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WO2018063873A1 - Polythérapie à base d'abémaciclib et d'un inhibiteur double de kinase pi3/mtor destinée à être utilisée dans le traitement du cancer du pancréas - Google Patents

Polythérapie à base d'abémaciclib et d'un inhibiteur double de kinase pi3/mtor destinée à être utilisée dans le traitement du cancer du pancréas Download PDF

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Publication number
WO2018063873A1
WO2018063873A1 PCT/US2017/052397 US2017052397W WO2018063873A1 WO 2018063873 A1 WO2018063873 A1 WO 2018063873A1 US 2017052397 W US2017052397 W US 2017052397W WO 2018063873 A1 WO2018063873 A1 WO 2018063873A1
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WO
WIPO (PCT)
Prior art keywords
abemaciclib
pancreatic cancer
pharmaceutically acceptable
salt
treatment
Prior art date
Application number
PCT/US2017/052397
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English (en)
Inventor
Richard Brian GAYNOR
Christopher Alan Slapak
Original Assignee
Eli Lilly And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Publication of WO2018063873A1 publication Critical patent/WO2018063873A1/fr

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Classifications

    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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 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 [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
  • 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:
  • 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:
  • 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.
  • 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.
  • the pancreatic cancer is metastatic pancreatic ductal
  • the pancreatic cancer is KRAS mutant metastatic pancreatic ductal adenocarcinoma.
  • kits comprising abemaciclib, or a pharmaceutically acceptable salt thereof, and LY3023414, or a pharmaceutically acceptable salt thereof, for the treatment of pancreatic cancer.
  • the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma.
  • the pancreatic cancer is KRAS mutant metastatic pancreatic ductal adenocarcinoma.
  • kits 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.
  • the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma.
  • the pancreatic cancer is KRAS mutant metastatic pancreatic ductal adenocarcinoma.
  • the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma.
  • the pancreatic cancer is KRAS mutant metastatic pancreatic ductal adenocarcinoma.
  • abemaciclib for use in simultaneous, separate, or sequential combination with LY3023414, or a pharmaceutically acceptable salt thereof, in the treatment of pancreatic cancer.
  • 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 is presented.
  • the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma.
  • pancreatic cancer is KRAS mutant metastatic pancreatic ductal
  • 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.
  • the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma.
  • the pancreatic cancer is KRAS mutant metastatic pancreatic ductal
  • 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.
  • the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma.
  • the pancreatic cancer is KRAS mutant metastatic pancreatic ductal adenocarcinoma.
  • abemaciclib is administered at a dose of 50 mg to 200 mg twice a day in a 28-day cycle.
  • abemaciclib or the pharmaceutically salt thereof
  • abemaciclib 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.
  • abemaciclib is administered orally. More preferably, abemaciclib is administered by capsule. Also more preferably, abemaciclib is administered by tablet.
  • LY3023414 is administered orally.
  • 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.
  • LY3023414, or a pharmaceutically acceptable salt thereof is administered at a dose of 200 mg twice a day in a 28-day cycle.
  • abemaciclib 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma.
  • the pancreatic cancer is KRAS mutant metastatic pancreatic ductal adenocarcinoma.
  • treating refers to restraining, slowing, stopping, reducing, shrinking, maintaining stable disease, or reversing the progression or severity of an existing symptom, disorder, condition, or disease.
  • the term "patient” refers to a mammal, preferably, a human.
  • 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.
  • 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.
  • 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.
  • 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.
  • PFS progression-free survival
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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
  • the safety and efficacy of each investigational arm will be assessed versus the standard-of-care arm by implementing a 2-stage design.
  • 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.
  • 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
  • PK pharmacokinetics
  • RECIST Response Criteria in Solid
  • 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.
  • 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.
  • Clinical benefit rate is the percentage of
  • 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
  • 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.
  • CA carbohydrate antigen
  • Biomarker research may be assessed from between biomarkers and tumor, whole blood, and plasma samples, clinical outcome unless precluded by local regulations.
  • CA carbohydrate antigen
  • PK pharmacokinetics
  • RECIST pharmacokinetics
  • abemaciclib is administered at 200 mg twice daily with or without food continuous dosing for 28-day cycles.
  • 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.
  • the Standard-of-Care Choice is the choice of either gemcitabine administered at 1000 mg/m 2 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/m 2 orally twice a day within 30 minutes after a meal (morning and evening; equivalent to 2500 mg/m 2 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.

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Abstract

La présente invention concerne une double combinaison d'abémaciclib et d'un inhibiteur double de PI3 kinase/mTOR connu dans l'art comme LY3023414, et des procédés d'utilisation de la combinaison pour traiter des patients atteints d'un cancer du pancréas, plus particulièrement chez des patients atteints d'un adénocarcinome canalaire du pancréas métastatique traité au préalable.
PCT/US2017/052397 2016-09-27 2017-09-20 Polythérapie à base d'abémaciclib et d'un inhibiteur double de kinase pi3/mtor destinée à être utilisée dans le traitement du cancer du pancréas WO2018063873A1 (fr)

Applications Claiming Priority (2)

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US201662400243P 2016-09-27 2016-09-27
US62/400,243 2016-09-27

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WO2018063873A1 true WO2018063873A1 (fr) 2018-04-05

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023114225A1 (fr) 2021-12-14 2023-06-22 Board Of Regents, The University Of Texas System Combinaison pharmaceutique comprenant de l'abémaciclib et une pi3k et/ou un inhibiteur de mtor pour le traitement du lymphome à cellules du manteau

Citations (2)

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US20100160340A1 (en) * 2008-12-22 2010-06-24 Coates David A Protein kinase inhibitors
WO2012097039A1 (fr) 2011-01-14 2012-07-19 Eli Lilly And Company Composé d'imidazo[4,5-c]quinolin-2-one et son utilisation comme inhibiteur double de kinase pi3/mtor

Patent Citations (4)

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US20100160340A1 (en) * 2008-12-22 2010-06-24 Coates David A Protein kinase inhibitors
WO2010075074A1 (fr) 2008-12-22 2010-07-01 Eli Lilly And Company Inhibiteurs de protéine kinases
WO2012097039A1 (fr) 2011-01-14 2012-07-19 Eli Lilly And Company Composé d'imidazo[4,5-c]quinolin-2-one et son utilisation comme inhibiteur double de kinase pi3/mtor
US20120184577A1 (en) * 2011-01-14 2012-07-19 Eli Lilly And Company PI3 KINASE/mTOR DUAL INHIBITOR

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"Remington: The Science and Practice of Pharmacy", 2012, PHARMACEUTICAL PRESS
ANONYMOUS: "A Study of Abemaciclib (LY2835219) Alone or in Combination With Other Agents in Participants With Previously Treated Pancreatic Ductal Adenocarcinoma - Full Text View - ClinicalTrials.gov", 5 December 2016 (2016-12-05), XP055423112, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/show/NCT02981342> [retrieved on 20171109] *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023114225A1 (fr) 2021-12-14 2023-06-22 Board Of Regents, The University Of Texas System Combinaison pharmaceutique comprenant de l'abémaciclib et une pi3k et/ou un inhibiteur de mtor pour le traitement du lymphome à cellules du manteau

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