WO2018063873A1

WO2018063873A1 - Combination therapy of abemaciclib and a pi3 kinase/mtor dual inhibitor for use in the treatment of pancreatic cancer

Info

Publication number: WO2018063873A1
Application number: PCT/US2017/052397
Authority: WO
Inventors: Richard Brian GAYNOR; Christopher Alan Slapak
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 2016-09-27
Filing date: 2017-09-20
Publication date: 2018-04-05
Anticipated expiration: 2019-03-27

Abstract

The present invention relates to a dual combination of abemaciclib and a PI3 kinase/mTOR dual inhibitor known in the art as LY3023414, and to methods of using the combination to treat patients with pancreatic cancer, more particularly in patients with previously treated metastatic pancreatic ductal adenocarcinoma.

Description

COMBINATION THERAPY OF ABEMACICLIB AND A PI3 KINASE/MTOR DUAL INHIBITOR FOR USE IN THE TREATMENT OF PANCREATIC CANCER

The present invention relates to a combination of abemaciclib and a PI3 kinase/mTOR dual inhibitor known in the art as LY3023414, and to methods of using the combination to treat patients with pancreatic cancer, more particularly in patients with previously treated metastatic pancreatic ductal adenocarcinoma.

Pancreatic cancer is one of the most deadly of all types of cancer. Many cases of pancreatic cancer aren't detected until the cancer has progressed and spread to other parts of the body. Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas. PDAC is an epithelial tumor that arises from the cells of the pancreatic duct or ductules and is an aggressive and difficult malignancy to treat. Cyclin-dependent kinase (CDK)4 and CDK6 pathway alterations, along with Kirsten rat sarcoma (KRAS) mutations, are key molecular signatures that occur in approximately 90% of pancreatic ductal adenocarcinoma. Complete surgical removal of the tumor remains the only chance for cure, however 80-90% of patients have disease that is surgically incurable at the time of clinical presentation.

Abemaciclib (LY2835219), [5-(4-ethyl-piperazin-l-ylmethyl)-pyridin-2-yl]-[5- fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine, is a CDK inhibitor that targets the CDK4 and CDK6 cell cycle pathway, with

antineoplastic activities. Abemaciclib, including salt forms, and methods of making and using this compound including for the treatment of cancer, in particular, pancreatic cancer are disclosed in WO2010/075074. Abemaciclib has also shown activity in KRAS mutant pancreatic cancer cell lines. Abemaciclib has the following structure:

8-[5-(l-Hydroxy-l-methylethyl)pyridin-3-yl]-l-[(2S)-2-methoxypropyl]-3- methyl-l,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, also known as LY3023414, is a dual inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of

rapamycin(mTOR). The compound and methods of making and using this compound including for the treatment of cancer and more specifically for the treatment of pancreatic cancer are disclosed in WO2012/097039. Furthermore, this compound is being investigated in clinical trials for advanced/metastatic cancer, mesothelioma (as monotherapy or in combination with pemetrexed/cisplatin), breast cancer (in combination with fulvestrant), as well as in squamous non-small cell lung cancer (as monotherapy or in combination with necitumumab), and metastatic castration resistant prostate cancer (in combination with enzalutamide). LY3023414 has the following structure:

Certain preclinical studies investigating selected aspects of the mechanism of action for the aforementioned targets have been described in the art. For example, preclinical studies suggest possible synergy in targeting both cell cycle via CDK inhibitors and the PI3K pathway (David-Pfeuty T. et al., Int J Oncol. 2010

Apr;36(4):873-81). It has been shown that PI3K and mTOR inhibitors cause Gl cell- cycle arrest and downregulation of cyclin Dl and CDKs (Gao N. et al., Am J Physiol Cell Physiol. 2004 Aug; 287(2):C281-91). PI3K inhibition also dramatically potentiates inhibition of CDK4 and CDK6 in leukemia cell models (Yu C, Cancer Res. 2003 Apr 15;63(8): 1822-33). It has also been reported that three PI3K/mTOR inhibitors (BEZ235, AZD0855 and GDC0980) showed cooperative effects in concert with PD0332991, a CDK4 and CDK6 inhibitor, treatment in in vitro pancreatic cells assessed by viability assay in drug screening and that these combinations have a synergistic effect in suppression of cell cycle (Franco, et al. Oncotarget (Aug. 2014)).

Broadly applicable therapies for cancer, in particular for pancreatic cancer still remain elusive and there exists a need for more and different therapies that may prove to be effective in treating patients with pancreatic cancer.

The present invention discloses methods of treating pancreatic cancer with a combination of abemaciclib and LY3023414 that may provide new treatment options for patients and may provide an enhanced and/or unexpected beneficial therapeutic effect in some patients over those of the individual agents alone.

According to one aspect of the present invention, there is presented a method of treating pancreatic cancer in a patient, comprising administering to the patient an effective amount of abemaciclib, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of LY3023414, or a pharmaceutically acceptable salt thereof. Preferably, the pancreatic cancer is metastatic pancreatic ductal

adenocarcinoma. Preferably, the pancreatic cancer is KRAS mutant metastatic pancreatic ductal adenocarcinoma.

According to another aspect of the present invention, there is presented a kit comprising abemaciclib, or a pharmaceutically acceptable salt thereof, and LY3023414, or a pharmaceutically acceptable salt thereof, for the treatment of pancreatic cancer. Preferably, the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma.

Preferably, the pancreatic cancer is KRAS mutant metastatic pancreatic ductal adenocarcinoma.

According to another aspect of the present invention, there is presented a kit comprising abemaciclib, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients, and LY3023414, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients, for the treatment of pancreatic cancer. Preferably, the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma. Preferably, the pancreatic cancer is KRAS mutant metastatic pancreatic ductal adenocarcinoma.

According to another aspect of the present invention, there is presented a combination comprising abemaciclib, or a pharmaceutically acceptable salt thereof, and LY3023414, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of pancreatic cancer. Preferably, the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma. Preferably, the pancreatic cancer is KRAS mutant metastatic pancreatic ductal adenocarcinoma.

According to another aspect of the present invention, there is presented

abemaciclib, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with LY3023414, or a pharmaceutically acceptable salt thereof, in the treatment of pancreatic cancer. According to another aspect of the present invention, there is presented LY3023414, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with abemaciclib, or a pharmaceutically acceptable salt thereof, in the treatment of pancreatic cancer.

Preferably, the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma.

Preferably the pancreatic cancer is KRAS mutant metastatic pancreatic ductal

adenocarcinoma.

The present invention also provides for use of abemaciclib, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of pancreatic cancer wherein abemaciclib, or the salt thereof, is to be administered in simultaneous, separate, or sequential combination with LY3023414, or a pharmaceutically acceptable salt thereof. Preferably, the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma.

Preferably, the pancreatic cancer is KRAS mutant metastatic pancreatic ductal

adenocarcinoma.

The present invention also provides for use of LY3023414, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of pancreatic cancer wherein LY3023414, or the salt thereof, is to be administered in simultaneous, separate, or sequential combination with abemaciclib, or a pharmaceutically salt thereof. Preferably, the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma. Preferably, the pancreatic cancer is KRAS mutant metastatic pancreatic ductal adenocarcinoma.

For all of the preceding aspects, the following are preferred dosing. Preferably, abemaciclib, or the pharmaceutically salt thereof, is administered at a dose of 50 mg to 200 mg twice a day in a 28-day cycle. Also preferably, abemaciclib, or the

pharmaceutically salt thereof, is administered at a dose of 100 mg to 150 mg twice a day in a 28-day cycle. More preferably, abemaciclib, or the pharmaceutically salt thereof, is administered at a dose of 150 mg twice a day in a 28-day cycle. Preferably, abemaciclib is administered orally. More preferably, abemaciclib is administered by capsule. Also more preferably, abemaciclib is administered by tablet.

Preferably, LY3023414 is administered orally. Preferably, LY3023414, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 150 mg to about 200 mg twice a day in a 28-day cycle. Preferably, LY3023414, or a

pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg twice a day in a 28-day cycle. Preferably, LY3023414, or a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg twice a day in a 28-day cycle.

Preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg twice a day in a 28-day cycle and LY3023414, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg twice a day in a 28-day cycle. Preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg twice a day in a 28-day cycle and LY3023414, or a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg twice a day in a 28-day cycle. Preferably, abemaciclib is administered at a dose of 200 mg twice a day in a 28-day cycle, LY3023414 is administered at a dose of 150 mg twice a day in a 28-day cycle. Preferably, abemaciclib is administered at a dose of 200 mg twice a day in a 28-day cycle, LY3023414 is administered at a dose of 200 mg twice a day in a 28-day cycle.

As used herein, the term "kit" refers to a package comprising at least two separate agents, wherein a first agent is abemaciclib, or a pharmaceutically acceptable salt thereof, and a second agent is LY3023414, or a pharmaceutically acceptable salt thereof. A "kit" may also include instructions to administer all or a portion of these agents to a cancer patient, preferably, a pancreatic cancer patient. Preferably, the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma. Preferably, the pancreatic cancer is KRAS mutant metastatic pancreatic ductal adenocarcinoma.

As used herein, the terms "treating", "to treat", or "treatment" refer to restraining, slowing, stopping, reducing, shrinking, maintaining stable disease, or reversing the progression or severity of an existing symptom, disorder, condition, or disease.

As used herein, the term "patient" refers to a mammal, preferably, a human.

As used herein, the terms "cancer" and "cancerous" refer to or describe the physiological condition in patients that is typically characterized by unregulated cell proliferation. Included in this definition are benign and malignant cancers.

As used herein, the term "effective amount" refers to the amount or dose of abemaciclib, or a pharmaceutically acceptable salt thereof, and the amount or dose of LY3023414, or a pharmaceutically acceptable salt thereof, which provides an effective response in the patient under diagnosis or treatment.

As used herein, the term "effective response" of a patient or a patient's

"responsiveness" to treatment with a combination of agents refers to the clinical or therapeutic benefit imparted to a patient upon administration of abemaciclib, or a pharmaceutically acceptable salt thereof, and LY3023414, or a pharmaceutically acceptable salt thereof.

As used herein, the term "in combination with" refers to the administration of abemaciclib, or a pharmaceutically acceptable salt thereof, and LY3023414, or a pharmaceutically acceptable salt thereof, either simultaneously or sequentially in any order, such as for example, at repeated intervals as during a standard course of treatment for a single cycle or more than one cycle, such that one agent can be administered prior to, at the same time, or subsequent to the administration of the other agent, or any combination thereof.

As used here, the term, "PFS" or "progression-free survival" refers to the time from randomization until disease progression or death.

A main advantage of the combination treatments of the invention is the ability to produce marked anti-cancer effects in a patient without causing significant toxicities or adverse events, so that the patient benefits from the combination treatment method overall. The efficacy of the combination treatment of the invention can be measured by various endpoints commonly used in evaluating cancer treatments, including but not limited to, tumor regression, tumor weight or size shrinkage, time to progression, overall survival, progression free survival, overall response rate, duration of response, and quality of life. The therapeutic agents used in the invention may cause inhibition of metastatic spread without shrinkage of the primary tumor, may induce shrinkage of the primary tumor, or may simply exert a tumoristatic effect. Because the invention relates to the use of a combination of unique anti-tumor agents, novel approaches to determining efficacy of any particular combination therapy of the present invention can be optionally employed, including, for example, measurement of plasma or urinary markers of angiogenesis and/or cell cycle activity, tissue-based biomarkers for angiogenesis and/or cell cycle activity, and measurement of response through radiological imaging.

The free base of the compounds is preferred. However, it will be understood by the skilled reader that compounds can react with any of a number of inorganic and organic acids to form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use (VCHA/Wiley-VCH, 2002); L.D. Bighley, et a/., Encyclopedia of Pharmaceutical Technology, 453-499 (1995); S.M. Berge, et a/., Journal of Pharmaceutical Sciences, 66, 1, (1977). The hydrochloride and mesylate salts are preferred salts for abemaciclib. The mesylate salt is an especially preferred salt for abemaciclib.

The route of administration may be varied in any way, limited by the physical properties of the drugs and the convenience of the patient and the caregiver. Preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered orally.

Abemaciclib, or a pharmaceutically acceptable salt thereof, may be formulated into a tablet or capsule. Preferably, LY3023414, or a pharmaceutically acceptable salt thereof, is administered orally. LY3023414, or a pharmaceutically acceptable salt thereof, may be formulated into a tablet or capsule. Abemaciclib, or a pharmaceutically acceptable salt thereof, may be formulated in combination with LY3023414, or a pharmaceutically acceptable salt thereof, in the same dosage form, for example into a tablet or capsule. Such pharmaceutical compositions and processes for preparing the aformention compositions are well known in the art. (See, e.g., Remington: The Science and Practice of Pharmacy, L.V. Allen, Editor, 22^nd Edition, Pharmaceutical Press, 2012).

An Adaptive, Open-Label Randomized Phase 2 Study of Abemaciclib as a Monotherapy and in Combination with Other Agents Versus Choice of Standard of Care (Gemcitabine or Capecitabine) in Patients with Previously Treated Metastatic Pancreatic

Ductal Adenocarcinoma

Study 13 Y-MC-JPCJ is a multicenter, randomized, open-label, Phase 2 trial in patients with metastatic pancreatic ductal adenocarcinoma who have been previously treated with at least one, but no more than two, prior therapies for metastatic disease. At least one of the prior therapies must have been either gemcitabine-based or

fluoropyrimidine-based therapy. The safety and efficacy of each investigational arm will be assessed versus the standard-of-care arm by implementing a 2-stage design. For Stage 1, the primary analyses of safety and efficacy will be evaluated for each of the investigational arms versus a standard-of-care arm approximately 16 weeks after the last planned Stage 1 patient enters treatment. The investigational arms include abemaciclib monotherapy and abemaciclib plus LY3023414. The comparator arm will be choice of standard-of-care (gemcitabine or capecitabine).

The primary objective is to evaluate disease control rate of the abemaciclib treatment arms versus the standard-of-care arm (gemcitabine or capecitabine).

The secondary objectives include evaluating objective response rate of the abemaciclib treatment arms versus the standard-of-care arm, evaluating safety and tolerability of the abemaciclib treatment arm and PK of abemaciclib and its metabolites and LY3023414.

For Stage 1, the analyses of safety and efficacy will be evaluated approximately 16 weeks after the last planned Stage 1 patient enters treatment. Initial evaluations will compare investigational arms (monotherapy and combination) with the standard-of-care arm, and will include assessment of disease control rate (DCR; complete response

[CR]+partial response [PR]+stable disease [SD]). Stage 1 Obi ectives and Endpoints

Abbreviations: PK = pharmacokinetics; RECIST = Response Criteria in Solid

Tumors Version 1.1; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

Following the completion of the Stage 1 assessment, any treatment arm(s) with a DCR difference > 0 as compared to the standard-of-care arm will be selected to advance to Stage 2. Enrollment in the nonadvancing arm(s) will be discontinued. While the analysis for Stage 1 is ongoing, enrollment for all arms may continue until the assessment is complete. Any patients enrolled during the time that Stage 1 analysis is ongoing will be included in planned enrollment for Stage 2. For the treatment arms that advance to Stage 2, an additional 50 patients will be randomized equally to each arm for further evaluation of safety and efficacy. The primary analysis of Stage 2 will be conducted when at least 120 total PFS events have occurred for the combination of each individual abemaciclib-containing arm and the standard-of-care arm, or all planned patients have been enrolled in Stage 2, whichever comes later. Data from both Stages 1 and 2 will be pooled for this analysis.

Stage 2 Obj ectives and Endpoints

Objectives EndDoints

Primarv

• To evaluate • Progression-free survival is measured from progression-free the date of randomization to the date of survival of the objective progression or the date of death due abemaciclib treatment to any cause, whichever is earlier.

arms versus the

standard-of-care arm

(gemcitabine or capecitabine)

Secondarv

• To evaluate disease control • Disease control rate is the percentage of

rate of the abemaciclib patients with a best overall response of stable treatment arms versus the disease, complete response, or partial standard-of-care arm response according to RECIST 1.1.

• To evaluate clinical benefit • Clinical benefit rate is the percentage of

rate of the abemaciclib patients with a best overall response of treatment arms versus the complete response, or partial response, or standard-of-care arm stable disease for >6 months according to

RECIST 1.1.

• To evaluate objective • Objective response rate is the percentage of response rate of the patients with a best overall response of abemaciclib treatment complete response or partial response arms versus the according to RECIST 1.1

standard-of-care arm

• To evaluate duration of • Duration of response is measured from the response of the abemaciclib date of first evidence of complete response or treatment arms versus the partial response to the date of objective standard-of-care arm progression or the date of death due to any cause, whichever is earlier.

• To evaluate overall • Overall survival is measured from the date of survival of the randomization to the date of death from any abemaciclib treatment cause.

• Evaluate the kinetics of • Change from baseline in CA 19-9

carbohydrate antigen (CA)

19-9 • Evaluate safety and tolerability The safety endpoints evaluated will include but are not limited to the following:

. TEAEs and SAEs

• Clinical laboratory tests and vital signs

• To evaluate pain and • modified Brief Pain Inventory short form

symptom burden of the (mBPI-sf) and the European Organization for abemaciclib treatment arms Research and Treatment of Cancer Quality of by best response group Life Questionnaire- Core 30 (EORTC QLQ- (partial response, stable C30)

• PK of abemaciclib and its • Exposure of abemaciclib and

metabolites and LY3023414 LY3023414

• Exposure-response for • Drug exposure and efficacy outcomes such as abemaciclib and objective response rate or progression-free LY3023414 survival and safety outcomes such as

neutropenia and diarrhea

Tertiary

• Assess the relationship • Biomarker research may be assessed from between biomarkers and tumor, whole blood, and plasma samples, clinical outcome unless precluded by local regulations.

Abbreviations: CA = carbohydrate antigen; PK = pharmacokinetics; RECIST =

Response Criteria in Solid Tumors Version 1.1; SAE = serious adverse event;

TEAE = treatment-emergent adverse event.

In the abemaciclib monotherapy arm, abemaciclib is administered at 200 mg twice daily with or without food continuous dosing for 28-day cycles.

In the abemaciclib and LY3023414 arm, abemaciclib is administered at 150 mg twice daily on an empty stomach (>1 hour before a meal and refrain from eating for>l hour after dose) continuous dosing for 28-day cycles.

LY3023414 is administered at 200 mg twice daily on an empty stomach (>1 hour before a meal and refrain from eating for >1 hour after dose) continuous dosing for 28- day cycles.

In the Standard-of-Care Choice Arm, the Standard-of-Care Choice is the choice of either gemcitabine administered at 1000 mg/m² over 30 minutes intravenously on days 1, 8, 15, and 22 of a 28-day cycle for Cycle 1 and on days 1, 8, and 15 of a 28-day cycle for Cycle 2 and any further cycles or capecitabine administered at 1250 mg/m² orally twice a day within 30 minutes after a meal (morning and evening; equivalent to 2500 mg/m² total daily dose) for 2 weeks followed by a 1-week rest period given as 21 -day cycles.

Abemaciclib and LY3023414 and their respective pharmaceutically acceptable salts are generally effective over a wide dosage range. In some instances dosage levels below the lowest dose herein may be more than adequate, while in other cases still larger doses may be employed without causing an adverse event, and therefore the doses disclosed herein are not intended to limit the scope of the invention in any way. It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

Claims

WE CLAIM:

1. A method of treating pancreatic cancer in a patient, comprising administering to the patient an effective amount of abemaciclib, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of LY3023414, or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 wherein abemaciclib, or the salt thereof, is administered at 150 mg twice a day for a 28-day cycle.

3. The method according to claim 1 wherein abemaciclib, or the salt thereof, is administered at 200 mg twice a day for a 28-day cycle.

4. The method according to any one of claims 1 to 3 wherein LY3023414, or the salt thereof, is administered at 150 mg twice a day for a 28-day cycle.

5. The method according to any one of claims 1 to 3 wherein LY3023414, or the salt thereof, is administered at 200 mg twice a day for a 28-day cycle.

6. The method according to any one of claims 1 to 5 wherein the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma.

7. The method according to any one of claims 1 to 6 wherein the pancreatic cancer is KRAS mutant metastatic pancreatic ductal adenocarcinoma.

8. A combination comprising abemaciclib, or a pharmaceutically acceptable salt thereof, and LY3023414, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of pancreatic cancer.

9. Abemaciclib, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with LY3023414, or a

pharmaceutically acceptable salt thereof, in the treatment of pancreatic cancer.

10. LY3023414, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with abemaciclib, or a

11. The combination, abemaciclib, or the salt thereof, or LY3023414, or the salt thereof, according to any one of claims 8 to 10 wherein abemaciclib, or the salt thereof, is administered at 150 mg twice a day for a 28-day cycle.

12. The combination, abemaciclib, or the salt thereof, or LY3023414, or the salt thereof, according to any one of claims 8 to 11 wherein LY3023414, or the salt thereof, is administered at 200 mg twice a day for a 28-day cycle.

13. The combination, abemaciclib, or the salt thereof, or LY3023414, or the salt thereof, according to any one of claims 8 to 12 wherein the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma.

14. The combination, abemaciclib, or the salt thereof, or LY3023414, or the salt thereof, according to any one of claims 8 to 13 wherein the pancreatic cancer is KRAS mutant metastatic pancreatic ductal adenocarcinoma.