTC QLQ-BR23, version 1.0, and the EQ-5D-5L will be used to evaluate PRO measures of health-related QOL, functioning, disease symptoms and treatment-related side effects.
  • the EORTC QLQ-C30, EORTC QLQ-BR23 and the EQ-5D-5L are recognized reliable and valid measures frequently used in clinical trials of patients with PAT059494-WO-PCT BC. 57–59
  • the HADS questionnaire will be used to determine the levels of anxiety and depression experienced by the patient.
  • the study coordinator cannot rephrase the question or translate the question into simpler language; the question has to be read verbatim.
  • Attempts should be made to collect responses to all questionnaires for all patients, including from those who discontinue prior to the trial completion. If a patient refuses to complete questionnaires or in the case a local language should not be available for the patient to complete questionnaires, this should be documented in source records. Patient’s refusal or if a local language is not available to complete questionnaires are not protocol deviations.
  • Investigators should not encourage the patient to change responses reported in questionnaires. Completed questionnaires, including both responses to the questions and any unsolicited comments written by the patient, should be reviewed and assessed by the Investigator before or during the visit, for responses which may indicate potential AEs or SAEs.
  • Table A20 Patient Reported Outcomes (PRO) Collection Plan Questionnaire Visit Day Time Screening Day -28 to -1 PAT059494-WO-PCT Questionnaire Visit Day Time EORTC QLQ-C30 Treatment and • After randomization every 12 For assessments before EORTC QLQ- follows-up weeks ( ⁇ 2 weeks) during the recurrence, BR23 Phases first 24 months, every 24 weeks questionnaires should EQ-5D-5L (including EOT) ( ⁇ 3 weeks) thereafter until be administered prior to HADS distant recurrence. any clinical • At EOT. assessments, drug dosing or diagnostic • At confirmation of first testing; for the recurrence.
  • PAT059494-WO-PCT Period AEs (non-serious) SAEs From: Main PICF signature Only if related to trial All (regardless of To: C1D1 (prior to dosing) participation relationship) From: C1D1 (during/after dosing) All (regardless of relationship) All (regardless of To: 36 months from randomization a relationship) From: 36 months from Not reportable All (regardless of randomization relationship) To: 30-Day Safety Follow-up visit From: 30-Day Safety Follow-up Not reportable Only if related to trial visit treatment To: End of trial a In the Investigational arm, collection according to 2 nd row in the Table should continue up until the 30-Day Post Ribociclib Safety Follow-up visit.
  • each sign or symptom should be reported as a separate AE.
  • the occurrence of AEs should be sought by non-directive questioning of the patient. AE also may be detected when they are volunteered by the patient during the screening process or between visits, or through physical examination, laboratory test, or other assessments. As far as possible, each AE should be evaluated to determine: • Severity grade (per NCI CTCAE v4.03. Refer to Table A22 for severity grade scale for events not listed in NCI CTCAE v4.03) • Duration (start and end dates) • Relationship to the trial treatments • Action taken with respect to trial treatment • Other action taken (e.g.
  • **Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
  • An AE should be followed until its resolution, until it is judged to be permanent, the patient is lost follow-up, or the patient withdraws consent.
  • Assessment should be made at each visit (or more frequently, if necessary) of any changes in: • Severity • Suspected relationship to the trial treatment • Action taken with trial treatment • Interventions required to treat it • Outcome 7.2.2.
  • Worsening of a Pre-existing Condition Worsening of a pre-existing condition after PICF signature should be recorded in the AE CRF. Conditions that were already present at the time of informed consent should be recorded in the Medical History page of the patient’s CRF. 7.2.3.
  • Laboratory test abnormalities that constitute an AE in their own right i.e. are considered clinically significant, induce signs or symptoms, require therapeutic intervention [e.g. hematologic abnormality that requires transfusion] or require changes in trial treatment), should be recorded on the AE CRF.
  • Laboratory abnormalities, that do not meet the definition of an AE should not be reported as AEs.
  • a Grade 3 or 4 event as per CTCAE does not automatically indicate a SAE unless it meets the definition of serious as defined below and/or as per PAT059494-WO-PCT Investigator’s discretion.
  • a dose hold of medication for the laboratory test abnormality may be required by the protocol in which case the abnormality would still, by definition, be an AE and must be reported as such.
  • Each recurrence of an AE should be recorded separately on the AE CRF. 7.2.5.
  • Death Death should be considered an outcome and not a distinct event. The event or condition that caused or contributed to the fatal outcome should be recorded as the single medical concept on the AE CRF. Information about any deaths (related to an AE or not) will also be collected through a Death CRF. 7.2.6.
  • Recurrence of Breast Cancer BC recurrence (including those resulting in fatal outcomes), if documented by use of appropriate method (for example, confirmed recurrence per STEEP Criteria), should not be reported as an AE, including SAE. Progression of malignancy should not be reported as an AE, including SAE. AEs separate from the progression of malignancy (e.g.
  • SAE Second Primary Malignancy Any second primary malignancy must be reported as an AE; if the event meets at least one seriousness criteria it must be reported as SAE.
  • PAT059494-WO-PCT 7.3.
  • An SAE occurring at a different time interval or otherwise considered completely unrelated to a previously reported one should be reported separately as a new event.
  • Any SAEs experienced after the 30-Day Safety Follow-up visit should be immediately reported to Novartis no later than 24 hours of learning of its occurrence if the Investigator suspects a causal relationship to the trial treatment.
  • Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form; all applicable sections of the form must be completed in order to provide a clinically thorough report.
  • the Investigator must assess and record the relationship of each SAE to each specific trial treatment (if there is more than one), complete the SAE Report Form in English, PAT059494-WO-PCT and submit the completed form to Novartis no later than 24 hours of learning about the occurrence. Detailed instructions regarding the SAE submission process and requirements for signatures are to be found in the Investigator folder provided to each site.
  • Follow-up information is submitted in the same way as the original SAE Report. Each re- occurrence, complication, or progression of the original event should be reported as a follow-up to that event regardless of when it occurs.
  • the follow-up information should describe whether the event has resolved or continues, if and how it was treated, and whether the patient continued or was discontinued from trial treatment or participation.
  • the IDMC will be responsible for reviewing the safety results and overseeing the safety data accruing in the trial at regular intervals of approximately every six months, provided that sufficient patients have been randomized. Additionally, the IDMC will perform a safety review when the first patient has completed 12 months of trial treatment. In addition, if requested by the IDMC Chair, additional safety reviews may be performed. The IDMC will also review efficacy data at the planned interim analyses. It is expected that the IDMC will consist at a minimum of two physicians with appropriate disease area qualifications, one patient advocate and one statistician. There will be a meeting with the IDMC describing their roles and responsibilities and discussing potential data format and process issues prior to the finalization of IDMC charter and the interim analysis plan. 8.
  • the actual treatment received corresponds to: • Ribociclib + ET if patients took at least one dose of ribociclib • ET if ribociclib was never received PAT059494-WO-PCT 8.1.3.
  • Per-Protocol Set The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant with requirements of the protocol. All protocol deviations or conditions leading to exclusion from the PPS will be detailed in specific trial document(s). Sensitivity analyses of the primary endpoint of iDFS may be performed using data from the PPS if the FAS and PPS differ and if the primary analysis is significant. 8.1.4.
  • the Pharmacokinetics Analysis Set (PAS) consists of all patients who received at least one dose of ribociclib and have at least one evaluable post-dose concentration measurement. 8.2. Patient Demographics/other Baseline Characteristics Demographic and other baseline data including disease characteristics/prognostic data will be listed and summarized descriptively by treatment arm for the FAS. Categorical data will be presented as frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, and maximum will be presented. Relevant medical histories and current medical conditions at baseline will be summarized by system organ class, preferred term and treatment arm. 8.3. Treatments (trial treatment, concomitant therapies, compliance) The Safety Set will be used for the analyses in this section.
  • Categorical data will be summarized as frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, and maximum will be presented. The duration of exposure in months to ribociclib and ET as well as the dose intensity (computed as the ratio of actual cumulative dose received and actual duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity) will be summarized by means of descriptive statistics. The cumulative doses and average daily doses of ribociclib and ET for each patient will be summarized using descriptive statistics (e.g. mean, standard deviation and median). The number of patients with dose adjustments (reduction, interruption, or permanent discontinuation) and the reasons will be summarized by treatment arm and all dosing data will be listed.
  • Concomitant medications and significant non-drug therapies prior to and after the start of the trial treatment will be listed and summarized according to the Anatomical Therapeutic Chemical (ATC) classification system, by treatment arm.
  • ATC Anatomical Therapeutic Chemical
  • PAT059494-WO-PCT 8.4.
  • Primary Objective The trial is to compare iDFS (per STEEP System) 35 for ribociclib and ET versus ET in pre and postmenopausal women and men with HR-positive, HER2-negative EBC. 8.4.1.
  • the primary efficacy variable of the trial is iDFS, defined as the time from the date of randomization to the date of the first event of local invasive breast recurrence, regional invasive recurrence, distant recurrence, death (any cause), contralateral invasive BC, or second primary non-breast invasive cancer (excluding basal and squamous cell carcinomas of the skin).
  • iDFS events will be assessed locally. Censoring conventions are provided below in Section 8.4.3. 8.4.2.
  • Statistical Hypothesis, Model, and Method of Analysis Assuming proportional hazards for iDFS, the following statistical hypotheses will be tested to address the primary efficacy objective: H 0: ⁇ 1 ⁇ 1 vs.
  • the primary efficacy variable, iDFS will be analyzed at three interim analyses (first interim that may allow the trial to stop due to futility and second and third interim that may allow the trial to declare superior efficacy) and final analysis of a group sequential design, using a Lan-DeMets (O’Brien-Fleming) alpha spending function and a non-binding Lan-DeMets (O’Brien-Fleming) beta spending function. Analyses will be based on the FAS population according to the treatment arm and strata assigned at randomization. The iDFS distribution will be estimated using the Kaplan-Meier method, and Kaplan-Meier curves will be presented for each treatment arm.
  • the iDFS at the end of each year along with 95% confidence intervals (CI) will be presented for each of the two treatment arms.
  • the hazard ratio for iDFS will be calculated, along with its 95% CI, from a stratified Cox model using the same stratification factors as for the log-rank test. PAT059494-WO-PCT If the primary efficacy analysis is statistically significant, additional descriptive analyses of iDFS will also be performed approximately two years after the primary iDFS analysis and at end of trial. 8.4.3. Handling of Missing Values/Censoring/Discontinuations analysis cut-off date. The censoring date will be the date of last recurrence assessment on or prior to data cut-off.
  • the hazard ratio and 95% CI for iDFS will be obtained from: • An unstratified and covariate unadjusted Cox model. • A stratified and covariate adjusted Cox model.
  • the covariates to be included will be detailed in the SAP.
  • iDFS will also be analyzed based on the PPS, using the same analysis conventions as in the primary efficacy analysis, if the FAS and PPS differ and if the primary analysis is significant. If the primary analysis is statistically significant, subgroup analyses to assess the homogeneity of the treatment effect across demographic and baseline disease characteristics (e.g. stage, menopausal status, prior anti-cancer treatment, etc.) will be performed. The subgroups to be considered will be defined in the SAP.
  • Patterns of censored data will be examined by the treatment arms using descriptive statistics (the numbers of censored patients and reasons for censoring). All secondary efficacy objectives will be analyzed at the primary analysis for iDFS (2 nd or 3 rd interim analyses if the efficacy boundary is crossed or final iDFS analysis) and at the time of end of trial (see Section 3.3). Each secondary efficacy endpoint will be analyzed in the FAS population according to the randomized treatment arm and strata assigned at randomization. The distribution of each efficacy objective will be estimated using the Kaplan-Meier method and compared between the two treatments arms using a stratified log-rank test at one-sided 2.5% level of significance, using strata assigned at randomization.
  • RFS Recurrence-Free Survival RFS is defined as the time from date of randomization to date of first event of local invasive breast recurrence, regional invasive recurrence, distant recurrence, or death (any cause). Patients who do not have a RFS event will be censored at the last recurrence assessment on or prior to the data cut-off. 8.5.1.2.
  • Distant Disease-Free Survival DDFS is defined as the time from date of randomization to date of first event of distant recurrence, death (any cause), or second primary non-breast invasive cancer (excluding basal and squamous cell carcinomas of the skin). Patients who do not have a DDFS event will be censored at the last recurrence assessment on or prior to the data cut-off. 8.5.1.3.
  • Overall Survival OS is defined as the time from date of randomization to date of death due to any cause. If a patient is not known to have died, then OS will be censored at the latest date the patient was known to be alive (on or prior to the data cut-off).
  • OS will be analyzed at the primary analysis for iDFS (2 nd or 3 rd interim analyses if the efficacy boundary is crossed or the final iDFS analysis), approximately two years after the primary iDFS analysis, and at the time of end of trial (See Section 3.3).
  • the expected numbers of OS events at the time of the 2 nd and 3 rd interim analyses, the final iDFS analysis, two years thereafter and end of trial are approximately 187, 225, 271, 474 and 641 respectively, assuming a 5-year OS rate of 87% in the control arm, a hazard ratio of 0.85 between the two arms and assuming approximately 10% of patients will be lost to follow-up for OS at the time of the final iDFS analysis (i.e.
  • the physical functioning sub-scale score of the EORTC QLQ-C30 will be the primary PRO variable of interest.
  • the global health status/QoL scale score of the EORTC QLQ-C30, emotional functioning and social functioning sub-scale scores of the EORTC QLQ-C30, the BC symptoms scale of the EORTC QLQ-BR23, the VAS of the EQ-5D-5L, the anxiety domain and depression domain scores of HADS will be the secondary PRO variables of interest.
  • the FAS will be used for analyzing PRO data. Descriptive statistics will be used to summarize the PRO scores and absolute change from baseline scored scales at each scheduled assessment.
  • PRO scores in all sub-scales obtained from EORTC QLQ-C30, the breast symptoms score of QLQ- BR23, the VAS of EQ-5D-5L and the anxiety domain and depression domain scores of HADS PAT059494-WO-PCT will be analyzed using a repeated measures model for longitudinal data to assess the treatment effect over time. The differences in least square means between treatment and control arm, and the corresponding 2-sided 95% CI at selected time points will be presented. 8.5.2.1. Handling of Missing Values/Censoring/Discontinuations manual. No imputation will be applied if the total or subscale scores are missing at a visit.
  • On-treatment period from day of first dose of trial treatment to 30 days after last dose of trial treatment 3.
  • Post-treatment period from 31 days after last dose of trial treatment 8.5.3.2.
  • Adverse Events Summary tables for AEs will include only AEs that started or worsened during the on-treatment period, the treatment-emergent AEs.
  • the incidence of treatment-emergent AEs (new or worsening from baseline) will be summarized by system organ class and/or preferred term, severity (based on CTCAE grades v4.03), type of AE, relation to trial treatment. SAEs and non-serious AEs during the on-treatment period will be tabulated. All deaths (on- treatment and post-treatment) will be summarized.
  • PAT059494-WO-PCT 8.5.3.6 Tolerability in terms of dose reductions and drug interruptions due to AE. Reasons for dose reductions and interruptions will be listed and summarized by treatment arm. Tolerability of ET during both on-treatment period and post-treatment period (Section 8.5.3.1) will be summarized. 8.5.4. Pharmacokinetics Objectives PK analysis will be done using the PAS. PK concentrations of ribociclib will be summarized using descriptive statistics by visit and scheduled time point. All PK concentration data will be listed as appropriate. All concentrations below the LLOQ will be displayed in listings as zero with a flag and handled as zero in any calculations of summary statistics, but handled as missing for the calculation of the geometric means and their CV.
  • LRRFS Loco-Regional Recurrence Free Survival LRRFS is defined as the time from date of randomization to date of first event of local (ipsilateral) invasive breast recurrence, regional invasive recurrence or death due to any cause. Patients who do not have a LRRFS event will be censored at the last recurrence on or prior to the data cut-off.
  • LRRFS will be analyzed at the primary analysis for iDFS (2 nd or 3 rd interim analyses if the efficacy boundary is crossed or the final iDFS analysis) and at the time of end of trial (See Section 3.3), if there is a sufficient number of events.
  • LRRFS data will be listed and summarized by treatment arm. 8.6.2.
  • Resource Utilization Data relating to resource utilization (described in Section 6.4.5) will be used to support health economic evaluations.
  • Trial-specific analyses will focus on descriptive statistics of hospitalizations and hospital facility visits, occurring during the Treatment and Follow-up Phases and will be summarized by treatment arm.
  • analyses may include but are not limited to the meta-analysis of data from this trial combined with data from other trials or the analysis of biomarkers generated from samples collected during the trial but analyzed after the database lock and completion of the CSR.
  • the data analysis will be described in an addendum of the SAP or in a stand-alone analysis plan document, as appropriate. 8.6.4.2. Data Analysis Principles Analysis Sets PAT059494-WO-PCT The FAS will be used for all biomarker analysis. Unless otherwise specified, all statistical analyses of biomarker data will be performed on patients with biomarker data.
  • Basic Tables, Figures and Listings IHC markers data (e.g. Ki67) will be listed by marker and treatment arm and summarized using summary statistics (mean, standard deviation, median, minimum, maximum).
  • Gene expression data and Next Generation Sequencing data will be generated on an oncology specific set of genes. As these data are extensive and complex, only those genes associated with BC and the key pathways of interest will be shown. To understand the relationship with response Kaplan Meier curves, median iDFS and 95% CI may be generated for the most interesting genes using altered vs. non-altered status. All these analyses will be detailed in the SAP or separate biomarker analysis plan. Blood samples will be collected to assess gene expression and alteration in ctDNA/ctRNA. Data will be generated from samples at baseline, on treatment, post treatment and at time of recurrence. The gene expression and alteration of genes relevant to the CDK pathway and BC (e.g.
  • ESR1, PIK3CA ESR1, PIK3CA will be assessed as feasible with the available technology for ctDNA/ctRNA at time of assessment.
  • Known mutation and amplifications in the displayed genes, as defined by the COSMIC (Catalogue of Somatic Mutations in Cancer) database will be listed and summarized by treatment arm and overall using counts and percentages. Those genes whose alteration status is assessed in both tumor tissue and ctDNA will be compared using 2 x 2 concordance table to assess their agreement. Finally, alteration data collected at recurrence will be listed simultaneously with the baseline sample data of the same type. Only positions where there is discordance between the two sources will be displayed. Any additional exploratory analyses on biomarkers will be detailed in the SAP or separate biomarker analysis plan.
  • Advanced analysis methods may be performed to explore relationship between biomarkers and trial endpoints and to identify patterns in the data. Further details will be provided in the SAP or separate biomarker analysis plan. 8.7. Interim and Final iDFS Analyses Three interim analyses are planned after approximately 200, 350 and 425 of the approximately 500 targeted iDFS events (i.e. at approximately 40%, 70% and 85% information fractions, respectively) have been documented. These interim analyses are expected to occur around 27, PAT059494-WO-PCT 35 and 39 months from the date of first patient randomized in the trial. The primary intent of the first interim analysis is to stop early for lack of efficacy (futility). There is no intent to carry out an analysis to declare superior efficacy at the time of the first interim analysis.
  • the second and third interim analyses will allow the trial to declare outstanding efficacy.
  • the second interim analysis will only be carried out after all patients have been randomized and (if not withdrawn early) have at least one post-baseline recurrence assessment as per Section 6.4.1.1.
  • An alpha-spending function according to a three-look (Lan-DeMets) group sequential design with (O’Brien-Fleming) type stopping boundary (as implemented in East 6.4) will be used to construct the efficacy stopping boundaries.
  • 61 A Lan-DeMets (O’Brien-Fleming) type stopping boundary as implemented in East 6.4 will be used as a beta-spending function to determine the non-binding futility boundary.
  • the choice of non-binding nature of the futility stopping boundary ensures that the efficacy stopping boundaries are not affected.
  • the efficacy and futility boundaries will need to be re- calculated using the pre-specified ⁇ -and ⁇ -spending functions and based on the actual number of observed events at interim and the total number of targeted events to calculate the exact information fraction.
  • the observed p-value (or Z-test statistic) at the interim analyses will then be compared against the re-calculated efficacy (or futility) boundary. If the trial continues to the final iDFS analysis, the final iDFS analysis will be performed when approximately 500 iDFS events have been documented.
  • the observed p-value will have to be less than 0.0202 (or the observed Z-statistics PAT059494-WO-PCT has to be ⁇ -2.0503) to declare statistical significance.
  • the final analysis will be based on the actual number of iDFS events documented at the cut-off date for the final iDFS analysis and the alpha already spent at the interim analyses.
  • the boundary for the final analysis will be derived accordingly from the pre-specified ⁇ -spending function such that the overall significance level across all analyses is maintained at 0.025.
  • Table A23 The statistical properties of the group sequential design are summarized in Table A23 below.
  • Table A24 Estimated Timelines for Interim and Final Analyses Months after randomization of the # iDFS Events Cumulative Power against a first patient (approximation) hazard ratio of 0.73 27 200 (40%) 0 35 350 (70%) 68.4% PAT059494-WO-PCT Months after randomization of the # iDFS Events Cumulative Power against a first patient (approximation) hazard ratio of 0.73 39 425 (85%) 84.8% 44 500 93.1% Calculated using East 6.4 8.8. Sample Size Calculation The sample size calculation is based on the primary variable iDFS. The hypothesis to be tested and details of the testing strategy are described in Sections 8.4.2 and 8.7.
  • the enrollment of patients is expected to be approximately 40% for the Anatomic Stage II and 60% for the Anatomic Stage III.
  • the 5-year iDFS rate for the patients with Anatomic Stage II (excluding low risk patients) is assumed to be approximately 79% (based on data from a retrospective study assessing the prognostic effect of Ki67 and other disease characteristics in HR-positive, HER2-negative EBC 62 ) and 72% (based on data for patients with ⁇ 4 lymph nodes treated with AIs in the EBCTCG meta-analysis 30 ) for the Anatomic Stage III patients, respectively. Based on these assumptions and the expected distribution of patients across the anatomical stages, the overall 5-year iDFS of the control arm is expected to be approximately 74.8%.
  • This calculation assumes analysis by a one-sided log-rank test at the overall 2.5% level of significance, patients randomized to the two treatment arms in a 1:1 ratio, and a 4-look group sequential design with a Lan-DeMets (O’Brien-Fleming) alpha spending function and a Lan-DeMets (O’Brien-Fleming) beta spending function to define a non-binding futility rule at the interim analyses, using an information fraction of 40% for the first interim analysis (futility only) and an information fraction of 70% and 85% for the second and third interim analyses (efficacy only), respectively. The final analysis will be done after approximately 500 iDFS events have been documented.
  • the Investigator/institution may also be subject to an audit by Novartis or designee or to inspections by CA during the conduct of the trial or after the end of the trial.
  • the auditors/inspectors will review documentation at the site to ensure that the trial is conducted, and data is generated, documented (recorded), and reported, in compliance with the protocol, GCP, and the applicable regulatory requirement(s).
  • the Investigator/institution will permit authorized representatives of the Sponsor and CA to examine (and when required by applicable law, to copy) clinical records. Investigators and their relevant personnel should be available as necessary during the monitoring visits, audits and regulatory inspections. 9.2. Ethical Considerations 9.2.1.
  • the IRB/IEC will be informed of SUSARs in other clinical trials conducted with the trial drug by the Investigator or the Sponsor according to the local regulations.
  • the IRB/IEC must be informed by the Investigator of the termination of the trial.
  • 9.2.3. Informed Consent Procedures Eligible patients may only be included in the trial after being given pertinent information about the intended purpose of the trial, the trial treatment, the procedures and possible benefits and hazards to which the patient will be exposed, and after providing written (witnessed by an impartial witness, where required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing so, after such consent has been provided by a legally acceptable representative of the patient, if permitted by local regulation.
  • a legally acceptable representative is an individual or other body authorized under applicable law to consent, on behalf of a prospective patient, to the patient’s participation in the trial.
  • the patient should be informed about the trial to the extent possible given his/her understanding. If the patient is capable of doing so, he/she should indicate assent by personally signing and dating the written informed consent document or a separate assent form.
  • the approved PICF will be read and dated and signed by the patient or her/his legal representative and an impartial witness when legally required, and the Investigator. The Investigator will keep the original PICF on site and the patient will be provided with an original copy (or a photocopy) of the signed PICF.
  • Informed consent must be obtained before conducting any trial-specific procedures, for example before any clinical procedures are PAT059494-WO-PCT performed solely for the purpose of determining eligibility. Procedures that are to be performed as part of the practice of medicine and which would be done whether or not trial entry was contemplated, such as for diagnosis or treatment of a disease or medical condition, may be performed and the results subsequently used for determining trial eligibility without first obtaining consent.
  • the process of obtaining informed consent should be documented in the patient source documents. The date when a patient’s informed consent was actually obtained will be captured in their CRFs.
  • Novartis (or authorized representatives) will provide to Investigators, in a separate document, a proposed PICF that is considered appropriate for this trial and complies with the ICH-GCP guideline and regulatory requirements.
  • the PICF will include a statement by which the patient allows the Sponsor’s duly authorized personnel and representatives, the IRB/IEC, and the CA to have direct access to their data that will be processed in accordance with applicable regulations, e.g. Health Insurance Portability and Accountability Act (HIPAA) and General Data Protection Regulation (GDPR). Any changes to this PICF suggested by the Investigator must be agreed by Novartis (or authorized representatives) before submission to the IRB/IEC, and a copy of the approved version must be provided to the monitor after IRB/IEC approval.
  • HIPAA Health Insurance Portability and Accountability Act
  • GDPR General Data Protection Regulation
  • Women of CBP should be informed that taking the trial drug may involve unknown risks to the fetus if pregnancy were to occur during the trial and agree that in order to participate in the trial they will adhere to the contraception requirement for the duration of the trial. If there is any question that the patient will not reliably comply with this requirement, they should not be entered in the trial. If important new information becomes available that may be relevant to the patient’s consent and willingness to continue participation in the trial, the PICF will be revised and submitted to IRB/IEC and CA (if applicable) for approval/favorable opinion. The new information will be then discussed with the patient in a timely manner and if she/he agrees to continue participation in the trial, the revised PICF will be signed and dated and the patient will receive a copy.
  • the patient may withdraw from the trial at anytime without prejudicing future medical treatment. In any case, withdrawal should be documented on patient ⁇ s clinical records.
  • 9.2.3.1. Additional Consent There are two optional consents from the patient: one for additional biomarker assessments to be performed when residual samples are remaining (see Section 6.4.4.2) and another for the collection of an additional blood sample to be collected for pharmacogenetic assessment (see Section 6.4.4.3).
  • PAT059494-WO-PCT In order to participate in these sub-studies, the patient must give his/her explicit consent. If a patient opts not to participate in the optional assessments, this in no way affects the patient’s ability to participate in the main research trial.
  • Essential documents are all information, original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.
  • Examples of these original documents and data records include, but are not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation PAT059494-WO-PCT checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and patients files and records kept at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical trial. Changes to Essential Documents must be traceable, should not obscure the original entry, and should be explained if necessary (e.g. via an audit trail).
  • the Investigator/institution must maintain the trial documents as specified in section 8 of the ICH E6 GCP and as required by applicable regulations and/or guidelines. The Investigator/institution must take measures to prevent accidental or premature destruction of these documents.
  • Essential documents written and electronic
  • the trial electronic CRF is the primary data collection instrument for the trial. Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained. All data requested on the CRF must be recorded. Any missing data must be explained.
  • An audit trail will be maintained by the system.
  • the designated site staff will enter the data required by the protocol into the CRF within 7 calendar days of availability.
  • the CRFs have been built using fully validated secure web- enabled software that conforms to 21 CFR Part 11 requirements.
  • Investigator site staff will not be given access to the Electronic Data Capture (EDC) system until they have been trained.
  • Automatic validation programs check for data discrepancies in the CRFs and, allow modification or verification of the entered data by the Investigator staff.
  • the Principal Investigator is responsible for assuring that the data entered into CRF and all other required reports is complete, accurate, and that entry and updates are performed in a timely manner.
  • PRO data will be recorded by patients on paper forms and entered in the CRF by site staff. Blood samples for laboratory data will be collected and processed locally.
  • ECG data will be sent to a central laboratory for processing, and the results will be sent electronically to sites and Novartis (or authorized representatives).
  • Biomarkers blood samples and tumor samples will be collected by sites and sent to the Novartis designated central laboratory for processing and the results will be sent electronically to Novartis (or authorized representatives).
  • PAT059494-WO-PCT 9.4.3. Database Management Novartis (or authorized representatives) will review the data entered by investigational staff for completeness and accuracy. This is an open-label trial. Investigators, patients, TRIO and the Sponsor will have full knowledge of the treatment allocation.
  • Randomization codes and data about all trial treatments dispensed to the patient and all IRT assigned dosage changes will be tracked in a system supplied by a vendor(s), who will also manage the IRT database.
  • the data will be sent electronically to Novartis personnel (or authorized representatives). After data have been verified to be complete and accurate, the database will be declared locked. Authorization is required prior to making any database changes to locked data, by joint written agreement between TRIO and Novartis’ Global Head of Biostatistics and Data Management and Global Head of Clinical Development. After database lock, the Investigator will receive electronic or paper copies of the patient data for archiving at the investigational site. 9.4.4.
  • the patient’s personal data and Investigator’s personal data will be utilized in the conduct of this trial and shall be treated in compliance with all applicable laws and regulations, e.g. HIPAA and GDPR.
  • the TRIO, Novartis, and their representatives shall take all appropriate measures to safeguard and prevent access to this data by any unauthorized third party.
  • PAT059494-WO-PCT 9.4.5.
  • Data Confidentiality The Investigator must ensure confidentiality of the patients; patients must not be identified in any documents submitted to TRIO or Novartis (or representatives), for example, signed PICFs and patient enrollment logs with patients’ names must be kept strictly confidential. Such documents must be kept at site to enable patient identification.
  • the data collection system for this trial uses built-in security features to encrypt all data for transmission in both directions, preventing unauthorized access to confidential participant information. Access to the system will be controlled by a sequence of individually assigned user identification codes and passwords, made available only to authorized personnel who have completed prerequisite training. Prior to entering key sensitive personally identifiable information (patient initials and exact Date of birth), the system will prompt site to verify that this data is allowed to be collected. If the site indicates that country rules or ethics committee standards do not permit collection of these items, the system will not solicit patient initials. Year of birth will be solicited (in the place of exact date of birth) to establish that the patient satisfies protocol age requirements and to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
  • Siegel RL Miller KD, Jemal A: Cancer statistics, 2018. CA Cancer J Clin 68:7–30, 2018 4.
  • Pfizer Provides Update on Phase 3 PALLAS Trial of IBRANCE® (palbociclib) Plus Endocrine Therapy in HR+, HER2- Early Breast Cancer
  • Tripathy D, Im S-A, Colleoni M, et al Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial [Internet].
  • NCCN 2018[cited 2018 Jul 12] Available from: https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf 51.
  • Elston CW, Ellis IO Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 41:154–161, 2002 52. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649–655, 1982 53. Dawson S-J, Rosenfeld N, Caldas C: Circulating tumor DNA to monitor metastatic breast cancer.
  • Murtaza M, Dawson S-J, Pogrebniak K, et al Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer. Nat Commun 6:8760, 2015 57.
  • Aaronson NK, Ahmedzai S, Bergman B, et al The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365–376, 1993 58.
  • Sprangers MA, Groenvold M, Arraras JI, et al The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three- country field study.
  • Appendices Appendix 1 Guidelines for Anatomic Stage Groups for Breast Cancer Staging Guidelines for Anatomic Stage Groups according to AJCC Ed.8 th applicable to this trial are presented in Table A25 below (modified from 63 ).
  • Recurrences will be classified into local, regional or distant recurrence, or contralateral invasive breast cancer or second primary non-breast invasive cancer according to the following guidelines: • Local invasive breast cancer recurrence or ipsilateral invasive breast tumor recurrence: invasive breast cancer involving the same breast as the original primary tumor. Ductal and lobular carcinoma in situ and tumors in the contralateral breast and/or contralateral lymph nodes are not considered a local invasive recurrence.
  • Local recurrence has to be confirmed histologically. Histological type of local invasive breast cancer recurrence should be recorded in the CRF. • Regional breast cancer recurrence: invasive breast cancer in the ipsilateral axilla, regional lymph nodes (all levels), chest wall, or skin of the ipsilateral breast. A tumor in the contralateral breast is not considered a regional recurrence. Regional recurrence has to be confirmed histologically (preferred) or cytologically. The specific site of regional recurrence should be recorded in the CRF.
  • Distant recurrence distant metastasis of breast cancer (bones, distant lymph nodes, internal organs, CNS, bone marrow, etc.) or any areas of invasive breast cancer recurrence that are not local or regional. Distant recurrence has to be confirmed histologically (preferred) or cytologically unless there is an unacceptable risk to the patient due to the procedure. If bone metastases were identified by a bone scan, it has to be confirmed histologically (preferred) or radiographically (CT, MRI or FDG-PET-CT) if biopsy confirmation is not possible.
  • CT radiographically
  • Metastases in the central nervous system has to be confirmed histologically (preferred), cytologically or radiographically (CT or MRI, both with IV contrast) if biopsy confirmation is not possible. All other sites of metastases have to be confirmed histologically (preferred) or cytologically unless there is an unacceptable risk to the patient due to the procedure. Location of first three most dominant distant metastases should be reported in the CRF with preference given to visceral (including brain) metastases, than to bone, than distant lymph node or skin metastases. • Contralateral invasive breast cancer: any invasive breast cancer in the contralateral breast with or without contralateral lymph nodes involvement. Contralateral invasive breast cancer has to be confirmed histologically.
  • Second primary non-breast invasive cancer any second primary non-breast invasive cancers. Second primary non-breast invasive cancer has to be confirmed histologically. In situ/non-invasive cancers and basal or squamous cell carcinomas of the skin are not considered as second primary non-breast invasive cancers. Histological type and location of second primary non-breast invasive cancer should be recorded in the CRF.
  • PAT059494-WO-PCT Appendix 4 Concomitant Medications
  • DAI drug-drug interactions
  • Table A27 List of Prohibited Medications During Ribociclib Treatment Category Drug Name S trong CYP3A4/5 inhibitors Atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, darunavir/ritonavir, elvitegravir/ritonavir, grapefruit juice, idelalisib, indinavir, indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, ombitasvir/paritaprevir/dasabuvir/ritonavir (VIEKIRA PAK), posaconazole, ritonavir, saquinavir/ritonavir, telaprevir, telithromycin, tipranavir/rit
  • NTI narrow therapeutic index drugs whose exposure-response indicates that increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g. TdP) or drugs which have ⁇ 2-fold difference in the minimum toxic concentrations and minimum effective concentrations in the blood.
  • TdP serious safety concerns
  • P-gp inducer 4 The list provided is as of December 2019. Check https www.crediblemeds.org/healthcare-providers/drug-list for the most updated list. 5 Drug has warning for risk of hepatotoxicity.
  • Table A28 List of Medications to be Used with Caution During Ribociclib Treatment Category Drug Name Moderate CYP3A4/5 Aprepitant, amprenavir, asafoetida resin (Ferula asafoetida) cimetidine, crizotinib, inhibitors diltiazem, faldaprevir, imatinib, isavuconazole, netupitant, nilotinib, tofisopam, Schisandra sphenanthera (nan wu wei zi), verapamil PAT059494-WO-PCT Category Drug Name Moderate CYP3A4/5 Bosentan, dabrafenib, efavirenz, etravirine, genistein,lopinavir 5 , modafinil, inducers nafcillin,telotristat Sensitive CYP3A4/5 Alpha-dihydroergocryptine
  • EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single- item measures. These include five functional scales (physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/QoL scale. 57
  • the EORTC QLQ-BR23 is used for women only in conjunction with the EORTC QLQ-C30 and provides information on an additional 23 items specifically related to breast cancer.
  • the EQ-5D-5L is a standardized measure of health utility that provides a single index value for one’s health status.
  • the EQ-5D-5L is frequently used for economic evaluations of health care and has been shown to be a valid and reliable instrument.
  • the EQ-5D-5L contains one item for each of five dimensions of health-related QOL (HRQOL, i.e. mobility, self-care, usual activities, pain or discomfort, and anxiety or depression). Response options for each item vary from having no problems (e.g. “...no problems walking about”), moderate problems (e.g. “...some problems walking about”), or extreme problems (e.g. “...unable to walk about”).
  • HRQOL health-related QOL
  • Patient responses to the five dimensions of HRQOL reflect a specific health state that corresponds to a population preference weight for that state on a continuous scale of 0 (death) to 1 (perfect health).
  • a visual analog scale (VAS), ranging from 0 to 100 is also included to capture patient’s rating of their overall health status. Higher scores of the EQ-5D-5L represent better health states. All scoring and handling of data will follow the User’s Guide defined by the EuroQoL Group. 59 An example of this questionnaire is found in FIG.7. The questionnaire provided here is a sample for information purposes only. Questionnaires for patient completion in the trial will be provided by TRIO to be used as source documents.
  • the HADS is a 14-item, self-completed questionnaire designed to screen for depression and anxiety in and outside of the hospital and in community settings.
  • the HADS takes approximately 10 minutes to complete and has been widely used to measure depression and anxiety in adults.
  • hospital refers to the setting in which the instrument was first developed, many studies conducted throughout the world have confirmed that it is valid when used in community settings and primary care medical practice.
  • Even-numbered questions relate to depression, and odd-numbered questions relate to anxiety. All items are scored on a scale from 3 to 0, with a maximum score of 21 for each subscale. A score of 11 or higher indicates the probable presence of a mood disorder, and a score of 8 to 10 is suggestive of a mood disorder.
  • depression and anxiety are independent measures and can be mapped into four ranges: normal (0-7), mild (8-10), moderate (11-15), and severe (16-21).
  • a score for a single item may be inferred by using the mean of the remaining six items. However, if more than one item is missing, the questionnaire should not be scored. An example of this questionnaire is found in FIG.8.
  • the questionnaire provided here is a sample for information purposes only. Questionnaires for patient completion in the trial will be provided by TRIO to be used as source documents.
  • Randomization was stratified by : • AJCC Anatomic Stage : II [2154 (42.2%)] vs III [2947 (57.8%)] • Menopausal Status : Premenopausal/Men [2253 (44.2%)] vs Postmenopausal [2848 (55.8%)] • Prior Chemotherapy : Yes [4432 (86.9%)] vs No [669 (13.1%)] • Region : North America/Western Europe/Oceania [3128 (61.3%)] vs ROW[1973 (39.7%)] • Based on the protocol pre-specified third interim analysis (IA3) review of the data on Mar 21, 2023 by the IDMC, the efficacy boundary was met.
  • IA3 third interim analysis
  • the RFS HR is 0.719, 95% CI (0.584, 0.884) for RIB + ET vs ET Only. One sided nominal p-value is 0.0008.
  • DDFS Distant Disease Free Survival
  • the DDFS HR is 0.739, 95% CI (0.603, 0.905) for RIB + ET vs ET Only.
  • One sided nominal p-value is 0.0017.
  • Overall survival (OS) There were 61/2549 (2.4%) OS events reported in the RIB + ET arm vs 73/2552 (2.9%) events in the ET only arm.
  • the OS HR is 0.759, 95% CI (0.539, 1.068) for RIB + ET vs ET Only.
  • One sided nominal p-value is 0.0563.
  • the p-values for the secondary efficacy endpoints are nominal and not adjusted for multiplicity Safety and Tolerability
  • the median duration of exposure to study treatment was 30.1 months in the RIB + ET arm, and 30.0 months in the ET Only arm (from start of treatment to last treatment as per data cut-off date) • 515 (20.2%) patients completed the 3-year RIB regimen and 1450 (56.9%) patients had achieved 2 years or more.
  • -T stage category T1 collects T1mi, T1a, T1b, and T1c.
  • Category T4 collects T4a, T4b, T4c, and T4d.
  • -N stage category N0 collects N0 and N0(i+).
  • Category N1 collects N1, N1a, N1c, and N1mi.
  • Category N2 collects N2a, N2b, and N2c.
  • Category N3 collects N3a, N3b, and N3c.
  • category Stage 1 collects Stage IA and Stage IB.
  • Category Stage II collects Stage IIA and Stage IIB.
  • Stage III collects Stage IIIA, Stage IIIB, and Stage IIIC.Stage is derived using TNM from surgery for patients having not received neo-/adjuvant treatment, or as worst stage derived using TNM at diagnosis and TNM from surgery for patients having received neo-/adjuvant treatment. -Patients may have had more than one Genomic test type but are only counted once per type.
  • Stage I collects Stage IA and Stage IB.
  • Category Stage III collects Stage IIIA, Stage IIIB, and Stage IIIC.
  • Stage is derived using TNM from surgery for patients having not received neo-/adjuvant treatment, or as worst stage derived using TNM at diagnosis and TNM from surgery for patients having received neo-/adjuvant treatment.
  • -Ki67 based on surgical specimen record. If surgical specimen for Ki67 unavailable, then score at diagnosis is used for the summary.
  • -Censoring date is the last assessment before the earliest of the following: analysis cut-off date, date of consent withdrawal, or date of last contact. -% is based on N in each arm.
  • [a] Baseline covariates included in the Cox proportional hazard model are Age category ( ⁇ 45, 45 - 54, and 55 - 64 vs. >64 years of age), ER/PR status (ER+/PR+ vs. other), and ET type (Letrozole vs. Anastrozole).
  • [b] Analysis excludes the event whenever it occurred after missing > 2 tumor assessments.
  • [c] Analysis uses the date of the next scheduled assessment for events occurring after missing > 1 assessment.
  • FIGS.12 and 13 for iDFS - Kaplan-Meier survival curves of iDFS by Anatomic Stage II and III, respectively.
  • -Hazard rate in group ET + ribociclib versus hazard rate in group ET only is computed using the Cox proportional hazards model with treatment as a single covariate and premenopausal women and men vs. postmenopausal women, anatomic stage group II vs. anatomic stage group III, prior neo-/adjuvant chemotherapy (yes vs. no) and North America/Western Europe/Oceania vs. rest of world as stratification factors.
  • the group ET only is the reference in the hazard ratio calculation.
  • PAT059494-WO-PCT See FIG.15 for Kaplan-Meier for DDFS (Full analysis set).
  • Figure 4.2-2 Kaplan-Meier for DDFS (Full analysis set)
  • Table B4.2-4 Cox regression model results for DDFS (Full analysis set) Treatment n/N (%) Comparison Hazard Ratio 95% CI ET + Ribociclib 167/2549 (6.6) vs. ET Only 0.739 (0.603, 0.905) ET Only 212/2552 (8.3) -n is the number of DDFS events.
  • -N total number of patients included in the analysis.
  • -Hazard rate in group ET + ribociclib versus hazard rate in group ET only is computed using the Cox proportional hazards model with treatment as a single covariate and premenopausal women and men vs. postmenopausal women, anatomic stage group II vs. anatomic stage group III, prior neo-/adjuvant chemotherapy (yes vs. no) and North America/Western Europe/Oceania vs. rest of world as stratification factors.
  • the group ET only is the reference in the hazard ratio calculation.
  • Table B4.2-6 Kaplan-Meier for Distant Disease Free Survival (Full analysis set) See FIG.16 for Kaplan-Meier for OS (Full analysis set).
  • Table B4.2-7 Cox regression model results for OS (Full analysis set) Treatment n/N (%) Comparison Hazard Ratio 95% CI ET + Ribociclib 61/2549 (2.4) vs.
  • -Hazard rate in group ET + ribociclib versus hazard rate in group ET only is computed using the Cox proportional hazards model with treatment as a single covariate and premenopausal women and men vs. postmenopausal women, anatomic stage group II vs. anatomic stage group III, prior neo-/adjuvant chemotherapy (yes vs. no) and North America/Western Europe/Oceania vs. rest of world as stratification factors.
  • the group ET only is the reference in the hazard ratio calculation.
  • -AESIs may fall under more than one category but are only reported once per AESI category.
  • -MedDRA Version 25.1 has been used for reporting.
  • Normalized Ratio 5 ( 0.2) 1 ( 0.0) 0 3 ( 0.1) 2 ( 0.1) 0 (sec) Hyper Grade -Baseline is defined as the last non-missing value prior to the start date of study treatment. -Percentages are based on N. -Patients are counted only for the worst grade observed post-baseline. - Laboratory assessments performed more than 30 days after last study treatment administration date are not summarized. -CTCAE Version 4.03 is used for reporting.
  • -Percentages are based on N. -Patients are counted only for the worst grade observed post-baseline. - Laboratory assessments performed more than 30 days after last study treatment administration date are not summarized. -CTCAE Version 4.03 is used for reporting.
  • - n Number of subjects who meet the designated criterion.
  • - m Number of subjects at risk for a specific category. This is the number of patients with a non-missing value at baseline and at least one non-missing post-baseline value.
  • - N Total number of patients in the treatment group in this analysis set.
  • -ECG assessments based on central laboratory results only.
  • -Baseline is defined as the last assessment on or before start of study treatment. For any replicate/triplicate ECGs per time point, the average of these measurements would be calculated for baseline.
  • -n Number of subjects who meet the designated criterion.
  • -m Number of subjects at risk for a specific category. For new abnormality post-baseline, this is the number of patients with both baseline and post-baseline evaluations, and baseline not meeting the criteria. For abnormal change from baseline, it is the number of patients with both baseline and post- baseline evaluations.
  • -N Total number of subjects in the treatment group in this analysis set.
  • Max 48 -Duration of follow-up is calculated as ⁇ min(Cut-off date, death date, date of dropout from study) - Date of randomization + 1 ⁇ /30.4375 (months).
  • -Randomization (recruitment) period (Date of last patient randomized - Date of first patient randomized + 1)/30.4375 (months).
  • -Duration between randomization and data cut-off date (Cut-off date - Date of randomization + 1)/30.4375 (months).

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Abstract

La présente invention concerne le traitement adjuvant du cancer du sein précoce HR+/HER2 de stade II ou III chez des patients adultes. Le procédé comprend l'administration de ribociclib (un inhibiteur de CDK4/6) en combinaison avec une thérapie endocrinienne.
PCT/IB2024/052897 2023-03-27 2024-03-26 Procédé de traitement du cancer du sein précoce avec du ribociclib en combinaison avec un inhibiteur d'aromatase Pending WO2024201299A1 (fr)

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AU2024244511A AU2024244511A1 (en) 2023-03-27 2024-03-26 Method of treating early breast cancer with ribociclib in combination with an aromatase inhibitor
KR1020257035128A KR20250163966A (ko) 2023-03-27 2024-03-26 리보시클립과 아로마타제 저해제를 병용하여 초기 유방암을 치료하는 방법
IL323411A IL323411A (en) 2023-03-27 2025-09-16 Early-stage breast cancer treatment method with ribociclib in combination with an aromatase inhibitor
MX2025011364A MX2025011364A (es) 2023-03-27 2025-09-25 Metodo de tratamiento de cancer de mama en estadio inicial con ribociclib en combinacion con un inhibidor de la aromatasa

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