WO2023281413A1

WO2023281413A1 - Methods and dosing regimens comprising pf-06873600 for the treatment of cancer

Info

Publication number: WO2023281413A1
Application number: PCT/IB2022/056241
Authority: WO
Inventors: Allison Rita MOREAU; Jason Hultin WILLIAMS
Original assignee: Pfizer Inc.
Priority date: 2021-07-09
Filing date: 2022-07-06
Publication date: 2023-01-12
Also published as: TW202308641A

Abstract

The disclosure provides methods of treating cancer comprising administering to a subject in need thereof a cyclin-dependent kinase (CDK) inhibitor PF-06873600 as a single agent or in combination with an endocrine therapy agent.

Description

METHODS AND DOSING REGIMENS COMPRISING PF-06873600 FOR THE TREATMENT OF CANCER

Field of the Disclosure

The present disclosure relates to the therapeutic treatment of cancer with a cyclin-dependent kinase (CDK) inhibitor, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2- methyl-cyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}-pyrido[2,3-c(]pyrimidin- 7(8H)-one (hereinafter PF-06873600) or a pharmaceutically acceptable salt thereof, either alone as a monotherapy or in combination with endocrine therapeutics.

Introduction

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.

PF-06873600 is a potent inhibitor of CDK2, CDK4 and CDK6 having the following structure of formula (I):

Preparation of PF-06873600 is described in International Patent Publication No. WO 2018033815 and U.S. Patent No. 10,233,188. An anhydrous crystalline form of PF- 06873600 free base (Form 1) is described in International Patent Publication No. WO 2020148635. A process for preparing PF-06873600 is described in International Patent Publication No. WO 2020065494. The contents of each of the foregoing documents are incorporated herein by reference in their entirety.

There is a need for appropriate dosing regimens of PF-06873600 as a single agent and in combination therapies for treating cancers while minimizing adverse events. Summary

The disclosure relates to both single agent and combination therapies, for treating cancer, which comprise the CDK inhibitor 2/4/6, PF-06873600, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the disclosure provides a method of treating cancer comprising administering to a subject in need thereof with PF-06873600, or a pharmaceutically acceptable salt thereof. Particularly, the method includes administering to the subject a pharmaceutical composition comprising an amount of PF-06873600, or a pharmaceutically acceptable salt thereof, in a total daily dose of from about 1 to about 75 mg per day.

In certain embodiments, the disclosure provides a method of treating cancer comprising administering to a subject in need thereof with PF-06873600, or a pharmaceutically acceptable salt thereof, and in combination with an endocrine therapy agent. In embodiments, the endocrine therapy agent is an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM). In certain embodiments, the endocrine therapy agent includes fulvestrant, tamoxifen, toremifene, anastrozole, exemestane, or letrozole.

The disclosure also relates to PF-06873600 or a pharmaceutically acceptable salt thereof for use in the method of treatment described herein.

In certain embodiments, the disclosure provides a use of PF-06873600 or a pharmaceutically acceptable salt 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 unit dosage of PF-06873600 or a pharmaceutically acceptable salt in the amount of from about 1 mg to about 75 mg per day. In certain embodiments, the disclosure provides a use of PF-06873600 or a pharmaceutically acceptable salt in combination with an endocrine therapy agent 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 unit dosage of PF-06873600 or a pharmaceutically acceptable salt in the amount of from about 1 mg to about 75 mg per day.

In certain embodiments, the disclosure provides a medicament comprising an amount of PF-06873600 or a pharmaceutically acceptable salt for use in treating cancer in a subject in need thereof, wherein the amount is from about 1 mg to about 75 mg per day. In certain embodiments, the disclosure provides a medicament comprising an amount of PF-06873600 or a pharmaceutically acceptable salt and in combination with an endocrine therapy agent for use in treating cancer in a subject in need thereof, wherein the amount is from about 1 mg to about 75 mg per day.

In certain embodiments of each of the methods, combinations and uses described herein, PF-06873600 or a pharmaceutically acceptable salt is administered once per day (QD), twice per day (BID), or three times per day (TID). In certain embodiments, PF- 06873600 or a pharmaceutically acceptable salt is administered continuously or intermittently. In certain embodiments, PF-06873600 or a pharmaceutically acceptable salt is administered orally.

Accordingly, embodiments herein provide dosing regimens for PF-06873600 or a pharmaceutically acceptable salt as a single agent, and in combination therapies, for treating cancer, by which adverse effects are minimized in a subject during the treatment period.

Brief Description of Drawings

FIG. 1 shows the median PF-06873600 plasma concentration-time profiles on Day 1 following the administration of a single oral dose of PF-06873600.

FIG. 2 shows the median PF-06873600 plasma concentration-time profiles on Day 15 following the administration of multiple oral doses of PF-06873600.

Detailed Description

The present disclosure may be understood more readily by reference to the following detailed description of the aspects and embodiments of the disclosure and the Examples included herein. It is to be understood that the terminology used herein is for describing specific embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art.

As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents.

The term "about" means having a value falling within an accepted standard of error of the mean, when considered by one of ordinary skill in the art. In some embodiments, the term "about" means within ± 10% of the indicated value. For example, a dose of about 25 mg should be understood to mean that the dose may vary between 22.5 mg and 27.5 mg.

The disclosure described herein may be suitably practiced in the absence of any element(s) not specifically disclosed herein.

As used herein, the term “subject”, “individual” or “patient” used interchangeably, may be a mammal, which refers to any animal species of the Mammalia class. Examples of 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. In one embodiment, the subject is a human.

PF-06873600 (Pfizer Inc.) is currently in phase I/I la clinical trials for the treatment of cancers, and has the following structure of formula (I):

Accordingly, certain embodiments of this disclosure provide a dose and dosing regimen comprising administering to a subject an amount, or a therapeutically effective amount, of PF-06873600 or a pharmaceutically acceptable salt. The amount, or the therapeutically effective amount, can be in the range of from about 1 mg to about 75 mg per day, in some embodiments, from about 10 mg to about 75 mg, from about 10 mg to about 70 mg, from about 10 mg to about 65 mg, from about 10 mg to about 60 mg, from about 10 mg to about 55 mg, from about 10 mg to about 50 mg, from about 10 mg to about 45 mg, from about 10 mg to about 40 mg, from about 20 mg to about 75 mg, from about 20 mg to about 70 mg, from about 20 mg to about 65 mg, from about 20 mg to about 60 mg, from about 20 mg to about 55 mg, from about 20 mg to about 50 mg, from about 20 mg to about 45 mg, from about 20 mg to about 40 mg, from about 30 mg to about 75 mg, from about 30 mg to about 70 mg, from about 30 mg to about 65 mg, from about 30 mg to about 60 mg, from about 30 mg to about 55 mg, from about 30 mg to about 50 mg, from about 40 mg to about 75 mg, from about 40 mg to about 70 mg, from about 40 mg to about 65 mg, from about 40 mg to about 60 mg, from about 40 mg to about 55 mg, or from about 40 mg to about 50 mg per day. In preferred embodiments, the amount is from 40 mg to 70 mg per day (i.e., the total daily dose is from 40 mg to 70 mg), or the amount is 50 mg per day (i.e., the total daily dose is 50 mg).

In various embodiments, the dosage can vary within the range depending upon the dosage form employed and the route of administration utilized. In some embodiments, an 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. Further, it will be understood that 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.

A "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 (i.e., not worsening) state of the disease, is considered a satisfactory outcome. The term “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.

As used herein, “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. Pharmaceutical Composition and Administration

PF-06873600 or a pharmaceutically acceptable salt may be present in a pharmaceutical composition which includes a pharmaceutically acceptable excipient. "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 nor therapeutic effects to a subject. The amount of PF-06873600 or a pharmaceutically acceptable salt in the pharmaceutical compositions can be any amounts disclosed herein.

The pharmaceutical compositions may be administered, for example, once a day (QD), twice a day (BID), or three times a day (TID).

In some embodiments, the subject is administered PF-06873600 or a pharmaceutically acceptable salt at a total daily dose of about 1 mg to about 75 mg, for example, in daily doses of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg.

In some embodiments, PF-06873600 or a pharmaceutically acceptable salt is administered in an amount of about 5 mg QD (/.e., 5 mg total daily dose), about 10 mg QD, about 15 mg QD, about 20 mg QD, about 25 mg QD, about 30 mg QD, about 35 mg QD, about 40 mg QD, about 45 mg QD, or about 50 mg QD.

In some embodiments, PF-06873600 or a pharmaceutically acceptable salt is administered in an amount of about 5 mg BID (/.e., 10 mg total daily dose), about 10 mg BID, about 15 mg BID, about 20 mg BID, about 25 mg BID, about 30 mg BID, or about 35 mg BID.

In some embodiments, PF-06873600 or a pharmaceutically acceptable salt is administered in an amount of about 5 mg TID (/.e., 15 mg total daily dose), about 10 mg TID, about 15 mg TID, about 20 mg TID, or about 25 mg TID.

In some embodiments, PF-06873600 or a pharmaceutically acceptable salt is administered in an amount of from about 1 mg to about 35 mg QD or BID, about 1 mg to about 30 mg QD or BID, about 1 mg to about 25 mg QD or BID, about 5 mg to about 35 mg QD or BID, about 5 mg to about 30 mg QD or BID, about 5 mg to about 25 mg QD or BID, about 10 mg to about 35 mg QD or BID, about 15 mg to about 30 mg QD or BID, about 15 mg to about 25 mg QD or BID, about 15 mg to about 35 mg QD or BID, about 15 mg to about 30 mg QD or BID, or about 15 mg to about 25 mg QD or BID. In preferred embodiments, PF-06873600 is administered in an amount of from about 20 mg to about 40 mg BID, or 25 mg BID, or 35 mg BID.

The term "mg/kg" of PF-06873600 means milligram of PF-06873600 or a pharmaceutically acceptable salt per one kilogram bodyweight of the subject, unless otherwise indicated.

In some embodiments, PF-06873600 or a pharmaceutically acceptable salt may be administered, either as a single agent or in combination with an endocrine therapy agent, in an amount sufficient to yield a maximum plasma concentration (Cmax) in the subject of from 0.1 to 800 ng/mL, for example, from 10 to 500 ng/mL, from 25 to 400 ng/mL, from 50 to 300 ng/mL, or from 100 to 300 ng/mL, etc. In specific embodiments, PF-06873600 may be administered to a subject in the range of 5 mg BID to 35 mg BID sufficient to yield a Cmax in the range of 10 to 500 ng/mL in the subject.

In some embodiments, PF-06873600 or a pharmaceutically acceptable salt may be administered, either as a single agent or in combination with an endocrine therapy agent, in an amount sufficient to yield an area under the plasma concentration-time curve (AUC) value in the subject from 1 to 3000 ng_*hr/mL, for example, from 10 to 2500 ng_*hr/mL, from 50 to 2000 ng_*hr/mL, from 100 to 2000 ng_*hr/mL, from 500 to 2000 ng_*hr/mL, etc. In specific embodiments, PF-06873600 may be administered to a subject in the range of 5 mg BID to 35 mg BID sufficient to yield an AUC in the range of 500 to 2000 ng_*hr/mL.

The amount of PF-06873600 or a pharmaceutically acceptable salt 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-06873600 or a pharmaceutically acceptable salt may be administered at the doses described herein continuously or intermittently. When administered continuously, PF-06873600 or a pharmaceutically acceptable salt is administered daily to a subject without any interruption, i.e. , no rest period. When administered intermittently, PF- 06873600 or a pharmaceutically acceptable salt is administered to subject for one or more consecutive day(s) followed by a rest period in which PF-06873600 or a pharmaceutically acceptable salt is not administered, and then repeats the process. In certain embodiments, PF-06873600 or a pharmaceutically acceptable salt is administered continuously (i.e., daily), for example, administered QD daily, or administered BID daily, or administered TID daily. In certain embodiments, PF-06873600 or a pharmaceutically acceptable salt is administered intermittently during the course of treatment, for example, administered daily for at least 3 consecutive days in a week, such as, 3 consecutive days a week, 4 consecutive days a week, 5 consecutive days a week or 6 consecutive days a week, and then followed by a rest period of 1 to 4 days in which PF-06873600 or a pharmaceutically acceptable salt is not administered. In certain embodiments, PF-06873600 or a pharmaceutically acceptable salt is administered daily for one day or 2 consecutive days followed by one day rest period. In one embodiment, PF-06873600 or a pharmaceutically acceptable salt is administered daily for five days followed by a rest period of two days in which PF-06873600 or a pharmaceutically acceptable salt is not administered. In certain embodiments, PF-06873600 or a pharmaceutically acceptable salt is administered intermittently every other day.

As used herein, the expression “week” means 7 consecutive days. Thus, a 4-week period is 28 consecutive days starting on any day of the calendar week. Administration for at least 3 consecutive days per week means at least one-unit dosage of the active agent, i.e. , PF-06873600 or a pharmaceutically acceptable salt, is administered to the subject for at least 3 consecutive days in a week. The period where PF-06873600 is not administered, also known as the “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. For example, if PF-06873600 or a pharmaceutically acceptable salt is administered daily for five days followed by a two-day rest period, PF-06873600 or a pharmaceutically acceptable salt is administered on day 1, day 2, day 3, day 4 and day 5, and the next dose will be administered after a rest period of two days later, or on day 8. This cycle is then repeated for another week and continue until terminated. That is, administration continues day 8, day 9, day 10, day 11 , day 12 and no administration will be given on day 13 and day 14, and so on.

PF-06873600 or a pharmaceutically acceptable salt may be administered in cycles, with or without rest periods in between the cycles. A cycle may be a duration of about 7 days, about 14 days, about 21 days, about 28 days, and so on, or any days in between, and a rest period can be a day to a week or to several weeks. For example, a treatment can be for, but not limiting to, about 2 weeks to about 10 weeks without any rest period in between (i.e., continuous treatment until termination), or with a rest period of one day or a few days or up to a week or two weeks or more between treatments. In some embodiments, PF-06873600 or a pharmaceutically acceptable salt is administered for about 21 days with a rest period of about one week. PF-06873600 or a pharmaceutically acceptable salt 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. In some embodiments, the patient may be treated with PF-06873600 or a pharmaceutically acceptable salt alone or in combination with an endocrine therapy agent, either continuously or intermittently as described above, for one or more 28-day cycles. In some embodiments, the patient may be treated with PF- 06873600 or a pharmaceutically acceptable salt alone or in combination with an endocrine therapy agent in one or more cycles. In some embodiments, the patient may be treated with one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or more cycles.

In some embodiments, the treatment is continued until the patient no longer benefits from the treatment. In some embodiments, the treatment continues until the patient shows unacceptable toxicity. In some embodiments, the treatment continues until the patient shows disease progression.

During the treatment period, the patient is monitored regularly for disease status and/or for dose adjustment.

During the treatment period (i.e., the one or more cycles), the patient may advantageously also be monitored for possible side effects, including toxicities and adverse events.

Because inhibition of CYP3A4/5 isoenzymes may increase PF-06873600 exposure leading to potential increases in toxicities, the use of known strong CYP3A4/5 inhibitors is not permitted within five half-lives of the respective CYP3A4/5 inhibitors, prior to the first dose of PF-06873600. Strong CYP3A4/5 inhibitors may include grapefruit juice or grapefruit/grapefruit related citrus fruits (e.g., Seville oranges, pomelos), ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir, nefazodone, lopinavir, troleandomycin, mibefradil, and conivaptan. Use of moderate CYP3A4/5 inhibitors should also be avoided which may include erythromycin, verapamil, atazanavir, fluconazole, darunavir, diltiazem, delavirdine, aprepitant, imatinib, tofisopam, ciprofloxacin, and cimetidine.

Because induction of CYP3A4/5 isoenzymes may decrease PF-06873600 exposure leading to potential decrease in efficacy, the use of strong CYP3A4/5 inducers is not permitted within five half-lives of the respective CYP3A4/5 inducers, prior to the first dose of PF-06873600. Strong CYP3A4/5 inducers may include phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, and St. John’s Wort. Use of moderate CYP3A4/5 inducers should also be avoided, which may include bosentan, efavirenz, etravirine, modafinil, and nafcillin.

Concomitant use of PF-06873600 and a CYP3A4/5 substrate may increase the exposure of the CYP3A4/5 substrate. Therefore, caution is warranted for the coadministration of PF-06873600 with CYP3A4/5 substrates with a narrow therapeutic index (e.g., astemizole, terfenadine, cisapride, pimozide, quinidine, tacrolimus, cyclosporine, sirolimus, (alfentanil and fentanyl, excluding transdermal patch), or ergot alkaloids (ergotamine, dihydroergotamine)).

Concomitant use of PF-06873600 and a substrate of the MATE1 or MATE2K renal transporters may increase the exposure of the MATE1 or MATE2K substrate. Therefore, caution is warranted for the coadministration of PF-06873600 with MATE1 or MATE2K substrates. MATE1 or MATE2K substrates may include metformin, cimetidine, procainamide, cephalexin, acyclovir, gancyclovir, fexofenadine

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. Where the compound is administered orally, it may be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable excipient. Where the compound is administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral vehicle or diluent, and in a unit dosage injectable form, as detailed below.

The pharmaceutical compositions may be in one or more dosage forms (e.g., capsule, liquid, tablet, powder).

In some embodiments, the pharmaceutical compositions may be administered in an immediate release formulation. By “immediate release” or “IR” is meant broadly to include 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. Method of Treatment

In certain embodiments, the disclosure provides a method for treating cancer of a subject in need thereof, which includes administering to the subject PF-06873600 as described herein. In certain embodiments, the disclosure also provides a method for treating cancer of a subject which includes administering to the subject PF-06873600 as described herein and an endocrine therapy agent. In such embodiments, the subject is administered an amount of PF-06873600 as described herein, or a therapeutically effective amount of PF-06873600 as described herein.

"Treat" or "treating" a cancer and/or a cancer-associated disease as used herein means to administer a monotherapy or combination therapy according to the present invention 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. The term "treatment" or “therapy,” as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject. For the purposes of this invention, 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 / 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)).

In certain embodiments, the cancer is cancer mediated by CDK2, CDK4 and/or CDK6. In some embodiments, the cancer is cancer mediated by CDK2. In some embodiments, the cancer is cancer mediated by CDK4 and/or CDK6. In some embodiments, the cancer is cancer mediated by CDK2 and CDK4/6. In some such embodiments, the cancer is characterized by amplification or overexpression of Cyclin E amplified alleles, CCNE1 and/or CCNE2. In some embodiments, the abnormal cell growth is cancer characterized as retinoblastoma (RB)-negative.

In some embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e. , gastric) cancer and thyroid cancer. In further embodiments of the methods provided herein, 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 and stomach cancer. In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2. In some embodiments, the cancer is characterized as retinoblastoma (RB)-negative. In some embodiments, the cancer is advanced or metastatic cancer.

In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is hormone receptor positive (HR+), i.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+). In some embodiments, the breast cancer is HR+/HER2- breast cancer. In other embodiments, the breast cancer is triple negative breast cancer (TNBC), i.e., the breast cancer is ER-, PR- and HER2-.

In some embodiments wherein the cancer is HR+ breast cancer, the methods, combinations and uses further comprise an endocrine therapy agent. In some such embodiments, the endocrine therapy agent is an aromatase inhibitor, a SERD or a SERM. In preferred embodiments, the endocrine therapy agent is letrozole orfulvestrant.

In some embodiments, 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., trastuzumab emtansine, fam-trastuzumab deruxtecan, pertuzumab, lapatinib, neratinib or tucatinib), or CDK4/6 inhibitors. In other embodiments, 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.

In some embodiments, the breast cancer is characterized by amplification or overexpression of cyclin E1 (CCNE1) and/or cyclin E2 (CCNE2). In some embodiments, the breast cancer is advanced or metastatic breast cancer.

In other embodiments, the cancer is lung cancer, including SCLC, characterized as retinoblastoma (RB)-negative.

In some embodiments, the breast cancer is locally advanced. In some embodiments, the breast cancer is metastatic breast cancer.

In certain embodiments, the method includes administering PF-06873600 to a subject who is suffering from cancer, for example, hormone receptor (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer, metastatic triple negative breast cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer (PPC).

In further embodiment, the ovarian cancer is advanced ovarian cancer. In one embodiment, the ovarian cancer is epithelial ovarian cancer (EOC) or platinum resistant epithelial ovarian cancer.

In certain embodiments, the method includes administering to a subject PF- 06873600 and an endocrine therapy agent. In certain embodiments, the method includes administering to a subject an amount of PF-06873600 and an endocrine therapy agent.

In some embodiments, the endocrine therapy agent is an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM). In some embodiments, the endocrine therapy agent is an aromatase inhibitor. In some such embodiments, the aromatase inhibitor is selected from the group consisting of letrozole, anastrozole, and exemestane. In some embodiments, the aromatase inhibitor is letrozole. In some embodiments, the endocrine therapy agent is a SERD. In some such embodiments, 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), SHR9549 (Jiansu Hengrui Medicine). In some embodiments, the SERD is fulvestrant. In some embodiments, the endocrine therapy agent is a SERM. In some such embodiments, the SERM is selected from the group consisting of tamoxifen, raloxifene, toremifene, lasofoxifene, bazedoxifene and afimoxifene. In some such embodiments, the SERM is tamoxifen or raloxifene.

The endocrine therapy agent may be administered according to the standard of care per package insert or provided by the health care professionals. The term "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.

In certain embodiments, the endocrine therapy agent is administered to the subject during the course of the treatment with PF-06873600 or a pharmaceutically acceptable salt. In certain embodiments, the first dose of the endocrine therapy agent is administered prior to administering the first dose of PF-06873600 or a pharmaceutically acceptable salt. In certain embodiments, the first dose of the endocrine therapy agent is administered on the same day as administering the first dose of PF-06873600 or a pharmaceutically acceptable salt. In certain embodiments, the first dose of the endocrine therapy agent is administered after the start of the treatment with PF-06873600 or a pharmaceutically acceptable salt.

In certain embodiments, letrozole is administered orally once daily together with PF-06873600 or a pharmaceutically acceptable salt. The administration of letrozole is performed according to the letrozole package insert instructions. Treatment interruption for letrozole-related toxicities is allowed as per the investigator’s best medical judgment.

In certain embodiments, fulvestrant is administered to the subject during the course of the treatment with PF-06873600 or a pharmaceutically acceptable salt. In certain embodiments, 500 mg of Fulvestrant is administered intramuscularly on certain days during the circle. The administration of fulvestrant is performed according to the fulvestrant package insert instructions. A single fulvestrant injection may be skipped in case of a fulvestrant-related toxicity or dosing may be delayed. Treatment delay for fulvestrant-related toxicities is allowed as per the investigator’s best medical judgment, but by no more than 7 days.

In certain embodiments, prior to the administration of PF-06873600 to the subject, the subject has been previously treated with one or more lines of endocrine therapy.

In certain embodiments, prior to the administration of PF-06873600 to the subject, the subject has been previously treated with chemotherapy, radiotherapy, and/or surgical resection. In certain embodiments, prior to the administration of PF-06873600 to the subject, the subject has been previously treated with a CDK4/6 inhibitor.

In certain embodiments, prior to the administration of PF-06873600 to the subject, the subject has failed at least one prior treatment.

Selection of Patients

The present treatment with PF-06873600, or a pharmaceutically acceptable salt thereof, either alone as a monotherapy or in combination with endocrine therapeutics may be administered to breast cancer patients. A patient may be a male or a female. In some embodiments, the patient is an adult male (³ 18 years of age). In some embodiments, the patient is an adult female (³ 18 years of age). In some embodiments, the female patient has achieved postmenopausal status.

In some embodiments, the patient has HR+ breast cancer. In some embodiments, the patient has HER2- breast cancer. In some embodiments, the patient has HR+ HER2- advanced or metastatic breast cancer. In some embodiments, the patient has TNBC. In some embodiments, the patient has locally recurrent/advanced or metastatic TNBC. In some embodiments, the patient has ovarian cancer. In some embodiments, the patient has advanced platinum resistant ovarian cancer. In some embodiments, the patient has advanced platinum resistant epithelial ovarian cancer (EOC). In some embodiments, the patient has fallopian tube cancer. In some embodiments, the patient has primary peritoneal cancer (PPC).

In some embodiments, the patient has undergone a documented hysterectomy and/or bilateral oophorectomy. In some embodiments, the patient has medically confirmed ovarian failure.

In some embodiments, the patient has a histologically or cytologically proven diagnosis of the breast adenocarcinoma with evidence of inoperability, metastatic disease, and/or locally advanced cancer not amenable to radiation therapy or surgery in a curative intent.

In some embodiments, the patient has received one or more prior line of combined CDK4/6 inhibitor and endocrine therapy. In some embodiments, the patient has failed prior combination of a CDK4/6 inhibitor and endocrine therapy. In some embodiments, the patient is naive to CDK4/6 inhibitors. In some embodiments, the patient has not received a CDK4/6 inhibitor as treatment as adjuvant therapy or as treatment in the advanced or metastatic setting. In some embodiments, the patient has not received an aromatase inhibitor in the advanced or metastatic setting.

In some embodiments, the patient has received one or more prior lines of cytotoxic chemotherapy in the advanced or metastatic setting.

In specific embodiments, the TNBC patient has received up to two prior lines of chemotherapy in the advanced or metastatic setting.

In specific embodiments, the ovarian cancer patient has received up to three prior lines of therapy.

In some embodiments, the patient is refractory to or intolerant of existing therapies known to provide clinical benefit for their condition.

In some embodiments, the patient is refractory to endocrine therapy.

In some embodiments, the patient has a primary tumor or any metastatic site that is positive for ER and does not also overexpress HER2. A primary tumor or any metastatic site is judged to be positive for ER when >1% of the tumor cells are stained by immunohistochemistry (IHC). A primary tumor or any metastatic site can be judged to not be overexpressing HER2 by using, for example, IHC (0, 1+) or in situ hybridization (FISH/CISH/SISH/DISH) (negative based on single-probe average HER2 copy number <4.0 signals/cell, or dual-probe /-/ER2/centromeric probe for chromosome 17 (CEP17) ratio <2, as per the American Society of Clinical Oncology guidelines).

In some embodiments, the patient has a measurable lesion or measurable malignant lymph node by the RECIST v1.1 criteria (Response Evaluation Criteria In Solid Tumors, see Eisenhauer et al. Eur J Cancer. (2009) 45(2):228-47). A measurable lesion refers to a tumor lesion (1) that has been accurately measured in at least one dimension; (2) 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); or (3) with longest diameter at least 20 mm when assessed by Chest X-ray. A measurable superficial lesion is a lesion with longest diameter ³10 mm when assessed by caliper. A measurable malignant lymph node is a lymph node that is pathologically enlarged and measurable, with ³15 mm in short axis when assessed by CT scan.

In some embodiments, the patient has undergone a prior chemotherapeutic regimen for advanced/metastatic disease. Prior chemotherapy treatment includes treatment with antibody drug conjugates (ADCs). In some embodiments, the patient has received no more than one prior chemotherapeutic regimen. In some embodiments, the patient has received at least six months of prior endocrine therapy for advanced breast cancer. In some embodiments, the patient has undergone no more than two prior lines of endocrine therapy. In some embodiments, the patient is a patient who has previously had early progression on adjuvant endocrine therapy, or a patient who progressed on adjuvant endocrine therapy within twelve months after completion of the treatment period.

Treatment Outcomes and Tumor Response Evaluation

The present therapy may result in a complete response (CR), partial response (PR), progressive disease (PD), or stable disease (SD) in patients. Bioimaging can be used to evaluate the level of response to the therapy. Cytology and histology may also be used as needed (e.g., to locate any residual lesions). In some embodiments, the various levels of response can be evaluated in accordance with Tables 1 and 2 below.

Table 1. Evaluation of Target Disease

Table 2. Evaluation of Non-Target Disease

Exemplary Embodiments

The present disclosure provides below some non-limiting exemplary embodiments.

E1. A method of treating cancer comprising administering to a subject in need thereof a total daily dose of from about 1 mg to about 75 mg of a cyclin-dependent kinase (CDK) inhibitor PF-06873600 having the structure

pharmaceutically acceptable salt thereof.

E2. The method of embodiment 1 , wherein the total daily dose is administered once per day (QD), or in divided doses twice per day (BID) or three times per day (TID).

E3. The method of any one of embodiments 1-2, wherein PF-06873600, or a pharmaceutically acceptable salt, is administered in an amount of from about 1 mg to about 35 mg QD or BID. E4. The method of any one of embodiments 1-3, wherein PF-06873600, or a pharmaceutically acceptable salt, is administered in an amount of about 30 mg BID.

E5. The method of any one of embodiments 1-3, wherein PF-06873600, or a pharmaceutically acceptable salt, is administered in an amount of about 25 mg BID.

E6. The method of any one of embodiments 1-3, wherein PF-06873600, or a pharmaceutically acceptable salt, is administered in an amount of about 20 mg BID.

E7. The method of any one of embodiments 1-6, wherein PF-06873600, or a pharmaceutically acceptable salt, is administered daily.

E8. The method of any one of embodiments 1-6, wherein PF-06873600, or a pharmaceutically acceptable salt, is administered daily for at least three consecutive days followed by a rest period of 1 to 4 days in which PF-06873600 is not administered.

E9. The method of embodiment 8, wherein PF-06873600, or a pharmaceutically acceptable salt, is administered daily for five consecutive days followed by a rest period of two days in which PF-06873600 is not administered.

E10. The method of any one of embodiments 1-9, wherein PF-06873600, or a pharmaceutically acceptable salt, is administered for one or more 28-day cycles.

11. The method of any one of embodiments 1-10 wherein PF-06873600, or a pharmaceutically acceptable salt, is administered orally.

12. A method of treating cancer comprising administering to a subject in need thereof a total daily dose of from about 1 mg to about 75 mg of a pharmaceutical composition comprising PF-06873600, or a pharmaceutically acceptable salt thereof, in combination with an endocrine therapy agent.

E13. A method of treating cancer comprising administering to a subject in need thereof PF-06873600 daily at about 25 mg twice per day alone or in combination with an endocrine therapy agent. E14. The method of any one of embodiments 12-13, wherein the endocrine therapy agent is an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).

E15. The method of embodiment 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, bazedoxifene and afimoxifene.

E16. The method of embodiment 15, wherein the endocrine therapy agent is fulvestrant or letrozole.

E17. The method of any one of embodiments 1-16, wherein the subject has been previously treated with chemotherapy, radiotherapy, and/or surgical resection.

E18. The method of embodiment 17, wherein the subject has been previously treated with a CDK4/6 inhibitor.

E19. The method of embodiment 17, wherein the subject has been previously treated with an endocrine therapy agent.

E20. The method of embodiment 17, wherein the subject has failed at least one prior treatment.

E21. The method of any one of embodiments 1-20, wherein the subject is a mammal.

E22. The method of any one of embodiments 1-21 , wherein the subject is suffering from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, or stomach cancer.

E23. The method of embodiment 22, wherein the cancer is cancer is hormone receptor (HR+) or human epidermal growth factor receptor 2 negative (HER2-) breast cancer, metastatic triple negative breast cancer, advanced platinum resistant epithelial ovarian cancer (EOC), fallopian tube cancer, or primary peritoneal cancer (PPC).

E24. The method of any one of embodiments 1-23, wherein the cancer is (a) breast cancer or ovarian cancer; (b) characterized by amplification or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2); or (c) both (a) and (b).

E25. The method of any one of embodiments 1-24, wherein the cancer is HR-positive HER2-negative advanced or metastatic breast cancer.

E26. Use of PF-06873600, or a pharmaceutically acceptable salt, in the manufacture of a medicament for use in the treatment of cancer in a subject in need thereof which the medicament is administered in a therapeutically effective unit dosage of PF- 06873600, or a pharmaceutically acceptable salt, in the amount of from about 1 mg to about 75 mg per day.

E27. Use of PF-06873600 or a pharmaceutically acceptable salt and an endocrine therapy agent in the manufacture of a medicament for use in the treatment of cancer in a subject in need thereof which the medicament is administered in a therapeutically effective unit dosage of PF-06873600, or a pharmaceutically acceptable salt, in the amount of from about 1 mg to about 75 mg per day.

E28. A medicament comprising a therapeutically effective amount of PF-06873600 or a pharmaceutically acceptable salt for use in treating cancer in a subject in need thereof, wherein the therapeutically effective amount is from about 1 mg to about 75 mg per day.

E29. A medicament comprising a therapeutically effective amount of PF-06873600 or a pharmaceutically acceptable salt and an endocrine therapy agent for use in treating cancer in a subject in need thereof, wherein the therapeutically effective amount is from about 1 mg to about 75 mg per day.

Examples

The following examples are merely illustrative of the disclosure and should not be considered limiting the scope of the invention in any way, as these examples and other equivalents thereof will become apparent to those skilled in the art in light of the present disclosure and the accompanying claims.

Phase 1/2a PF-06873600 Clinical Trial PF-06873600 is being examined in an ongoing open-label, multi-center, non- randomized, multiple-dose study to evaluate safety, tolerability, PK, PD, and anti-tumor activity of increasing doses of PF-06873600 as a single agent in sequential dose levels and then in combination with endocrine therapy.

Study Design: The study contains two parts, dose escalation (Part 1) with single agent (Part 1A) and then dose finding with PF-06873600 in combination with endocrine therapy (letrozole or fulvestrant) (Part 1 B) followed by dose expansion arms in combination with endocrine therapy (Part 2). Details of the studies are presented below.

Example 1 Pharmacokinetics (PK) study

The preliminary PK of PF-06873600 following single and multiple oral doses of PF-06873600 ranging from 1 mg BID to 50 mg BID was characterized in 101 patients with advanced cancer. Preliminary PK analysis was conducted based on available samples collected from patients in phase 1/2a PF-06873600 clinical trial cohorts, where the dose levels of these cohorts are presented in Table 3.

Table 3: Phase 1/2a study Cohorts PF-06873600 Immediate Release (IR) Formulation

FIG. 1 shows the median PF-06873600 plasma concentration-time profiles on Day 1 following the administration of a single oral dose of PF-06873600. FIG. 2 shows the median PF-06873600 plasma concentration-time profiles on Day 15 following the administration of multiple oral doses of PF-06873600. Table 4 presents the summary statistics of pharmacokinetic parameters of plasma PF-06873600. Note that the cutoff date for Table 4 is March 26, 2022 and the cutoff date for FIGS. 1 and 2 is May 5, 2022. Two additional patients were included in cohort 11 since March 26, 2022 and there was no significant changes or influence to the summary/conclusion.

Table 4

Phase 1/2a Study: Preliminary Plasma PF-06873600 Pharmacokinetic Parameters Following Single and Multiple Oral Doses of PF-06873600 Immediate Release Administered to Subjects with Advanced Cancer

Data cutoff date: March 26, 2022

Abbreviations: CV = coefficient of variation; N = number of subjects in the treatment group evaluable for PK parameters; ND = not determined; AUCiast = AUC to last measurable concentration; AUCin_f = AUC extrapolated to infinity; AUCtau = AUC over a dosing interval; Cmax_,ss = maximum plasma concentration at steady-state; Cmin.ss = minimum plasma concentration at steady-state; T_max = time of the first occurrence of Cmax; Rac = accumulation ratio; n = number of subjects with AUCtau and CL/F determined; PK = pharmacokinetic; SD = standard deviation.

Concentration values below the lower limit of quantification (LLOQ) are set to zero. The LLOQ is 1.00 ng/ml_. Estimation of AUCiast includes O to 12 hours post-dose.

Geometric mean (geometric %CV) for all except median (range) for Tmax, arithmetic mean ± SD fort½ and arithmetic mean (%CV) for Cmm.

SD and %CV not reported when the number of subjects with available parameters is less than 3.

Following single oral administration, the PF-06873600 IR formulation was rapidly absorbed with a Tmax ranging from 1 to 4 hours after the first dose. A descriptive summary of plasma PF-06873600 PK parameters is presented in Table 4 above. Summary statistics are represented in median (min-max). The mean plasma exposure parameters of PF-06873600, including Cmax, Cmin, and AUC, in general increased with dose up to at least 35 mg BID. There was minimal accumulation following repeated BID dosing, with mean Rac (accumulation ratio) ranging from 0.7 to 1.3. The mean terminal half-life (t½) ranged from 2 to 3 hours.

PF-06873600 exhibited moderate to high inter-subject variability in PK following oral administration with the IR formulation. At 25 mg BID, the %CV values were 36% and 38% for Cycle 1 Day 1 AUCinf and Cmax, respectively. After multiple dosing at 25 mg BID, the %CV values were 43%, 45% and 116% for AUCtau, Cmax and Cmin, respectively.

The plasma PK of PF-06873600 was largely comparable between monotherapy and the combination therapy with fulvestrant or letrozole.

Example 2

Part 1A PF-06873600 Single Agent Dose Escalation

The objective of Part 1A study was to evaluate safety including dose-limiting toxicities (DLTs) in the first 28-day cycle, adverse events (AEs), and laboratory abnormalities, and to estimate the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D) and recommended dose for expansion (RDE) in sequential dose escalation safety cohorts for PF-06873600 as a single agent and in combination with endocrine therapy in women of any menopausal status and men with HR-positive HER2-negative advanced or metastatic breast cancer (mBC), and in women/men with locally recurrent/advanced or metastatic TNBC, and women with advanced platinum resistant ovarian cancer (OVCA). The RDE is the dose chosen for further investigation based on Part 1 study results. If the RDE proves to be clinically feasible for long-term administration in a reasonable number of patients, then this dose usually becomes the RP2D.

Patients with locally recurrent/advanced or metastatic TNBC who have received up to two prior lines of chemotherapy in the advanced or metastatic setting, and patients with advanced platinum resistant epithelial ovarian cancer (EOC) or fallopian tube cancer or primary peritoneal cancer (PPC) who have received up to three prior lines of therapy, were eligible to participate in the Part 1 dose escalation study.

Patients received escalating doses of PF-06873600 starting from 1 mg administered orally BID on a continuous basis in 28-day cycles, and dose escalation proceeded according to the modified toxicity probability interval (mTPI) method described in Y. Ji, et ai, “A modified toxicity probability interval method for dose-finding trials”; Clinical Trials, 7:653663, 2010. When a dose level was deemed safe following a DLT observation period of 28 days, dose escalation to the next dose level occurred as shown in Table 5. The starting dose of PF-06873600 was 1 mg administered orally BID on a continuous basis in 28-day cycle.

Table 5: PF-06873600 Dose Levels (Immediate Release Formulation)

Part 1B PF-06873600 Dose Finding in Combination with Endocrine Therapy

The objective of Part IB study was to access the safety and tolerability of PF-06873600 in combination with letrozole and in combination with fulvestrant in independent cohorts in women with HR-positive HER2-negative advanced or mBC. PF- 06873600 was administered orally on a continuous basis, while letrozole and fulvestrant were administered per standard of care.

In Part 1B, the PF-06873600 dose could be de-escalated at full or intermediate dose levels. In addition, the PF-06873600 formulations at the respective RDE were studied in combination with endocrine therapy in Part 1B.

The PF-06873600 dose de-escalated in combination with fulvestrant followed the modified toxicity probability interval (mTPI) method.

Part 2 PF-06873600 Combination Dose Expansion

Part 2 dose expansion was an open-label, multi-center, non-randomized study to assess the preliminary anti-tumor activity and the safety and tolerability of PF-06873600. PF-06873600 is administered at the RDE in 28 days cycles in combination with endocrine therapy (letrozole and fulvestrant) in two separate dose expansion arms. The single agent PF-06873600 RDE from Part 1A was used to initiate the Part 2 dose expansion arm studies. Additionally, the PF-06873600 RDE in combination with letrozole and PF-06873600 RDE in combination with fulvestrant from Part 1 B was used to initiate the Part 2 respective combination dose expansion arm studies.

Part 2/Arm A - PF-06873600 in Combination with Fulvestrant in HR-Positive HER2-Neqative Locally Advanced or mBC

PF-06873600 was evaluated in combination with fulvestrant at the RDE in HR-positive HER2-negative advanced or mBC in patients who have received prior combined CDK4/6 inhibitor and a nonsteroidal aromatase inhibitor, and up to one prior line of chemotherapy.

Part 2/Arm B - PF-06873600 in Combination with Letrozole in HR-Positive HER2-Neqative Locally Advanced or mBC (naive to CDK4/6 inhibitors!

PF-06873600 is evaluated in combination with letrozole at the RDE in HR-positive HER2-negative advanced or mBC in patients, with supportive available preliminary PF-06873600 clinical data. Patients who have not received any prior treatment with a CDK4/6 inhibitor in the advanced or metastatic setting is enrolled.

Part 2/Arm C - PF-06873600 in Combination with Fulvestrant in HR-Positive HER2-Negative Locally Advanced or mBC (naive to CDK4/6 inhibitors)

PF-06873600 was evaluated in combination with fulvestrant at the RDE in HR-positive HER2-negative advanced or mBC in patients who have not previously received treatment with a CDK4/6 inhibitor in the advanced or metastatic setting. Participants who have prior treatment with CDK4/6 inhibitors, fulvestrant, everolimus, and any agents with MOA that inhibits PI3k-mTOR pathway are excluded.

Method of Administration

Given the predicted human disposition and plasma half-life of approximately 9 hours, the starting dose was selected to be 1 mg administered orally BID. Study participants received an IR formulation up to 50 mg BID with continuous dosing or 35 mg BID on an intermittent (5 days on 2 days off) schedule.

The dosing intervals are as follows: for the QD dosing regimen, the single dose should be administered in 24 ± 4 hour intervals (/.e., no less than 20 hours and no more than 28 hours apart); for the BID dosing regimen, the doses should be administered in 12 ± 4 hour intervals (/.e., no less than 8 hours and no more than 16 hours apart).

All cycles are 28 days in length and treatment will continue until progression of disease, uncontrollable toxicity, a decision by the patient or investigator to discontinue treatment or the study is terminated. Patients experiencing toxicity including a dose limiting toxicity (DLT) may be managed with dose modification or discontinuation from treatment. The proposed doses, schedule(s) and PK time points may be reconsidered and amended during the study based on the emerging safety and PK data.

Fulvestrant 500 mg was administered intramuscularly into the buttocks slowly (1-2 minutes per injection) as two 5 ml_ injections, one in each buttock, per administration instructions provided in the Faslodex^® label.

Letrozole was administered orally once daily continuously together with PF- 06873600.

Definitions:

As used herein, “dose limiting toxicity” (DLT) refers to the dosage of PF-06873600 that is contraindicative of a further increase in dosage. Any of the following adverse events (AEs) occurring in the first cycle of treatment (28 days) which are attributable to PF-06873600 and/or the endocrine therapy agent will be classified as DLTs:

Hematologic - Grade 4 neutropenia lasting >7 days; Febrile neutropenia defined as an absolute neutrophil count (ANC) <1.0 x 109/L with a single temperature of >38.3°C, or 101°F, or a sustained temperature of ³38°C, or 100.4°F, for more than one hour; Grade ³3 neutropenia with associated infection; Grade 3 thrombocytopenia with clinically significant bleeding as indicated by ³ Grade 2 bleeding; Grade 4 thrombocytopenia.

Nonhematologic - Confirmed case of drug-induced liver injury; Grade ³3 AEs that are clinically significant with the following exceptions: (1) Grade 3 nausea, vomiting, or diarrhea for ³72 hours despite optimal supportive care will be considered a DLT; (2) Grade 3 fatigue for ³5 days will be considered a DLT ; (3) Grade 5 event unless attributed to a cause clearly not related to study treatment.

As used herein “maximum tolerated dose” (MTD) refers to the highest dosage of PF-06873600 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%. Results:

The Phase 1/2a PF-06873600 clinical trial is ongoing. As of May 6, 2022, a total of 122 patients have received treatments, of which 51 patients received PF-06873600 alone and 64 patients received PF-06873600 in combination with fulvestrant and 7 patients in combination with Letrozole.

I. Safety

Dose Limiting Toxicities (DLTs)

A total of 54 patients (Cohorts 1-7, 9, 11-13) were evaluated for a minimum DLT observation period of 28 days to inform dose escalation and determine the maximum tolerable dose (MTD). Of those, six patients experienced DLTs in the two highest dosing cohorts. Specifically, two patients experienced DLTs in the 35 mg BID continuous dosing cohort (cohort 9), where one patient experienced Grade 4 neutropenia and Grade 4 thrombocytopenia, and the other experienced Grade 4 neutropenia; three patients experienced Grade ³3 DLTs, and there was one patient experienced Grade 5 DLTs in the 50 mg BID cohort (cohort 6) (included as one of the four patients discussed in the SAEs below).

There was no report of DLTs in all 12 evaluable patients within the PF-06873600 in combination with fulvestrant or letrozole. Dose limiting toxicities for all dose levels in Cohorts 1-7, 9 and 11-13 are summarized below in Table 6.

Table 6

A participant is classified as DLT-evaluable if he/she receives at least 75% of the planned doses or has a DLT in the first 28 cycle. Adverse Events

Adverse events of the patients dosed with PF-06873600 in the Phase 1/2a clinical trial were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. As of May 6, 2022 the following adverse events data were obtained.

All-Causality Treatment-Emergent Adverse Events (TEAE)

A total of 115 (94.7%) patients of the 122 (100.0%) patients dosed with PF-06873600 experienced at least one all-causality TEAE. A total of 943 all-causality TEAEs were reported during the study.

The majority of all-causality TEAEs reported were of Grade 3 severity or lower. Eleven patients (9%) reported Grade 4 all-causality TEAE, including febrile neutropenia (n=2, 1.5%), neutrophil count decreased (n=5, 3.8%), and platelet count decreased (n=2, 1.4%), anaemia (n=1, 0.8%), haemolysis (n=1, 1.3%), neutropenia (n=4, 3%), thrombocytopenia (n= 3, 2.3%), colitis (n=1 , 0.8%), multiple organ dysfunction syndrome (n=1, 0.8%), lipase increased (n=1 , 0.8%), white blood cell (WBC) decreased (n=1, 0.8%), and hypophosphataemia (n=2, 1.5%). Four patients experienced Grade 5 all causality SAEs. Among these four patients, two patients participated in the 50 mg BID continuous dosing cohort, of which one of them experienced Grade 5 cardiac arrest and the other experienced Grade 5 disease progression; the other two patients participated in the 25 mg BID in combination with fulvestrant cohort, of which one of them experienced Grade 5 gastrointestinal bacterial infection and the other experienced Grade 5 hemolysis, Grade 5 cardiac arrest and Grade 5 respiratory failure.

Treatment Related Treatment-Emergent Adverse Events

A total of 106 (87.2%) patients of the 122 patients dosed with PF-06873600 experienced at least one treatment-related AE.

A total of 596 TEAEs were reported to be treatment related during the study. 39 (32.3%) patients reported treatment related Grade 3 or 4 TEAEs. Three patients (2.3%) reported a treatment related Grade 5 TEAE including cardiac arrest, respiratory failure, and gastrointestinal bacterial infection. All-Causality Serious Adverse Events (SAEs)

A total 23 (19.5 %) patients reported all-causality SAEs. The most frequently reported (³2%) all-causality SAEs were abdominal pain (n=3, 2.3%) and febrile neutropenia (n=4, 3.0%), anaemia (n=2, 1.5%), cardiac arrest (n=2, 1.5%), colitis (n=3, 2.3%), neutropenia (n=2, 1.5%) and hypotension (n=3, 2.3%). Grade 4 all-causality SAEs were febrile neutropenia (n=2, 1.5 %), anaemia (n=1, 0.8%), colitis (n=1, 0.8%), neutropenia (2, 1.5%) multiple organ dysfunction syndrome (n=1, 0.8%), thrombocytopenia (n=1 , 0.8%). Four patients experienced Grade 5 all-causality SAEs. Among these four patients, two patients participated in the 50 mg BID continuous dosing cohort, of which one of them experienced Grade 5 cardiac arrest and the other experienced Grade 5 disease progression; the other two patients participated in the 25 mg BID in combination with fulvestrant cohort, of which one of them experienced Grade 5 gastrointestinal bacterial infection and the other experienced Grade 5 hemolysis, Grade 5 cardiac arrest and Grade 5 respiratory failure.

Treatment Related Serious Adverse Events :

Ten (8.3%) patients reported SAEs which were considered to be related to the study drug PF-06873600. The most frequently reported (³2%) treatment-related SAE was febrile neutropenia reported in 4 patients (3%), neutropenia (n=2, 1.5%), colitis (n=2,

I .5%) Grade 4 treatment- related SAEs were febrile neutropenia (n=2, 1.5%), neutropenia (n=2, 1.5%), thrombocytopenia (n=1, 0.8%), colitis (n=1 , 0.8%), and multiple organ dysfunction syndrome (n=1, 1.3%). Three patients experienced Grade 5 treatment- related SAEs which include cardiac arrest, respiratory failure, and gastrointestinal bacterial infection.

The most frequently reported treatment-related AEs for the PF-06873600 monotherapy group and the PF-06873600 in combination with fulvestrant group, respectively, were nausea, anemia, fatigue and neutrophil count decrease.

II. Efficacy

The efficacy data was obtained from the 100 evaluable patients. As of May 6, 2022, PF-06873600 demonstrated a disease control rate of 65% (n=65/100) in evaluable patients across all cohorts. This included two patients with confirmed partial responses. Among the evaluable patients who assessed as per RECISTv.1.1 (Table 7), the disease control rate was 53.5% (n=23/43) in the single agent PF 06873600 group (Total Part 1A), 73.7% (n=42/57) in the combination group PF 06873600 + endocrine therapy (Part 2A + Part 2C + T otal Part 1 B) . Table 7

III. Patient Population

Among the 122 treated patients, 116 patients (95.0%) had breast cancer, including 110 patients (90.1%) HR+Her2- and 4 patients (3.3%) with TNBC; 6 patients (4.9 %) had ovarian cancer.

The patient age range was from 28 to 84 years old.

A total of 87 (71.3%) patients had prior surgery. A total of 88 (72.1%) patients had received prior hormonotherapy, which includes anastrozole, exemestane, fulvestrant, letrozole, and tamoxifen. A total of 56 (45.9%) patients had received prior radiotherapy. A total of 99 (82.7%) patients had received prior systemic therapy, among whom 46 (38.3%) patients received >3 regimens of prior systemic therapy. PF-06873600 exposure increased with dose and was not significantly impacted by fulvestrant and at the RDE remained above the preclinical efficacious concentrations in relevant models for ³75% of the dosing interval. Dosage Forms and Packaging

PF-06873600 is provided as tablets for oral administration, as the 5 mg and 25 mg immediate release tablets.

Letrozole (Femara^®) was supplied by Pfizer. Letrozole is available as 2.5 mg tablets. Fulvestrant (Faslodex^®) was supplied by Pfizer. Fulvestrant 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.

Claims

What is claimed:

1. A method of treating cancer comprising administering to a subject in need thereof a total daily dose of from about 1 mg to about 75 mg of a cyclin-dependent kinase (CDK) inhibitor PF-06873600 having the structure

pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the total daily dose is administered once per day (QD), or in divided doses twice per day (BID) or three times per day (TID).

3. The method of any one of claims 1-2, wherein PF-06873600, ora pharmaceutically acceptable salt, is administered in an amount of from about 1 mg to about 35 mg QD or BID.

4. The method of any one of claims 1-3, wherein PF-06873600, ora pharmaceutically acceptable salt, is administered in an amount of about 30 mg BID.

5. The method of any one of claims 1-3, wherein PF-06873600, ora pharmaceutically acceptable salt, is administered in an amount of about 25 mg BID.

6. The method of any one of claims 1-3, wherein PF-06873600, ora pharmaceutically acceptable salt, is administered in an amount of about 20 mg BID.

7. The method of any one of claims 1-6, wherein PF-06873600, or a pharmaceutically acceptable salt, is administered daily.

8. The method of any one of claims 1-6, wherein PF-06873600, ora pharmaceutically acceptable salt, is administered daily for at least three consecutive days followed by a rest period of 1 to 4 days in which PF-06873600 is not administered.

9. The method of claim 8, wherein PF-06873600, or a pharmaceutically acceptable salt, is administered daily for five consecutive days followed by a rest period of two days in which PF-06873600 is not administered.

10. The method of any one of claims 1-9, wherein PF-06873600, ora pharmaceutically acceptable salt, is administered for one or more 28-day cycles.

11. The method of any one of claims 1-10 wherein PF-06873600, or a pharmaceutically acceptable salt, is administered orally.

13. A method of treating cancer comprising administering to a subject in need thereof PF-06873600 daily at about 25 mg twice per day alone or in combination with an endocrine therapy agent.

14. The method of any one of claims 12-13, wherein the endocrine therapy agent is an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).

15. The method of claim 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, bazedoxifene and afimoxifene.

16. The method of claim 15, wherein the endocrine therapy agent is fulvestrant or letrozole.

17. The method of any one of claims 1-16, wherein the subject has been previously treated with chemotherapy, radiotherapy, and/or surgical resection.

18. The method of claim 17, wherein the subject has been previously treated with a CDK4/6 inhibitor.

19. The method of claim 17, wherein the subject has been previously treated with an endocrine therapy agent.

20. The method of claim 17, wherein the subject has failed at least one prior treatment.

21. The method of any one of claims 1-20, wherein the subject is a mammal.

22. The method of any one of claims 1-21 , wherein the subject is suffering from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, or stomach cancer.

23. The method of claim 22, wherein the cancer is cancer is hormone receptor (HR+) or human epidermal growth factor receptor 2 negative (HER2-) breast cancer, metastatic triple negative breast cancer, advanced platinum resistant epithelial ovarian cancer (EOC), fallopian tube cancer, or primary peritoneal cancer (PPC).

24. The method of any one of claims 1-23, wherein the cancer is (a) breast cancer or ovarian cancer; (b) characterized by amplification or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2); or (c) both (a) and (b).

25. The method of any one of claims 1-24, wherein the cancer is HR-positive HER2-negative advanced or metastatic breast cancer.

26. Use of PF-06873600, or a pharmaceutically acceptable salt, in the manufacture of a medicament for use in the treatment of cancer in a subject in need thereof which the medicament is administered in a therapeutically effective unit dosage of PF- 06873600, or a pharmaceutically acceptable salt, in the amount of from about 1 mg to about 75 mg per day.

27. Use of PF-06873600 or a pharmaceutically acceptable salt and an endocrine therapy agent in the manufacture of a medicament for use in the treatment of cancer in a subject in need thereof which the medicament is administered in a therapeutically effective unit dosage of PF-06873600, or a pharmaceutically acceptable salt, in the amount of from about 1 mg to about 75 mg per day.

28. A medicament comprising a therapeutically effective amount of PF-06873600 or a pharmaceutically acceptable salt for use in treating cancer in a subject in need thereof, wherein the therapeutically effective amount is from about 1 mg to about 75 mg per day.

29. A medicament comprising a therapeutically effective amount of PF-06873600 or a pharmaceutically acceptable salt and an endocrine therapy agent for use in treating cancer in a subject in need thereof, wherein the therapeutically effective amount is from about 1 mg to about 75 mg per day.