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WO2024246824A1 - Méthodes et schémas posologiques modifiés comprenant un inhibiteur de cdk4 pour le traitement du cancer - Google Patents

Méthodes et schémas posologiques modifiés comprenant un inhibiteur de cdk4 pour le traitement du cancer Download PDF

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Publication number
WO2024246824A1
WO2024246824A1 PCT/IB2024/055296 IB2024055296W WO2024246824A1 WO 2024246824 A1 WO2024246824 A1 WO 2024246824A1 IB 2024055296 W IB2024055296 W IB 2024055296W WO 2024246824 A1 WO2024246824 A1 WO 2024246824A1
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Prior art keywords
cancer
subject
administered
inhibitor
cdk4
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English (en)
Inventor
Justin Thomas HOFFMAN
Jing Yang
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Pfizer Corp Belgium
Pfizer Corp SRL
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Pfizer Corp Belgium
Pfizer Corp SRL
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Publication of WO2024246824A1 publication Critical patent/WO2024246824A1/fr
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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
    • A61K31/495—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to the therapeutic treatment of cancer with a cyclin-dependent kinase (CDK) inhibitor, 1 ,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-1-(propan-2-yl)-1 H-benzimidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3- dideoxy-D-threo-pentitol (hereinafter PF-07220060), either alone as a monotherapy or in combination with endocrine therapeutics.
  • CDK cyclin-dependent kinase
  • the invention also relates to associated combination therapies, pharmaceutical compositions, and pharmaceutical uses.
  • CDKs are important cellular enzymes that perform essential functions in regulating eukaryotic cell division and proliferation. CDK inhibitors may be useful for the treatment of proliferative disorders, including cancer.
  • Rb1 retinoblastoma protein
  • CDK4 or CDK6 phosphorylated by CDK4 or CDK6.
  • CDK4/6- retinoblastoma protein axis in cancer is supported by gene alterations commonly identified in breast cancers, such as cyclin D1 (CCND1) and cyclin E1 (CCNE1) gene amplification and alterations in endogenous CDK4-cyclin D1 inhibitor p16 (INK4a, encoded by the CDKN2A gene), TP53 and PIK3CA genes.
  • CCND1 cyclin D1
  • CCNE1 cyclin E1
  • INK4a endogenous CDK4-cyclin D1 inhibitor p16
  • TP53 TP53
  • PIK3CA PIK3CA
  • CDK4/6 inhibition has emerged as a promising strategy for cancer therapy, especially for the treatment of endocrine resistant BC.
  • CDK4/6 inhibitors e.g., palbociclib, abemaciclib, ribociclib
  • CDK4/6 inhibitors when dosed in combination with endocrine therapy, have significantly improved progression-free survival and/or overall survival for patients with HR-positive/HER2-negative metastatic breast cancer.
  • CDK4/6 inhibitors increase response rates and prolong disease control in patients with HR+, HER2- breast cancer, they are associated with dose-limiting hematologic toxicities, primarily neutropenia.
  • PF-07220060 is a potent inhibitor of cyclin dependent kinase 4 (CDK4).
  • CDK4 cyclin dependent kinase 4
  • Preparation of PF-07220060 is described in International Patent Publication No. WO 2019/207463, U.S. Patent Nos. 10,766,884 and 11 ,220,494, and US Patent Publication US 2022/0089580; International Publication No. WO 2022/058871 , and International Publication No. WO 2023/100070. The contents of which are incorporated herein by reference in their entirety.
  • references herein to PF- 07220060 include references to salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labelled versions thereof.
  • PF-07220060 differs from currently approved dual CDK4/6 inhibitors in that it displays greater CDK4-over-CDK6 selectivity. In in vivo models, PF-07220060 reduces dose-limiting neutropenia and is projected to potentially attain higher tolerated plasma concentrations than dual CDK4/6 inhibitors, thus potentially enabling increased inhibition of the CDK4 oncogene in tumors.
  • the disclosure relates to both single agent and combination therapies, for treating cancer, which comprise the CDK4 inhibitor, PF-07220060.
  • the disclosure provides a method of treating cancer comprising orally administering to a subject in need thereof a therapeutically effective amount of PF-07220060.
  • the method includes administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of PF- 07220060 in a total daily dose of from about 10 mg to about 190 mg per day.
  • the disclosure provides a method of treating cancer comprising administering to a subject in need thereof with a therapeutically effective amount of PF-07220060, and an endocrine therapy agent.
  • the endocrine therapy agent is an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).
  • the endocrine therapy agent includes fulvestrant, tamoxifen, toremifene, anastrozole, exemestane, or letrozole.
  • embodiments herein provide dosing regimens for PF-07220060 as a single agent and in combination therapies for treating cancer, by which adverse effects are minimized in a subject during the treatment period.
  • a dose of about 100 mg should be understood to mean that the dose may vary between 90 mg and 110 mg.
  • dose limiting toxicity refers to the dosage of PF-07220060 that is contraindicative of a further increase in dosage.
  • measurable lesion refers to Lesions that can be accurately measured in at least one dimension, lesions with longest diameter twice the slice thickness and at least 10 mm or greater when assessed by CT or MRI (slice thickness 5-8 mm), lesions with longest diameter at least 20 mm when assessed by Chest X-ray, superficial lesions with longest diameter 10 mm or greater when assessed by caliper, or malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
  • maximum tolerated dose refers to the highest dosage of PF-07220060 that does not cause unacceptable side effects or intolerable toxicities. MTD is estimated using the mTPI based on observed DLT rate, with a target DLT rate of 27.5% and equivalence interval of 22.5-32.5%.
  • the term "pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refers to a component that may be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and causes no significant adverse effects to a subject.
  • a “rest period” is the number of days from administration of one complete dose of the active agent to the next administration of one complete dose of the active agent.
  • week means 7 consecutive days.
  • a 4-week period is 28 consecutive days starting on any day of the calendar week.
  • the term “subject” may be a mammal, which refers to any animal species of the Mammalia class.
  • mammals include: humans; non-human primates such as monkeys; laboratory animals such as rats, mice, guinea pigs; domestic animals such as cats, dogs, rabbits, cattle, sheep, goats, horses, and pigs; and captive wild animals such as lions, tigers, and the like.
  • the subject is a human.
  • the subject is a female.
  • the subject is a male.
  • the phrase "therapeutically effective amount" for use and/or for treating a subject refers to an amount that provides, in single or multiple doses, alone, or in combination with one or more other agents, treatments, protocols, or therapeutic regimens, a detectable response of any duration of time (transient, medium or long term), a desired outcome in or an objective or subjective benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for hours, days, months, years, in remission or cured).
  • Such amounts typically are effective to ameliorate a disease, or one, multiple or all adverse effects / symptoms, consequences, or complications of the disease, to a measurable extent, although reducing or inhibiting a progression or worsening of the disease, or providing stability (/.e., not worsening) state of the disease, is considered a satisfactory outcome.
  • therapeutically effective amount also means an amount of an active agent effective for producing a desired therapeutic effect upon administration to a subject, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor.
  • a therapeutically effective amount is well within the capability of those skilled in the art.
  • the dosage can vary within the range depending upon the dosage form employed and the route of administration utilized.
  • a therapeutically effective amount of a compound described herein administered to a subject can be dependent upon factors known to a skilled artisan, including bioactivity and bioavailability of the compound (e.g., half-life and stability of the compound in the body), chemical properties of the compound (e.g., molecular weight, hydrophobility and solubility); route and frequency of administration, and the like.
  • the specific dose of the pharmaceutical composition comprising a compound as disclosed herein can depend on a variety of factors including physical condition of the subject (e.g., age, gender, weight), and medical history of the subject (e.g., medications being taken, health condition other diseases or disorders).
  • the precise dose of a pharmaceutical composition administered to a subject can be determined by methods known to a skilled artisan such as a pharmacologist, or an anesthesiologist.
  • ameliorate refers to any reduction in the extent, severity, frequency, and/or likelihood of a symptom or clinical sign characteristic of a particular disease.
  • Symptom refers to any subjective evidence of disease or of a subject’s condition.
  • “treat” or “treating” a cancer and/or a cancer-associated disease means to administer a mono- or combination therapy according to the present disclosure to a subject, patient or individual having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and I or prolonging survival of patients the cancer.
  • Positive therapeutic effects in cancer can be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. 50:1S-10S (2009)).
  • Tumor as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumors and secondary neoplasms.
  • a solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukaemia’s (cancers of the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).
  • metastatic breast cancer refers to the spread of cancer from a primary tumor site to distant organs.
  • metastatic breast cancer refers to breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body, e.g., bones, liver, lungs, brain. (www.cancer.org/cancer/breast-cancer.)
  • combination refers to the administration of two or more therapeutic agents of the combination therapy, either alone or in the form of a pharmaceutical composition or medicament.
  • the combination therapy may be administered sequentially, concurrently, or simultaneously.
  • the agents may be administered on the same treatment cycle or using different cycles.
  • PF-07220060 is administered continuously on a 28-day cycle.
  • letrozole is typically administered continuously on a 28-day treatment cycle.
  • Palbociclib is typically administered using an intermittent 28-day treatment cycle, comprising administration of the drug for 21 days, with a rest period of 7 days between the cycles.
  • Fulvestrant is typically administered intramuscularly on days 1 , 15, 29 of the first treatment cycle and once monthly thereafter.
  • Each therapeutic agent of the methods and combination therapies described herein may be administered either alone, or in a medicament (also referred to herein as a pharmaceutical composition) which comprises the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients, or diluents, according to pharmaceutical practice.
  • sequential refers to the administration of each therapeutic agent of the combination therapy, either alone or in a medicament, one after the other, wherein each therapeutic agent can be administered in any order. Sequential administration may be particularly useful when the therapeutic agents in the combination therapy are in different dosage forms, for example, one agent is a tablet and another agent is a sterile liquid, and/or the agents are administered according to different dosing schedules, for example, one agent is administered daily, and the second agent is administered less frequently such as weekly.
  • each therapeutic agent in a combination therapy, either alone or in separate medicaments, wherein the second therapeutic agent is administered immediately after the first therapeutic agent, but that the therapeutic agents can be administered in any order.
  • the therapeutic agents are administered concurrently.
  • spontaneous refers to the administration of each therapeutic agent of the combination therapy in the same medicament, for example as a fixed dose combination comprising two or more drugs in a single dosage form.
  • a “dosing regimen” refers to the period of administration of one or more drugs, compounds or compositions, comprising one or more treatment cycles, wherein each treatment cycle may include administration of one or more agents at different times, frequencies or amounts, using the same or different routes of administration. Repetition of the administration or dosing regimens, or adjustment of the administration or dosing regimen may be conducted as necessary to achieve the desired treatment effect.
  • Dosage amounts are calculated as the free base equivalent of an administered PF-07220060 free base form, hydrate form or salt form.
  • a dosage or amount of PF-07220060 such as about 10 mg, about 50 mg, about 75 mg, or about 100 mg, refers to the free base equivalent.
  • the ECOG Scale of Performance Status was developed by the Eastern Cooperative Oncology Group as standard criteria for measuring how the disease impacts a patient’s daily living abilities. It describes a participant’s level of functioning in terms of their ability to care for themself, daily activity, and physical ability (walking, working, etc.).
  • PF-07220060 (Pfizer Inc.) is a selective CDK4 inhibitor that is currently in phase III clinical trial for the treatment of cancers, and has the following structure of formula (I):
  • certain embodiments of this disclosure provide a therapeutic dose and dosing regimen comprising administering to a subject a therapeutically effective amount of PF-07220060.
  • PF-07220060 may be present in a pharmaceutical composition which includes a pharmaceutically acceptable carrier.
  • the therapeutically effective amount of PF- 07220060 in the pharmaceutical compositions can be from about 10 mg to about 190 mg, or any of the therapeutically effective amounts disclosed herein.
  • the therapeutically effective amount of PF-07220060 is from about 10 mg to about 190 mg per day (i.e., total daily dose), for example, from about 20 mg to about 180 mg, from about 30 mg to about 170 mg, from about 40 mg to about 160 mg per day.
  • PF-07220060 may be administered once a day (QD) or twice a day (BID).
  • PF-07220060 is administered in doses of from about 10 mg to about 100 mg once a day (QD), for example, from about 20 mg to about 100 mg QD, from about 30 mg to about 100 mg QD, from about 40 mg to about 100 mg QD, from about 50 mg to about 100 mg QD, from about 60 mg to about 100 mg QD, from about 70 mg to about 100 mg QD, from about 80 mg to about 100 mg QD.
  • QD 10 mg to about 100 mg once a day
  • the daily dose is about 20 mg QD, about 25 mg QD, about 30 mg QD, about 35 mg QD, about 40 mg QD, about 45 mg QD, about 50 mg QD, about 55 mg QD, about 60 mg QD, about 65 mg QD, about 70 mg QD, about 75 mg QD, about 80 mg QD, about 85 mg QD, about 90 mg QD, or about 100 mg QD.
  • PF-07220060 is administered in doses of from about 10 mg to about 90 mg twice a day (BID), for example, from about 20 mg to about 90 mg BID, from about 30 mg to about 90 mg BID, from about 40 mg to about 90 mg BID, from about 50 mg to about 90 mg BID, from about 60 mg to about 90 mg BID, from about 70 mg to about 90 mg BID, from about 80 mg to about 90 mg BID.
  • BID 10 mg to about 90 mg twice a day
  • PF- 07220060 is administered at a dose of about 20 mg BID, about 25 mg BID, about 30 mg BID, about 35 mg BID, about 40 mg BID, about 45 mg BID, about 50 mg BID, about 55 mg BID, about 60 mg BID, about 65 mg BID, about 70 mg BID, about 75 mg BID, about 80 mg BID, about 85 mg BID, or about 90 mg BID.
  • the subject is administered PF-07220060 at a dose of any of the therapeutically effective amounts disclosed herein.
  • the amount of PF-07220060 administered may be increased or decreased based on the weight, age, health, sex, or medical condition of the subject.
  • One of skill in the art would be able to determine the proper dose for a subject based on this disclosure.
  • PF-07220060 may be administered in treatment cycles, with or without rest periods in between the treatment cycles.
  • a treatment cycle may be a duration of about 7 days, about 14 days, about 21 days, about 28 days, about 35 days and so on, or any days in between.
  • a rest period can be one day, a few days (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, and so on), one week, several weeks (e.g., 2 weeks, 3 weeks and so on), or any days in between (e.g., 1 week and 3 days).
  • PF-07220060 is administered continuously without any rest period in between (/.e., continuous treatment until termination).
  • PF-07220060 is administered for a treatment cycle (e.g., about 28 days) with or without a rest period. In some embodiments, PF-07220060 is administered for about 28 days with a rest period of about one week. PF-07220060 may be administered for at least about 7 days, about 14 days, about 21 days, about 28 days, about 2 months, about 3 months, about 12 months, about 24 months, and more.
  • the pharmaceutical compositions may be administered with or without food.
  • the pharmaceutical compositions may be administered by one or more routes as considered appropriate by a skilled person in the art and depending on the dosage form.
  • Formulation of drugs is discussed in Remington's Pharmaceutical Sciences, 18th Ed., (1995) Mack Publishing Co., Easton, Pa.
  • Other examples of drug formulations can be found in Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, Vol 3, 2nd Ed., New York, N.Y.
  • the compound may be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable carrier, glidant, or excipient.
  • compositions may be in one or more dosage forms (e.g., capsule, liquid, tablet, powder).
  • the pharmaceutical compositions may be administered in an immediate release formulation or a modified release formulation.
  • immediate release or “IR” is meant broadly an oral dosage form formulated to release an API immediately after oral administration. In IR formulations, no deliberate effort is made to modify the drug release rate.
  • the disclosure provides a method for treating cancer of a subject in need thereof, which includes administering to the subject a therapeutically effective amount of PF-07220060 as described herein.
  • the disclosure also provides a method for treating cancer of a subject which includes administering to the subject a therapeutically effective amount of PF-07220060 as described herein and an endocrine therapy agent.
  • the disclosure provides a use of PF-07220060 in the manufacture of a medicament for use in the treatment of cancer in a subject in need thereof wherein the medicament is administered in a therapeutically effective unit dosage of PF-07220060 as described herein.
  • the disclosure provides a use of PF-07220060 together with endocrine therapy in the manufacture of a medicament for use in the treatment of cancer in a subject in need thereof wherein the medicament is administered in a therapeutically effective unit dosage of PF-07220060 as described herein.
  • the disclosure provides a medicament comprising a therapeutically effective amount of PF-07220060 as described herein for use in treating cancer in a subject in need thereof. In embodiments, the disclosure provides a medicament comprising a therapeutically effective amount of PF-07220060 as described herein and an endocrine therapy agent for use in treating cancer in a subject in need thereof.
  • PF-07220060 is administered continuously (/.e., daily).
  • the method disclosed herein includes administering PF- 07220060 to a subject who is suffering from cancer that is mediated by CDK4.
  • the cancer is characterized by amplification or overexpression of CDK4 and/or CCND1.
  • the cancer is characterized by amplification or overexpression of CDK4.
  • the cancer is characterized by amplification of the CCND1 gene or overexpression of cyclin D1.
  • the method disclosed herein includes administering PF- 07220060 to a subject who is suffering from cancer that is selected from breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer (PPC), bladder cancer, uterine cancer, prostate cancer, lung cancer (including non-small-cell lung carcinoma (NSCLC)), small-cell lung carcinoma (SCLC), squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer (including head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC), kidney cancer (including renal cell carcinoma (RCC)), liver cancer (including hepatocellular carcinoma (HCC)), pancreatic cancer, stomach (/.e., gastric) cancer, endometrial cancer, liposarcoma, and thyroid cancer.
  • PPC primary peritoneal cancer
  • bladder cancer including uterine cancer, prostate cancer, lung cancer (including non-small-cell lung carcinoma (NSCLC)), small-cell lung carcinoma (SCLC),
  • the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, stomach cancer, or combinations thereof.
  • the cancer is advanced or metastatic solid tumors.
  • the cancer is NSCLC. In some embodiments, the cancer is adenocarcinoma of NSCLC. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is liposarcoma.
  • the cancer is breast cancer. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments, the breast cancer is locally advanced. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is hormone receptor positive (HR+), /.e., the breast cancer is estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+). In some embodiments, the breast cancer is hormone receptor negative (HR-), i.e., the breast cancer is estrogen receptor negative (ER-) and progesterone receptor negative (PR-). In some embodiments, the breast cancer is human epidermal growth factor receptor 2 negative (HER2-). In some embodiments, the breast cancer is human epidermal growth factor receptor 2 positive (HER2+).
  • the breast cancer is HR+/HER2- breast cancer. In some embodiments, the breast cancer is HR-/HER2+ breast cancer. In some embodiments, the breast cancer is ER+/HR+. In some embodiments, the breast cancer is ER+/HER2-. In some embodiments, the breast cancer is triple negative breast cancer (TNBC), i.e., the breast cancer is ER-, PR- and HER2-.
  • TNBC triple negative breast cancer
  • the breast cancer is endocrine resistant breast cancer, trastuzumab or pertuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition.
  • the breast cancer is resistant to treatment with a standard of care agent; for example, the breast cancer may demonstrate primary or acquired resistance to endocrine therapy, HER2-targeted agents (e.g., tamoxifen, trastuzumab emtansine, fam-trastuzumab deruxtecan, pertuzumab, lapatinib, neratinib or tucatinib), or CDK4/6 inhibitors.
  • the subject is refractory to endocrine therapy.
  • the breast cancer is refractory or resistant to treatment with, or has progressed on, treatment with antineoplastic chemotherapeutic agents such as platinum agents, taxanes, anthracyclines or anti-metabolites.
  • antineoplastic chemotherapeutic agents such as platinum agents, taxanes, anthracyclines or anti-metabolites.
  • the breast cancer has progressed during treatment or within 12 months of completion of adjuvant therapy with an aromatase inhibitor. In some embodiments, the breast cancer has progressed during treatment or within 12 months of completion of adjuvant therapy with tamxifen.
  • PF-07220060 is administered as first line therapy. In other embodiments, PF-07220060 is administered as second (or later) line therapy. In some embodiments, PF-07220060 is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent and/or a CDK4/CDK6 inhibitor. In some embodiments, PF-07220060 is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent, such as, an aromatase inhibitor; a selective estrogen receptor modulator (SERM), e.g., tamoxifen; or a selective estrogen degrader/downregulator (SERD). In some embodiments, PF-07220060 is administered as second (or later) line therapy following treatment with one or more chemotherapy regimens. In some embodiments, PF-07220060 is administered as second (or later) line therapy following treatment with HER2 targeted agents.
  • SERM selective estrogen receptor modulator
  • PF-07220060 is administered as second (
  • the method disclosed herein further includes administering to a subject a therapeutically effective amount of PF-07220060 and an endocrine therapy agent.
  • An "endocrine therapy agent” is a biological (large molecule) or chemical (small molecule) compound useful in the treatment of cancer, regardless of mechanism of action.
  • the endocrine therapy agent is an aromatase inhibitor, an androgen receptor inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).
  • the endocrine therapy agent is an androgen receptor inhibitor.
  • the endocrine therapy agent is an aromatase inhibitor.
  • the aromatase inhibitor is selected from the group consisting of letrozole, anastrozole and exemestane.
  • the aromatase inhibitor is letrozole.
  • the endocrine therapy agent is a SERD.
  • the SERD is selected from the group consisting of fulvestrant, elacestrant (RAD-1901 , Radius Health/Menarini), amcenestrant (SAR439859, Sanofi), giredestrant (GDC9545, Roche), RG6171 (Roche), camizestrant (AZD9833, AstraZeneca), AZD9496 (AstraZeneca), rintodestrant (G1 Therapeutics), ZN-c5 (Zentalis), LSZ102 (Novartis), D-0502 (Inventisbio), LY3484356 (Eli Lilly), and SHR9549 (Jiansu Hengrui Medicine).
  • the SERD is fulvestrant.
  • the endocrine therapy agent is a SERM.
  • the SERM is selected from the group consisting of tamoxifen, raloxifene, toremifene, lasofoxifene, apeledoxifene and afimoxifene.
  • the SERM is tamoxifen or raloxifene.
  • the endocrine therapy agent is letrozole or fulvestrant.
  • the endocrine therapy agent may be administered according to the standard of care per package insert or provided by the health care professionals.
  • package insert refers to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.
  • the endocrine therapy agent is administered to the subject during the course of the treatment with PF-07220060.
  • the first dose of the endocrine therapy agent is administered prior to administering the first dose of PF-07220060.
  • the first dose of the endocrine therapy agent is administered on the same day as administering the first dose of PF- 07220060.
  • the first dose of the endocrine therapy agent is administered after the start of the treatment with PF-07220060.
  • the subject prior to the administration of PF-07220060 to the subject, the subject has been previously treated with one or more lines of endocrine therapy.
  • the subject prior to the administration of PF-07220060 to the subject, the subject has been previously treated with chemotherapy, radiotherapy, and/or surgical resection.
  • the subject prior to the administration of PF-07220060 to the subject, the subject has been previously treated with a CDK4/6 inhibitor.
  • the present treatment results in complete response (CR), partial response (PR), or stable disease (SD) in the subject.
  • CR complete response
  • PR partial response
  • SD stable disease
  • the present disclosure provides a number of exemplary embodiments. Nonlimiting exemplary embodiments of the present disclosure are shown below.
  • Embodiment 1 A method of treating cancer comprising administering to a subject in need thereof a total daily dose of from about 10 mg to about 190 mg of a cyclin-dependent kinase (CDK) inhibitor PF-07220060.
  • CDK cyclin-dependent kinase
  • Embodiment 2 The method of embodiment 1 , wherein the total daily dose is administered once per day (QD) or in divided doses twice per day (BID).
  • QD once per day
  • BID twice per day
  • Embodiment 3 The method of any one of embodiments 1 to 2, wherein PF-
  • 07220060 is administered in an amount of from about 10 mg to about 100 mg QD.
  • Embodiment 4 The method of any one of embodiments 1 to 2, wherein PF-
  • 07220060 is administered in an amount of from about 50 mg QD.
  • Embodiment 5 The method of any one of embodiments 1 to 2, wherein PF-
  • 07220060 is administered in an amount of from about 75 mg QD.
  • Embodiment 6 The method of any one of embodiments 1 to 2, wherein PF-
  • 07220060 is administered in an amount of from about 100 mg QD.
  • Embodiment ? The method of any one of embodiments 1 to 2, wherein PF- 07220060 is administered in an amount of from about 10 mg to about 75 mg BID.
  • Embodiment s The method of any one of embodiments 1 to 2, wherein PF- 07220060 is administered in an amount of from about 50 mg BID.
  • Embodiment 9 The method of any one of embodiments 1 to 2, wherein PF- 07220060 is administered in an amount of from about 75 mg BID.
  • Embodiment 10 The method of any one of embodiments 1 to 9, wherein PF- 07220060 is administered continuously.
  • Embodiment 11 The method of any one of embodiments 1 to 10, wherein PF- 07220060 is administered in a tablet or capsule form.
  • Embodiment 12 A method for treating cancer comprising administering to a subject in need thereof a daily dose of from about 10 mg to about 190 mg of PF-07220060, in combination with an endocrine therapy agent.
  • Embodiment 13 The method of embodiment 12, wherein the endocrine therapy agent is an aromatase inhibitor, an androgen receptor inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).
  • the endocrine therapy agent is an aromatase inhibitor, an androgen receptor inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).
  • Embodiment 14 The method of embodiment 13, wherein the aromatase inhibitor is a non-steroidal aromatase inhibitor.
  • Embodiment 15 The method of any one of embodiments 12 to 14, wherein the endocrine therapy agent is selected from the group consisting of letrozole, anastrozole, exemestane, fulvestrant, elacestrant, amcenestrant, giredestrant, RG6171, camizestrant, AZD9496, rintodestrant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549, tamoxifen, raloxifene, toremifene, lasofoxifene, afimoxifene.
  • Embodiment 16 The method of any one of embodiments 12 to 15, wherein the endocrine therapy agent is letrozole or fulvestrant.
  • Embodiment 17 The method of any one of embodiments 12 to 16, wherein the subject is administered the endocrine therapy agent and subsequently administered PF- 07220060.
  • Embodiment 18 The method of any one of the previous embodiments, wherein the subject has been previously treated with systemic therapy (such as, chemotherapy), radiotherapy, and/or surgical resection.
  • systemic therapy such as, chemotherapy
  • radiotherapy radiotherapy
  • surgical resection any one of the previous embodiments, wherein the subject has been previously treated with systemic therapy (such as, chemotherapy), radiotherapy, and/or surgical resection.
  • Embodiment 19 The method of any one of the previous embodiments, wherein the subject has been previously treated with a CDK4/6 inhibitor.
  • Embodiment 20 The method of any one of the previous embodiments, wherein the subject has been previously treated with an endocrine therapy agent.
  • Embodiment 21 The method of any one of the previous embodiments, wherein the subject has been previously treated with a CDK4/6 inhibitor in combination with an endocrine therapy agent.
  • Embodiment 22 The method of any one of the previous embodiments, wherein the endocrine therapy agent is a non-steroidal aromatase inhibitor.
  • Embodiment 23 The method of any one of the previous embodiments, wherein the subject has been previously received with a treatment targeting estrogen receptor 1 (ESR1), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), AKT1 , phosphatase and tensin homolog (PTEN), or breast cancer gene (BRCA).
  • ESR1 estrogen receptor 1
  • PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
  • AKT1 phosphatase and tensin homolog
  • BRCA breast cancer gene
  • Embodiment 24 The method of any one of the previous embodiments, wherein the subject has been previously treated with a prior line of systemic therapy for breast cancer.
  • Embodiment 25 The method of any one of the previous embodiments, wherein the subject has been previously treated with two prior lines of systemic therapy for breast cancer.
  • Embodiment 26 The method of any one of the previous embodiments, wherein the subject has been previously treated with one prior line of systemic therapy comprises a CDK4/6 inhibitor and a non-steroidal aromatase inhibitor.
  • Embodiment 27 The method of any one of the previous embodiments, wherein the subject has been previously treated with two prior lines of systemic therapy, wherein one of the two prior lines of systemic therapy comprises a CDK4/6 inhibitor.
  • Embodiment 28 The method of any one of the previous embodiments, wherein the subject has been previously treated with two prior lines of systemic therapy, wherein one of the two prior lines of systemic therapy comprises a CDK4/6 inhibitor and a nonsteroidal aromatase inhibitor, and the other one of the two prior lines of systemic therapy comprises a treatment targeting ESR1 , PIK3CA, AKT1 , PTEN, or BRCA.
  • Embodiment 29 The method of any one of the previous embodiments, wherein the subject has not received any prior systemic therapies but has been previously treated with an adjuvant therapy comprising a CDK4/6 inhibitor and a non-steroidal aromatase inhibitor.
  • Embodiment 30 The method of any one of embodiments 1 to 29, wherein the subject is a mammal.
  • Embodiment 31 The method of any one of embodiments 1 to 30, wherein the subject is suffering from breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, and thyroid cancer.
  • Embodiment 32 The method of any one of embodiments 1 to 31 , wherein the cancer is breast cancer selected from any one or more of: hormone receptor positive (HR+), hormone receptor negative (HR-), human epidermal growth factor receptor 2 negative (HER2-), human epidermal growth factor receptor 2 positive (HER2+), HR+/HER2-, ER- /HR+, ER+/HER2-and triple negative breast cancer (TNBC).
  • HR+ hormone receptor positive
  • HR- hormone receptor negative
  • HER2- human epidermal growth factor receptor 2 negative
  • HER2+ human epidermal growth factor receptor 2 positive
  • HR+/HER2- HR+/HER2-
  • ER- /HR+ ER+/HER2-and triple negative breast cancer (TNBC).
  • Embodiment 33 The method of any one of embodiments 1 to 31 , wherein the cancer is NSCLC, prostate, colorectal cancer, liposarcoma, or tumors characterized by amplification or overexpression of CDK4 and/or CCND1.
  • Embodiment 34 A method of treating cancer comprising administering to a subject in need thereof the following steps:
  • ICT choice of therapy
  • Arm B Comparator Arm; N ⁇ 250
  • participants will receive ICT of either: fulvestrant 500 mg, intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle starting from C2D1 (28-day cycle), or everolimus 10 mg orally, once daily, continuously, in a 28-day cycle, plus exemestane 25 mg orally, once daily continuously, in a 28-day cycle.
  • Per- and peri-menopausal female and male participants must receive therapy with a luteinizing hormone-releasing hormone (LHRH) agonist starting at least 4 weeks prior to Cycle 1 Day 1 and continue during the study.
  • LHRH luteinizing hormone-releasing hormone
  • ER Documented estrogen receptor
  • PR progesterone receptor
  • CDK4/6i plus endocrine therapy as the most recent systemic treatment for breast cancer (BC), either as the 1st line treatment for advanced/mBC or as the adjuvant treatment for early BC. There must be documented progression of disease during or after CDK4/6i treatment.
  • ESR1 estrogen receptor 1
  • PIK3CA phosphatidylinositol-4,5-bisphosphate 3- kinase catalytic subunit alpha
  • PTEN phosphatase and tensin homolog
  • BRCA breast cancer gene
  • Non-measurable bone-only disease may include any of the following: blastic bone lesions, lytic bone lesions without a measurable soft tissue component, or mixed lytic-blastic bone lesions without a measurable soft tissue component.
  • CNS metastases Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Participants with a history of CNS metastases or cord compression are eligible if they have been definitively treated (e.g., radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization.
  • Inadequate renal function as defined by an estimated glomerular filtration rate (eGFR) ⁇ 45 mL/min/1.73 m 2 calculated using the chronic kidney disease epidemiology collaboration (CKD-EPI) equations outlined in Table 1.
  • eGFR estimated glomerular filtration rate
  • CKD-EPI chronic kidney disease epidemiology collaboration
  • Hepatic dysfunction defined as:
  • PF-07220060 was provided as tablets for oral administration, as the 100 mg immediate release tablets.
  • the PF-07220060 dose may remain at the same dose level or be reduced by one dose level when treatment is resumed. Once a dose has been reduced for a given participant, all subsequent cycles will be administered at that dose level.
  • PF-07220060 for Study Intervention Related Toxicity
  • Recurrent Grade 3 toxicity is defined as the same event reoccurring within the next 8 weeks as measured from the stop date of the preceding event.
  • Persistent Grade 2 toxicity is defined as toxicity that does not resolve despite supportive measures within 7 days to Grade ⁇ 1 or to baseline.
  • Grade 3 ILD/pneumonitis requires permanent discontinuation of PF-07220060.
  • Grade 4 ILD/pneumonitis and hepatotoxicity require permanent discontinuation of PF-07220060.
  • Fulvestrant monotherapy is considered a standard treatment option in patients with progressive disease after previous endocrine therapy including an aromatase inhibitor (Rugo et al., 2016; Cardoso et al, 2020). Further, fulvestrant monotherapy is a standard treatment option in patients with progressive disease after previous CDK4/6i plus ET recommended by NCCN Guidelines Version 3.2023 and ESMO Clinical Practice Guidelines).
  • Fulvestrant (Faslodex®) is available as two 5-mL clear neutral glass (Type 1) barrels, each containing 250 mg/5 mL of fulvestrant solution for intramuscular injection and fitted with a tamper evident closure. The syringes are presented in a tray with polystyrene plunger rod and safety needles (SafetyGlideTM) for connection to the barrel. For Arm A participants, Fulvestrant injections are completed before PF-07220060 administration.
  • Fulvestrant was administered intramuscularly in the gluteal area slowly (1-2 minutes per injection) as two 5 mL injections (total dose of 500 mg), per administration instructions provided in the Faslodex® label, during Cycle 1 , on Days 1 and 15 and on Day 1 of each subsequent 28-day cycle.
  • Everolimus in combination with exemestane is an established therapy option for HR-positive, HER2-negative mBC (Ashai et al., Post-CDK 4/6 Inhibitor Therapy: Current Agents and Novel Targets; Cancers (Basel); 2023;15(6)); and this combination is a standard treatment option in patients with progressive disease after previous CDK4/6i plus endocrine therapy recommended by NCCN Guidelines 2023 and ESMO Clinical Practice Guidelines (Gennari et al, 2021).
  • Everolimus will be administered orally 10 mg QD.
  • Exemestane will be administered orally 25 mg QD.

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Abstract

L'invention concerne une méthode de traitement du cancer comprenant l'administration à un sujet en ayant besoin d'une quantité thérapeutiquement efficace de PF-07220060. L'invention concerne également une méthode de traitement du cancer comprenant l'administration à un sujet en ayant besoin d'une quantité thérapeutiquement efficace de PF -07220060 et d'un agent d'endocrinothérapie.
PCT/IB2024/055296 2023-06-02 2024-05-30 Méthodes et schémas posologiques modifiés comprenant un inhibiteur de cdk4 pour le traitement du cancer Pending WO2024246824A1 (fr)

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