CN118338901A - CDK4 inhibitors for the treatment of cancer - Google Patents

Abstract

The present disclosure provides a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of PF-07220060. The present disclosure also provides a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of PF-07220060 and an endocrine therapeutic agent.

Description

CDK4 inhibitors for the treatment of cancer

Technical Field

The present disclosure relates to the therapeutic treatment of cancer with the Cyclin Dependent Kinase (CDK) inhibitor 1, 5-anhydro-3- ({ 5-chloro-4- [ 4-fluoro-2- (2-hydroxypropyl-2-yl) -1- (propan-2-yl) -1H-benzimidazol-6-yl ] pyrimidin-2-yl } amino) -2, 3-dideoxy-D-threo-pent-anol (hereinafter PF-07220060) or a pharmaceutically acceptable salt thereof alone in monotherapy or in combination with an endocrine therapeutic agent. The invention also relates to a related combination therapy, a pharmaceutical composition and pharmaceutical application.

Introduction to the invention

CDKs are important cellular enzymes that perform essential functions in regulating eukaryotic cell division and proliferation. CDK inhibitors may be used to treat proliferative disorders, including cancer.

Cancer is produced via unregulated cell proliferation, which is reflected by an unchecked progression of the cell cycle followed by loss of checkpoint control permitting uncontrolled cell proliferation. Retinoblastoma protein (Rb 1) is a key negative regulator of the G1 and resting G0 phases of the cell cycle until and unless phosphorylated by CDK4 or CDK6 (Weinberg, R.A.the retinoblastoma protein AND CELL CYCLE control.cell, vol. 81, 323-330, 1995). The concept of CDK 4/6-retinoblastoma protein axis imbalance in cancer is supported by genetic alterations commonly identified in breast cancer, such as cyclin D1 (CCND 1) and cyclin E1 (CCNE 1) gene amplification and alterations in endogenous CDK 4-cyclin D1 inhibitor p16 (INK 4a, encoded by CDKN2A gene), TP53 and PIK3CA genes (Cancer Genome Atlas Network.Comprehensive genomic characterization of human breast tumours.Nature,490,61-70,2012).

CDK4/6 inhibition has become a promising strategy for cancer therapy, particularly for the treatment of endocrine-resistant breast cancer BC (Rani, A. Et al ,Endocrine Resistance in Hormone Receptor Positive Breast Cancer-From Mechanism to Therapy.Front Endocrinol(Lausanne)10:245,2019).CDK4/6 inhibitors such as palbociclib (palbociclib), arbeli (abemaciclib), rabociclib (ribociclib)) when administered in combination with endocrine therapy significantly improve the progression free and/or overall survival of patients with HR-positive/HER 2-negative metastatic breast cancer (Spring, L.M. et al) ,Cyclin-dependent kinase 4and 6inhibitors for hormone receptor-positive breast cancer:past,present,and future.Lancet,395,817-827,2020).

Although CDK4/6 inhibitors increase response rates and prolong disease control in patients with hr+, HER 2-breast cancer, they are associated with dose-limiting hematologic toxicity (major neutropenia).

PF-07220060 is a potent inhibitor of cyclin-dependent kinase 4 (CDK 4). The preparation of PF-07220060 is described in International patent publication No. WO 2019/207463 and U.S. Pat. No. 10,766,884. The contents of each of the foregoing documents are incorporated by reference herein in their entirety. PF-07220060 differs from currently approved dual CDK4/6 inhibitors in that it exhibits CDK4 over CDK6 selectivity. In an in vivo model, PF-07220060 reduced dose-limiting neutropenia and was predicted to achieve higher tolerogenic plasma concentrations than dual CDK4/6 inhibitors, and thus increased inhibition of CDK4 oncogenes in the resulting tumors.

There is a need for an appropriate and effective dosing regimen for PF-07220060 in single agent form and in combination therapy for the treatment of cancer while minimizing adverse events.

SUMMARY

The present disclosure relates to both single agents and combination therapies for treating cancer, comprising the CDK4 inhibitor PF-07220060, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present disclosure provides methods of treating cancer comprising orally administering to a subject in need thereof a therapeutically effective amount of PF-07220060, or a pharmaceutically acceptable salt thereof. In particular, the method comprises administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of PF-07220060, a total daily dose of PF-07220060 of about 200mg to about 1000mg per day, and in certain embodiments about 100mg to about 500mg, twice daily (BID).

In certain embodiments, the present disclosure provides methods of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of PF-07220060, or a pharmaceutically acceptable salt thereof, and an endocrine therapeutic agent. In embodiments, the endocrine therapeutic agent is an aromatase inhibitor, a selective estrogen receptor degrading agent (SERD), or a Selective Estrogen Receptor Modulator (SERM). In embodiments, the endocrine therapeutic agent comprises fulvestrant (fulvestrant), tamoxifen (tamoxifen), toremifene (toremifene), anastrozole (anastrozole), exemestane (exemestane), or letrozole (letrozole).

Thus, embodiments herein provide a dosing regimen for PF-07220060 in the form of a single agent and in the form of a combination therapy for the treatment of cancer by which side effects in an individual during treatment are minimized.

Brief Description of Drawings

Figure 1 shows the plasma concentration of PF-07220060 versus nominal time profile at day 1 of cycle 1 after administration of PF-07220060 as monotherapy or as an oral dose in combination with letrozole or fulvestrant.

Figure 2 shows the plasma concentration of PF-07220060 versus nominal time profile at day 15 of cycle 1 after repeated BID oral dosing of PF-07220060 in monotherapy or in combination with letrozole or fulvestrant.

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 the purpose of describing particular embodiments only and is not intended to be limiting. It will be further understood that the terms used herein have their ordinary meaning as known in the relevant art unless specifically limited herein.

Definition:

As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. For example, a "substituent includes one or more substituents.

The term "about" when considered by one of ordinary skill in the art means having a value that falls within an acceptable average error criteria. In some embodiments, the term "about" means within ±10% of the indicated value. For example, it is understood that a dose of about 400mg means that the dose can vary between 360mg and 440 mg.

The invention described herein may be suitably practiced in the absence of any element not specifically disclosed herein. Thus, for example, in each instance herein, any of the terms "comprising," "consisting essentially of … … (consisting essentially of)" and "consisting of … … (consisting of)" can be replaced with either of the other two terms.

As used herein, "dose limiting toxicity" (DLT) refers to a dose of PF-07220060 that is contraindicated to further increases in dose.

As used herein, "measurable lesions" refers to lesions that can be accurately measured in at least one dimension, lesions that have a longest diameter of twice the slice thickness and at least 10mm or more (slice thickness 5 to 8 mm) when assessed by CT or MRI, lesions that have a longest diameter of at least 20mm when assessed by chest X-rays, superficial lesions that have a longest diameter of 10mm or more when assessed by calipers, or malignant lymph nodes that have a short axis of 15mm or more when assessed by CT.

As used herein, "maximum tolerated dose" (MTD) refers to the highest dose of PF-07220060 that does not cause unacceptable side effects or intolerance of toxicity. MTD was estimated based on observed DLT rate using mTPI, with target DLT rate of 27.5% and equivalent interval of 22.5% to 32.5%.

As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a component that can be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and does not cause significant side effects to an individual.

As used herein, a "period of discontinuation" is the number of days between the administration of one complete dose of the active agent to the next administration of one complete dose of the active agent.

As used herein, the term "week" means 7 consecutive days. Thus, the 4 week period is 28 consecutive days starting on any one day of the calendar week.

As used herein, the term "individual" may be a mammal, which refers to any animal species of the mammalian species. Examples of mammals include humans; a non-human primate, such as a monkey; laboratory animals such as rats, mice, guinea pigs; domestic animals such as cats, dogs, rabbits, cattle, sheep, goats, horses, and pigs; and wild animals such as lions, tigers, etc. in containment. In some embodiments, the subject is a human. In some embodiments, the subject is a female. In some embodiments, the individual is a male.

As used herein, the expression "therapeutically effective amount" for use and/or for treating an individual refers to an amount that provides a detectable response of any duration (short, medium, or long term), desired outcome, or objective or subjective benefit to the individual of any measurable or detectable extent or duration (e.g., hours, days, months, years, in remission or cure) alone or in combination with one or more other agents, treatments, regimens, or therapeutic regimens in a single or multiple doses. Such amounts are typically effective to ameliorate the disease, or one or more or all of the side effects/symptoms, consequences or complications of the disease, to a measurable extent, but reducing or inhibiting the progression or exacerbation of the disease or providing a stable (i.e., non-exacerbating) state of the disease is also considered a satisfactory result. The term "therapeutically effective amount" also means an amount of an active agent that is effective to produce a desired therapeutic effect upon administration to an individual, e.g., to prevent the growth of a cancerous tumor or to cause the shrinkage of a cancerous tumor.

Determination of a therapeutically effective amount is well within the ability of those skilled in the art. In various embodiments, the dosage may vary within this range depending upon the dosage form employed and the route of administration employed. In some embodiments, a therapeutically effective amount of a compound described herein administered to a subject can depend on factors known to those of skill in the art, including the biological activity and bioavailability of the compound (e.g., the half-life and stability of the compound in vivo), the chemical properties of the compound (e.g., molecular weight, hydrophobicity, and solubility); the route and frequency of administration, etc. Furthermore, it is to be understood that the specific dosage of a pharmaceutical composition comprising a compound as disclosed herein may depend on a variety of factors, including the physical condition of the individual (e.g., age, sex, weight) and the medical history of the individual (e.g., the drug administered, the health condition, other diseases or conditions). The precise dosage of the pharmaceutical composition to be administered to an individual can be determined by methods known to those skilled in the art, such as a pharmacologist or anesthesiologist.

As used herein, the term "ameliorating" refers to any reduction in the extent, severity, frequency, and/or likelihood of a symptom or clinical sign of a particular disease. "symptom" refers to any subjective sign of a disease or individual condition.

As used herein, "treating" or "treatment" cancer and/or cancer-related diseases means administering a monotherapy or a combination therapy according to the invention to an individual, patient or person suffering from or diagnosed with cancer to achieve at least one positive therapeutic effect, such as a reduction in the number of cancer cells, a reduction in tumor size, a reduction in the rate of cancer cells infiltrating the peripheral organ or a reduction in the rate of tumor metastasis or tumor growth, reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition or one or more symptoms of the disorder or condition to which the term is applied. The term "treatment" as used herein refers to a therapeutic action as defined immediately above, unless indicated otherwise. The term "treatment" also includes adjuvant treatment and neoadjuvant treatment of an individual. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing (or destroying) proliferation of neoplastic or cancerous cells; inhibit cancer metastasis or neoplastic cells; reducing or shrinking the tumor size; alleviating cancer; reducing symptoms caused by cancer; improving the quality of life of those patients suffering from cancer; reducing the dosage of other drugs required to treat cancer; delay the progression of cancer; cure cancer; overcoming one or more drug resistance mechanisms of cancer; and/or to extend the survival of cancer patients. The positive therapeutic effect of cancer can be measured in a number of ways (see, e.g., W.A.Weber, J.Nucl.Med.50:1S-10S (2009)).

"Tumor" when applied to an individual diagnosed with or suspected of having cancer refers to malignant or potentially malignant neoplasms or tissue masses of any size, and includes primary tumors and secondary neoplasms. Solid tumors are abnormal growths or masses of tissue that do not typically contain cysts or liquid areas. Examples of solid tumors are sarcomas, carcinomas and lymphomas. Leukemia (hematological cancer) generally does not form a solid tumor (national cancer institute (National Cancer Institute), dictionary of cancer terms (CANCER TERMS)).

As used herein, the term "combination" or "combination therapy" refers to the administration of two or more therapeutic agents of a combination therapy alone or in a pharmaceutical composition or pharmaceutical form. The combination therapies may be administered sequentially, concurrently or simultaneously.

When a combination therapy of two or more agents is administered, the agents may be administered during the same treatment cycle or using different cycles. In a preferred embodiment, PF-07220060 is administered continuously over a 28 day period. Similarly, letrozole is typically administered continuously over a 28 day treatment period. Palbociclib is typically administered using intermittent 28-day treatment cycles, which involve 21 days of drug administration with a 7-day withdrawal period between cycles. Fulvestrant is typically administered intramuscularly on days 1, 15, 29 of the first treatment cycle and once a month thereafter.

Each therapeutic agent of the methods and combination therapies described herein may be administered according to pharmaceutical practice alone or in the form of a medicament (also referred to herein as a pharmaceutical composition) comprising the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients, or diluents.

The term "sequential" or "sequential" refers to the administration of the therapeutic agents of a combination therapy alone or in a medicament one after the other, wherein the therapeutic agents may be administered in any order. Sequential administration may be particularly useful when the therapeutic agents in combination therapy are in different dosage forms (e.g., one agent is a tablet and the other agent is a sterile liquid), and/or the agents are administered according to different dosing schedules, e.g., one agent is administered daily, and the second agent is administered less frequently (such as weekly).

The term "concurrently" refers to administration of each therapeutic agent in combination therapy alone or in separate dosage forms, wherein the second therapeutic agent is administered immediately after the first therapeutic agent, but the therapeutic agents may be administered in any order. In a preferred embodiment, the therapeutic agents are administered concurrently.

The term "simultaneously" refers to administration of each therapeutic agent of a combination therapy in the same agent, e.g., in the form of a fixed dose combination comprising two or more drugs in a single dosage form.

"Dosing regimen" refers to a period of administration of one or more drugs, compounds, or compositions that comprises one or more treatment cycles, wherein each treatment cycle may include administration of one or more agents at different times, frequencies, or amounts using the same or different routes of administration. Repetition of or adjustment of the dosing or dosing regimen may be performed as needed to achieve the desired therapeutic effect.

PF-07220060 (Pfizer Inc.) is a selective CDK4 inhibitor, which is currently in phase I/Ib clinical trials for the treatment of cancer and has the structure of formula (I):

Accordingly, certain embodiments of the present disclosure provide therapeutic dosages and regimens comprising administering to an individual a therapeutically effective amount of PF-07220060.

PF-07220060 may be present in a pharmaceutical composition comprising a pharmaceutically acceptable carrier. The therapeutically effective amount of PF-07220060 in the pharmaceutical composition may be about 200mg to about 1000mg, or any of the therapeutically effective amounts disclosed herein.

In certain embodiments, a therapeutically effective amount of PF-07220060 is about 200mg to about 1000mg per day (i.e., total daily dose), such as about 200mg to about 500mg, about 200mg to about 450mg, about 200mg to about 400mg, about 200mg to about 350mg, about 200mg to about 300mg, about 400mg to about 950mg, about 400mg to about 900mg, about 400mg to about 850mg, about 400mg to about 800mg, about 500mg to about 950mg, about 500mg to about 900mg, about 500mg to about 850mg, about 500mg to about 800mg, about 600mg to about 950mg, about 600mg to about 900mg, about 600mg to about 850mg, or about 600mg to about 800mg per day.

In certain embodiments, PF-07220060 is administered in a dose of about 200mg to about 1000mg once a day (QD), for example about 200mg to about 500mg QD, about 200mg to about 450mg QD, about 200mg to about 400mg QD, about 200mg to about 350mg QD, about 200mg to about 300mg QD, about 400mg to about 950mg QD, about 400mg to about 900mg QD, about 400mg to about 850mg QD, about 400mg to about 800mg QD, about 500mg to about 950mg QD, about 500mg to about 900mg QD, about 500mg to about 850mg QD, about 500mg to about 800mg QD, about 600mg to about 950mg QD, about 600mg to about 900mg QD, about 600mg to about 850mg QD, or about 600mg to about 800mg QD.

In certain embodiments, a therapeutically effective amount of PF-07220060 is about 100mg to about 500mg twice a day (BID), such as about 200mg to about 500mg BID, about 250mg to about 500mg BID, about 300mg to about 500mg BID, about 350mg to about 500mg BID, about 400mg to about 500mg BID, about 100mg to about 450mg BID, about 150mg to about 450mg BID, about 200mg to about 450mg BID, about 250mg to about 450mg BID, about 300mg to about 450mg BID, about 350mg to about 450mg BID, about 400mg to about 450mg BID, about 100mg to about 400mg BID, about 150mg to about 400mg BID, about 200mg to about 400mg BID, about 250mg to about 400mg BID, about 300mg to about 400mg BID, about 350mg to about 400mg BID.

In some embodiments, PF-07220060 is administered to a subject at a dose of any of the therapeutically effective amounts disclosed herein.

The pharmaceutical compositions comprising a therapeutically effective amount of PF-07220060 described herein may be administered once a day (QD) or twice a day (BID).

In some embodiments, PF-07220060 is administered to an individual at a dose of about 200mg to about 1000mg per day, e.g., at a daily dose of about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, or 1000 mg.

In some embodiments, PF-07220060 is administered at the following doses: about 200mg QD, about 300mg QD, about 400mg QD, about 500mg QD, about 600mg QD, about 700mg QD, about 800mg QD, about 900mg QD or 1000mg QD.

In some embodiments, PF-07220060 is administered at the following doses: about 100mg BID, about 200mg BID, about 300mg BID, about 400mg BID, or about 500mg BID.

The amount of PF-07220060 administered may be increased or decreased based on the weight, age, health, sex, or medical condition of the individual. One of ordinary skill in the art will be able to determine an appropriate dosage for an individual based on this disclosure.

PF-07220060 can be administered in treatment cycles with or without withdrawal periods between treatment cycles. The treatment period may be about 7 days, about 14 days, about 21 days, about 28 days, about 35 days, etc., or the duration of any day in between. The withdrawal period may be one day, several days (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, etc.), one week, several weeks (e.g., 2 weeks, 3 weeks, etc.), or any day in between (e.g., 1 week and 3 days). In some embodiments, PF-07220060 is administered continuously without any withdrawal period therebetween (i.e., treatment is continued until termination). In some embodiments, PF-07220060 is administered with or without a withdrawal period for a treatment period (e.g., about 28 days). In some embodiments, PF-07220060 is administered with a withdrawal period of about one week for about 28 days. PF-07220060 can 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 longer.

The pharmaceutical composition may be administered with or without food.

The pharmaceutical compositions may be administered by one or more routes deemed appropriate by the person skilled in the art and based on the dosage form. Pharmaceutical formulations are discussed in Remington's Pharmaceutical Sciences, 18 th edition, (1995) Mack Publishing co., easton, pa. Other examples of pharmaceutical formulations can be found in Liberman, h.a. and Lachman, l., editions, pharmaceutical Dosage Forms, MARCEL DECKER, volume 3, 2 nd edition, new York, n.y. If the compound is administered orally, it may be formulated into pills, capsules, tablets, etc. with pharmaceutically acceptable carriers, glidants or excipients.

The pharmaceutical composition may be in one or more dosage forms (e.g., capsules, liquids, tablets, powders).

In some embodiments, the pharmaceutical composition may be administered in an immediate release formulation or a modified release formulation.

"Immediate release" or "IR" broadly means an oral dosage form formulated to release the API immediately following oral administration. In IR formulations, no deliberate effort was made to alter the drug release rate.

Therapeutic methods and uses

In certain embodiments, the present disclosure provides a method for treating cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of PF-07220060 as described herein.

In certain embodiments, the present disclosure also provides a method for treating cancer in an individual comprising administering to the individual a therapeutically effective amount of PF-07220060 and an endocrine therapeutic agent as described herein.

In certain embodiments, the present disclosure provides the use of PF-07220060 in the manufacture of a medicament for treating cancer in an individual in need thereof, wherein the medicament is administered in a therapeutically effective unit dose of PF-07220060 as described herein.

In certain embodiments, the present disclosure provides the use of PF-07220060 in conjunction with endocrine therapy in the manufacture of a medicament for treating cancer in an individual in need thereof, wherein the medicament is administered in a therapeutically effective unit dose of PF-07220060 as described herein.

In certain embodiments, the present disclosure provides a medicament comprising a therapeutically effective amount of PF-07220060 as described herein for treating cancer in an individual in need thereof.

In embodiments, the present disclosure provides a medicament comprising a therapeutically effective amount of PF-07220060 as described herein and an endocrine therapeutic agent for treating cancer in an individual in need thereof.

In certain embodiments of the methods, medicaments, combinations and uses described herein, PF-07220060 is administered continuously (i.e., daily).

In certain embodiments, the methods included herein comprise administering PF-07220060 to a subject afflicted with a cancer mediated by CDK 4. In some embodiments, the cancer is characterized by amplification or overexpression of CDK4 and/or CCND 1. In one embodiment, the cancer is characterized by the amplification or overexpression of CDK 4. In one embodiment, the cancer is characterized by amplification of the CCND1 gene or overexpression of cyclin D1.

In certain embodiments, the methods disclosed herein comprise administering PF-07220060 to a subject suffering from a cancer selected from the group consisting of breast cancer, ovarian cancer, fallopian tube cancer, primary Peritoneal Cancer (PPC), bladder cancer, uterine cancer, prostate cancer, lung cancer (including non-small cell lung cancer (NSCLC), small Cell Lung Cancer (SCLC), squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer (including Head and Neck Squamous Cell Carcinoma (HNSCC), colorectal cancer (CRC), renal cancer (including Renal Cell Carcinoma (RCC)), liver cancer (including hepatocellular carcinoma (HCC)), pancreatic cancer, gastric (i.e., stomach) cancer, endometrial cancer, liposarcoma, and thyroid cancer in other 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, gastric cancer, or a combination thereof.

In some embodiments, the cancer is an advanced or metastatic solid tumor.

In some embodiments, the cancer is NSCLC. In some embodiments, the cancer is NSCLC adenocarcinoma. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is liposarcoma.

In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments, the breast cancer is locally advanced. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is hormone receptor positive (hr+), 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 negative for human epidermal growth factor receptor 2 (HER 2-). In some embodiments, the breast cancer is human epidermal growth factor receptor 2 positive (her2+). In some embodiments, the breast cancer is HR+/HER 2-breast cancer. In some embodiments, the breast cancer is HR-/her2+ breast cancer. In some embodiments, the breast cancer is er+/hr+. In some embodiments, the breast cancer is er+/HER2-. In some embodiments, the breast cancer is Triple Negative Breast Cancer (TNBC), i.e., the breast cancer is ER-, PR-, and HER2-.

In some embodiments, the breast cancer is endocrine-resistant breast cancer, trastuzumab (trastuzumab) or pertuzumab (pertuzumab) -resistant breast cancer, or breast cancer that indicates inhibition of CDK4/CDK6 with primary or acquired resistance. In some embodiments, the breast cancer is resistant to treatment with a standard of care agent; for example, the breast cancer may exhibit primary or acquired resistance to endocrine therapy, HER2 targeting agents (e.g., tamoxifen, enmeltrastuzumab (trastuzumab emtansine), fam-trastuzumab Shan Kangde lutecan (deruxtecan), pertuzumab, lapatinib (lapatinib), nilatinib (neratinib), or fig. carttinib (tucatinib)), or CDK4/6 inhibitors. In some embodiments, the individual is refractory to endocrine therapy.

In some embodiments, the breast cancer is refractory to or resistant to treatment with an anti-tumor chemotherapeutic agent (such as a platinum agent, a taxane, an anthracycline, or an antimetabolite), or progresses under treatment thereof.

In some embodiments, the breast cancer has progressed during treatment with an aromatase inhibitor or within 12 months of completion of adjuvant therapy with an aromatase inhibitor. In some embodiments, the breast cancer has progressed during treatment with tamoxifen or within 12 months of completion of adjuvant therapy with tamoxifen.

In some embodiments, PF-07220060 is administered as a first line therapy. In other embodiments, PF-07220060 is administered as a second (or subsequent) line therapy. In some embodiments, PF-07220060 is administered as a second (or subsequent) line therapy following treatment with an endocrine therapeutic agent and/or a CDK4/CDK6 inhibitor. In some embodiments, PF-07220060 is administered as a second (or subsequent) line therapy following treatment with an endocrine therapeutic agent, such as an aromatase inhibitor, a Selective Estrogen Receptor Modulator (SERM), e.g., tamoxifen, or a selective estrogen degradation agent/downregulator (SERD). In some embodiments, PF-07220060 is administered as a second (or subsequent) line therapy following treatment with one or more chemotherapeutic regimens. In some embodiments, PF-07220060 is administered as a second (or subsequent) line therapy following HER2 targeting agent treatment.

In certain embodiments, the methods disclosed herein further comprise administering to the subject a therapeutically effective amount of PF-07220060 and an endocrine therapeutic agent. An "endocrine therapeutic agent" is a biological (macromolecular) or chemical (small molecule) compound suitable for treating cancer, regardless of the mechanism of action.

In some embodiments, the endocrine therapeutic agent is an aromatase inhibitor, an androgen receptor inhibitor, a selective estrogen receptor degradation agent (SERD), or a Selective Estrogen Receptor Modulator (SERM). In some embodiments, the endocrine therapeutic agent is an androgen receptor inhibitor. In some embodiments, the endocrine therapeutic agent is an aromatase inhibitor. In some such embodiments, the aromatase inhibitor is selected from the group consisting of: letrozole, anastrozole, and exemestane. In one embodiment, the aromatase inhibitor is letrozole. In some embodiments, the endocrine therapeutic agent is a SERD. In some such embodiments, the SERD is selected from: fulvestrant, alapristone (elacestrant, RAD-1901,Radius Health/Menarini), axletree (AMCENESTRANT, SAR439859, sanofi), ji Leisi (GIREDESTRANT, GDC9545, roche), RG6171 (Roche), card Mi Siqun (camizestrant, AZD9833, astraZeneca), AZD9496 (AstraZeneca), rettescens (rintodestrant,G1Therapeutics)、ZN-c5(Zentalis)、LSZ102(Novartis)、D-0502(Inventisbio)、LY3484356(Eli Lilly) and SHR9549 (Jiansu Hengrui Medicine). In some embodiments, the SERD is fulvestrant. In some embodiments, the endocrine therapeutic agent is a SERM. In some such embodiments, the SERM is selected from: tamoxifen, raloxifene, toremifene, lasofoxifene, bazedoxifene, and afzedoxifene. In some such embodiments, the SERM is tamoxifen or raloxifene. In a preferred embodiment, the endocrine therapeutic agent is letrozole or fulvestrant.

The endocrine therapeutic agent may be administered according to the standard of care of the drug instructions or provided by a health care professional. The term "pharmaceutical instructions" refers to instructions that are typically included in commercial packages of therapeutic products that contain information about the indication, usage, dosage, administration, contraindications, and/or warnings associated with the use of such therapeutic products.

In certain embodiments, the endocrine therapeutic agent is administered to the subject during the course of treatment with PF-07220060. In certain embodiments, the first dose of the endocrine therapeutic agent is administered prior to the administration of the first dose of PF-07220060. In certain embodiments, the first dose of the endocrine therapeutic agent is administered on the same day as the first dose of PF-07220060. In certain embodiments, the first dose of the endocrine therapeutic agent is administered after the initiation of treatment with PF-07220060.

In certain embodiments, the subject has been previously treated with one or more endocrine therapy lines prior to administration of PF-07220060 to the subject.

In certain embodiments, the subject has been previously treated with chemotherapy, radiation therapy, and/or surgical excision prior to administration of PF-07220060 to the subject.

In certain embodiments, the subject has been previously treated with a CDK4/6 inhibitor prior to administration of PF-07220060 to the subject.

In some embodiments, the treatment of the invention results in a Complete Response (CR), partial Response (PR), or Stable Disease (SD) in the subject.

Treatment outcome and tumor response assessment

The therapies of the invention may elicit a Complete Response (CR), a Partial Response (PR), a Progressive Disease (PD) or a Stable Disease (SD) in a patient. Biological imaging can be used to assess the level of response to therapy. Cytology and histology may also be used as desired (e.g., to locate any residual lesions). In some embodiments, various response levels can be assessed according to table 1 below.

TABLE 1 evaluation of target diseases

The present disclosure provides a number of exemplary embodiments. Non-limiting exemplary embodiments of the present disclosure are presented below.

Embodiment 1. A method of treating cancer comprising orally administering to a subject in need thereof a therapeutically effective amount of PF-07220060, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is about 100mg to about 500mg twice daily (BID).

Embodiment 2. The method of embodiment 1, wherein the therapeutically effective amount is from about 300mg to about 500mg BID.

Embodiment 3. The method of embodiment 1 or 2, wherein the therapeutically effective amount is about 300mg BID.

Embodiment 4. The method of embodiment 1 or 2, wherein the therapeutically effective amount is about 400mg BID.

Embodiment 5. The method of any one of embodiments 1 to 4, wherein PF-07220060 is administered continuously.

Embodiment 6. The method of any one of embodiments 1 to 5, wherein PF-07220060 is administered in the form of a tablet or capsule.

Embodiment 7. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising PF-07220060 and an endocrine therapeutic agent, wherein the therapeutically effective amount of PF-07220060 is from about 100mg to about 500mg BID.

Embodiment 8. The method of embodiment 7, wherein the endocrine therapeutic agent is an aromatase inhibitor, an androgen receptor inhibitor, a selective estrogen receptor degradation agent (SERD), or a Selective Estrogen Receptor Modulator (SERM).

Embodiment 9 the method of embodiment 7, wherein the endocrine therapeutic agent is selected from the group consisting of: letrozole, anastrozole, exemestane, fulvestrant, ilast, axletree, ji Leisi, RG6171, ka Mi Siqun, AZD9496, rituximab, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549, tamoxifen, raloxifene, toremifene, lasofoxifene, bazedoxifene, and alfexifene.

Embodiment 10. The method of embodiment 7 wherein the endocrine therapeutic agent is letrozole or fulvestrant.

Embodiment 11. The method of any one of embodiments 7 to 10, wherein the endocrine therapeutic agent is administered to the subject and then PF-07220060 is administered.

Embodiment 12. The method of embodiment 1 or 7, wherein the subject has been previously treated with chemotherapy, radiation therapy, and/or surgical excision.

Embodiment 13. The method of embodiment 1 or 7, wherein the subject has been previously treated with a CDK4/6 inhibitor.

Embodiment 14. The method of embodiment 1 or 7, wherein the subject has been previously treated with an endocrine therapeutic agent.

Embodiment 15. The method of embodiment 1 or 13, wherein the subject is a mammal.

Embodiment 16. The method of any one of embodiments 1 to 15, wherein the subject suffers from breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, and thyroid cancer.

Embodiment 17 the method of any one of embodiments 1 to 16, wherein the cancer is breast cancer selected from any one or more of the following: hormone receptor positive (HR+), hormone receptor negative (HR-), HER2 negative (HER 2-), HER2 positive (HER2+), HR+/HER2-, ER-/HR+, ER+/HER2-, and Triple Negative Breast Cancer (TNBC).

Embodiment 18. The method of any one of embodiments 1 to 16, wherein the cancer is NSCLC, prostate cancer, colorectal cancer, liposarcoma, or a tumor characterized by amplification or overexpression of CDK4 and/or CCND 1.

Embodiment 19 use of PF-07220060 in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the medicament is administered in a therapeutically effective unit dose of PF-07220060 in an amount of about 100mg to about 500mg BID.

Embodiment 20 use of PF-07220060 and an endocrine therapeutic agent in the manufacture of a medicament for treating cancer in an individual in need thereof, wherein the medicament is administered in a therapeutically effective unit dose of PF-07220060 in an amount of from about 100mg to about 500mg BID.

Embodiment 21. A medicament comprising a therapeutically effective amount of PF-07220060 for treating cancer in a subject in need thereof, wherein the therapeutically effective amount is from about 100mg to about 500mg BID.

Embodiment 22. A medicament comprising a therapeutically effective amount of PF-07220060 and an endocrine therapeutic agent for treating cancer in an individual in need thereof, wherein the therapeutically effective amount is from about 100mg to about 500mg BID.

Examples

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

Example 1

Multicellular tumor spheroid growth inhibition by single agent PF-07220060 in combination with fulvestrant

The purpose of this example was to evaluate the combined effect of PF-07220060 and endocrine therapy in multicellular tumor spheroid growth inhibition (spheroid growth inhibition; SGI).

To model the characteristics and cellular behavior of human tumors, the activity of PF-07220060 was evaluated after PF-07220060 was treated as a single agent and in combination with fulvestrant in a three-dimensional MCTS model of HR+breast cancer and AR+prostate cancer.

1) In the HR+, HER2-T47D breast cancer sphere,

2) In hr+, her2+bt474 breast cancer spheres,

3) In BT474 spheres, and

4) In the ar+ prostate cancer cell line (LNCaP) prostate cancer sphere.

Spheres were treated with increasing concentrations of 100, 300 or 1000nM PF-07220060 and compared to clinically relevant concentrations of 30nM of palbociclib. The single agent PF-07220060 inhibited sphere growth in a dose-dependent manner, with the highest efficacy (86% SGI for the duration of treatment with 1000 nM) exhibited in the T47D BC sphere model (table 1). Compared to single agent alone (57% to 67% SGI at 100nM PF-07220060, or 79% SGI at fulvestrant), 100nM PF-07220060 in combination with 1nM fulvestrant increased SGI to 96% in T47D cells (table 1). BT474 spheres were relatively insensitive to PF-07220060, yielding 52% SGI at 1000 nM.

PF-07220060 showed dose-dependent inhibition of LNCaP prostate cancer spheroid growth, up to 53% SGI at 1000nM (Table 1).

Overall, these data support the use of PF-07220060 in hr+, HER 2-breast cancer in combination with endocrine therapy. The PF-07220060 combination has additive or synergistic benefits in multiple tumor types. PF-07220060 inhibited spheroid growth in a dose-dependent manner when used as a single agent, with highest activity observed in the HR+, HER 2-breast cancer spheroid model.

Table 1: multicellular tumor spheroid growth inhibition by PF-07220060 single agent in combination with fulvestrant

Sgi= (1-AUC treatment/aucdmso) ×100%. SGI of all treatment groups was obtained at the time point when vehicle (0.01% DMSO) -treated spheres reached their maximum diameter

Example 2: clinical trial protocol

Continuous open-label, non-randomized phase 1/1b dose-search studies examined the safety, tolerability, PK and PD of PF-07220060 administered as a single agent in combination with endocrine therapy.

Study design

In section 1A, a single ascending dose of PF-07220060 alone would be started at a dose of 100mg BID, administered on a continuous basis to determine the Maximum Tolerated Dose (MTD) and/or select PF-07220060 as the proposed phase 2 dose (RP 2D) for monotherapy.

In part 1B and part 1C, PF-07220060 would be administered in combination with endocrine therapy (letrozole or fulvestrant) to identify PF-07220060 with MTD and/or select RP2D for each endocrine agent.

Part 1D will evaluate the effect of food on PK of PF-07220060 at or below the MTD of monotherapy. In part 1D, participants will receive PF-07220060 in the form of a single agent at or below the MTD of monotherapy on a continuous basis starting on day-7 and following day 1 to assess food impact.

Part 1E will evaluate the potential drug-drug interaction (DDI) established in part 1A between PF-07220060 and midazolam (midazolam) given at or below the monotherapy MTD.

Part 2B is an expanded set of combination therapies of PF-07220060 and letrozole in patients with HR-positive/HER 2-negative advanced or metastatic breast cancer (mBC) who did not receive any prior systemic anti-cancer therapy for their advanced disease.

Part 2C is an expanded set of combination therapies of PF-07220060 and fulvestrant (with or without goserelin (goserelin)) in patients with HR-positive/HER 2-negative advanced or mBC whose disease has progressed on previous therapies.

The entry study was defined as day 1 of dosing. All cycles were 28 days in length. Alternative dosing regimens (e.g., QDs) may be considered during the dose escalation process or after determination of the MTD/RP2D of the BID regimen based on emerging and available preliminary clinical data, including safety/tolerability, laboratory, PK and PD study results. Intermittent dosing PF-07220060 dosing schedules (e.g., 3 weeks of dosing, 1 week of discontinuation) can also be assessed based on emerging clinical data, if indicated.

Participants experiencing toxicity including DLT may be managed by dose adjustment or discontinuing therapy. The proposed dose, schedule and PK time points can be varied during the study based on emerging safety and PK data.

The study time may vary depending on the toxicity observed and the potential benefit obtained by the individual participants. It is estimated that each participant can remain treated for approximately 6 to 8 cycles such that the total study duration is approximately 24 to 32 weeks. The actual duration may be longer if the participants gain benefit from study treatment.

Based on the progress PK, PD and safety profiles assessed in section 1A, the starting dose of PF-07220060 in section 1B and section 1C can be started at or before the MTD is reached with a dose determined to be safe by the Bayesian logistic regression model (Bayesian Logistic Regression Model; BLRM) to meet the incremental under the excessive control (EWOC) standard in section 1A (Rogatko, A. Et al Translation of Innovative Designs Into PHASE TRIALS, J.CLIN.ONCOL.,25 (31), 4982-6, 2007). The risk of treating participants at doses above the MTD is limited using EWOC principles. In addition, more than one dosing regimen (e.g., different dosages, dosing frequency) of PF-07220060 can be studied in section 1B and section 1C.

Study population

Suitability criteria are designed to select participants deemed appropriate for participation in the study. Inclusion criteria for patient selection included the following:

All participants-histologically or cytologically confirmed locally advanced or metastatic solid tumors, which are bad (unrespectable) and not amenable to irradiation for cure intent.

Disease requirement for part 1

Part 1B and part 1C:

■ Refractory HR-positive/HER 2-negative (2l+, under previous CDK 4/6) breast cancers.

Part 1A, part 1D, and part 1E:

■ Refractory HR-positive/HER 2-positive breast cancer.

■ Tumors other than breast cancer: NSCLC, prostate, CRC, liposarcoma, or tumors with previously confirmed CDK4 or CCND1 amplification according to local standard tests.

Disease requirement for part 2

Part 2B and part 2C:

■ HR-positive/HER 2-negative breast cancer

■ The following participants:

post-menstrual female defined by at least one of the following criteria:

■ The age is more than or equal to 60 years old;

■ Age <60 years and stop regular menstruation without alternative pathological or physiological etiology for at least 12 consecutive months; and serum estradiol and Follicle Stimulating Hormone (FSH) content is within laboratory reference range for post-menopausal women;

■ Described bilateral ovariectomy;

■ Ovarian failure was medically confirmed.

Or (b)

For part 2C: before/during the stop of menstruation, i.e. the criterion after the stop of menstruation is not fulfilled.

■ If it is possible to treat with the luteinizing hormone-releasing hormone (LHRH) agonist goserelin, pre-menopausal/menopausal women may be selected. Participants had to begin treatment with goserelin or an alternative LHRH agonist at least 4 weeks prior to enrollment. If the participants have received an alternative LHRH agonist prior to entering the study, cheng Geshe relin is preferably switched for the duration of the trial. However, other LHRH antagonists, such as leuprorelin (leuprolide), are also acceptable.

Focal requirement:

■ For part 1: participants must have an evaluable lesion (including only skin or bone lesions).

■ For part 2B and part 2C: participants must have a measurable disease as defined in accordance with RECIST (response assessment criteria for solid tumors) version 1.1 (Eisenhauer et al, european Journal of Cancer,2009,45 (2): 228-47). If it is clearly stated that after completion of the therapy, the tumor lesions previously irradiated or undergoing local treatment will only be considered measurable, if they have progressed at the treatment site.

Previous systemic treatment:

For part 1:

HR-positive/HER 2-negative breast cancer (part 1A/part 1B/part 1C/part 1D/part 1E). The participants should have accepted:

■ At least 1 line of care Standard (SOC), including CDK4/6 inhibitor therapy for advanced or metastatic disease, or where CDK4/6 inhibitors are available but appear to be uncomfortable to the researcher, participants may be enrolled with the researcher providing a powerful clinical rationale and being approved by the test delegate; or (b)

■ In countries where no CDK4/6 inhibitors are approved or reimbursed, at least 1 line of anti-endocrine therapy is used for advanced or metastatic disease.

In both cases, prior chemotherapy for the background of advanced disease is allowed.

■ HR-positive/HER 2-positive breast cancer (part 1A/part 1D): the participant should have received a prior treatment of at least one approved HER 2-targeted therapy.

■ Tumors other than breast cancer (part 1A/part 1D): tumors that are resistant to at least 2 lines of standard systemic therapy for advanced or recurrent disease or for which no standard therapy is available.

For part 2:

part 2B: participants who have not received any previous systemic anti-cancer therapy for advanced/metastatic breast cancer.

Part 2C:

■ Has progressed during treatment or within 12 months of completion of adjuvant therapy with aromatase inhibitor (if post-menopausal) or tamoxifen (if pre-menopausal or menstrual), or

■ Has progressed within 1 month or 1 month after the end of previous aromatase inhibitor therapy for advanced/metastatic breast cancer (if post-menopausal) or previous endocrine therapy for advanced/metastatic breast cancer (if pre-menopausal or post-menstrual).

■ In addition to endocrine therapy, a pre-chemotherapy normal for advanced/metastatic disease is allowed.

Inclusion criteria

The inclusion criteria for the two parts studied were as follows:

1. Participants in both part 1 and part 2 (except part 2B) must be refractory or intolerant to known existing therapies that provide clinical benefit for their condition.

2. The participants were greater than or equal to 18 years old.

3. The eastern tumor clinical research Cooperation organization (Eastern Cooperative Oncology Group; ECOG) of the United states was either a 0 or 1 physical stamina.

4. Adequate bone marrow function, as demonstrated by:

ANC is not less than 1,500/mm ³ or not less than 1.5X10: 10 ⁹/L;

b. platelets not less than 100,000/mm ³ or not less than 100X 10 ⁹/L;

c. Heme is more than or equal to 9g/dL. After a discussion with the medical monitor of the experimental commissioner, limited transfusion to this value is allowed. There is a long felt need not to deal with blood transfusion in the near future (about 3 months).

5. Adequate kidney function, defined as: the estimated creatinine clearance for part 1 was ≡50mL/min as calculated using institutional method standards. In unknown cases, the 24-hour urine collection test can be used to more accurately estimate creatinine clearance.

6. Adequate liver function, as demonstrated by:

a. Total serum bilirubin is less than or equal to 1.5 XULN unless the participants describe Gilbert syndrome (in which case, up to 3.0 XULN will be allowed).

AST and ALT are less than or equal to 2.5 XULN; when the liver is affected in the tumor, the liver is less than or equal to 5.0 XULN;

ALKP is less than or equal to 2.5 XULN (in the case of bone or liver metastases, less than or equal to 5.0 XULN).

Exclusion criteria

Participants were excluded from the study if they were appropriate for any of the following criteria:

1. For part 1D: participants with gastrectomy or other limitations with diet or exclusion of overnight fast (water allowed) or high fat, high calorie meals for 10 hours.

2. For part 2B: previous neoadjuvant or adjuvant treatment with a non-steroidal aromatase inhibitor (i.e., anastrozole or letrozole) or with any CDK4/6 inhibitor, in the event of disease recurrence within 12 months or 12 months of treatment.

3. For part 2C: previous treatments were performed with any CDK inhibitor or fulvestrant or everolimus (everolimus) or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway.

4. Uncontrolled or symptomatic CNS cancer metastasis, cancerous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema and/or progressive growth are known to be active. Participants with CNS cancer metastasis or umbilical cord compression are eligible if they have been specifically treated (e.g., radiotherapy, stereotactic surgery) and clinically stable for at least 4 weeks at cessation of anticonvulsants and steroids prior to enrollment and have no signs of progression at study enrollment.

5. Participants with advanced/metastatic, symptomatic, visceral spread are at risk of life threatening complications in the short term (including those with large uncontrolled effusions [ pleura, pericardium, peritoneum ], pulmonary lymphangitis and more than 50% of liver involvement).

6. Any other active malignant disease, except basal cell or squamous cell skin cancer or carcinoma in situ, was seen within 3 years prior to enrollment.

7. The major surgery was performed within 4 weeks prior to entry into the study.

8. Radiation therapy with therapeutic intent within 4 weeks prior to entry into the study. Any palliative radiation therapy must be completed within 7 days prior to study intervention administration day 1.

9. The last anticancer treatment is within 2 weeks (or 5 half-lives, whichever is shorter) and, unless the last real-time anticancer treatment contains an (approved or investigational) antibody-based agent, an interval of 4 weeks (or 5 half-lives, whichever is shorter) is required before the study intervention is received.

10. For part 1C, participants who received fulvestrant as part of the last previous therapy were eligible.

11. The aforementioned high dose chemotherapy requiring stem cell rescue.

12. Active and clinically significant bacterial, fungal or viral infections including, but not limited to, HBV, HCV, known HIV or AIDS related diseases.

13. Baseline 12 lead ECG demonstrated clinically relevant abnormalities that could affect participant safety or interpretation of study results (e.g., baseline QTc interval >470 ms, complete LBBB, signs of acute or age-insensitive myocardial infarction, ST-T interval changes indicative of active myocardial ischemia, secondary or tertiary AV block, or severe slow or rapid arrhythmias (TACHYARRHYTHMIAS)). If the baseline uncorrected QT interval is >470 milliseconds, this interval should be rate corrected using the fischer-tropsch (FRIDERICIA METHOD) and the resulting QTcF applied for decision making and reporting. If QTc exceeds 470 milliseconds or QRS exceeds 120 milliseconds, the ECG should be repeated 2 more times and the average of 3 QTc or QRS values should be used to determine eligibility of the participant. Prior to the exclusion of the participants, the computer interpreted ECG should be reread by a physician with experience interpreting the ECG. Cases must be discussed in detail with the medical monitor of the test commissioner to determine eligibility.

14. Within the previous 6 months there were any of the following: myocardial infarction, congenital long QT syndrome, torsional ventricular tachycardia (Torsades de pointes), cardiac arrhythmias (including sustained ventricular tachyarrhythmias and ventricular fibrillation), severe conduction system abnormalities (e.g., double branch block (defined as right bundle branch and left anterior or posterior half branch block), grade 3 AV block), unstable angina, coronary artery/peripheral arterial bypass graft, symptomatic CHF, new york heart association grade III or IV, cerebrovascular accident, transient ischemic attacks, or symptomatic pulmonary embolism; deep venous thrombosis; arterial occlusive disease; sustained arrhythmia at NCI CTCAE grade > 2, any level of atrial fibrillation that is uncontrolled, or QTcF interval >470 milliseconds at screening.

15. Uncontrollable blood pressure (. Gtoreq.150/100 mmHg), although optimal for medical therapy).

16. Therapeutic doses of anticoagulant therapy (prophylactic doses of anticoagulant allowed) are disabled.

17. Known coagulation abnormalities, such as bleeding diathesis.

18. Hypersensitivity reactions are known or suspected to be present for the active ingredients/excipients of PF-07220060, letrozole, fulvestrant, enzalutamide and/or goserelin (or equivalent agents inducing chemical menopause/chemical castration).

19. Active inflammatory GI disease, known diverticulosis, or prior gastrectomy or banding. Impairment of GI function or GI disease can significantly alter absorption of PF-07220060, such as a history of GI surgery, which can cause intestinal blind and clinically significant gastroparesis, short bowel syndrome, unresolved nausea, vomiting, active inflammatory bowel disease, or diarrhea of CTCAE grade > 1.

20. Drugs with a risk of QTc prolongation are currently used.

21. Prior to the first dose of study intervention, treatment with a potent and appropriate CYP3A4/5 or UGT2B7 inhibitor includes its administration within 5 half-lives (whichever is longer) of the CYP3A4/5 or UGT2B7 inhibitor.

22. Treatment with proton pump inhibitors such as dexlansoprazole (dexlansoprazole), esomeprazole (esmerpraole), lansoprazole (lansoprazole), omeprazole, pantoprazole (pantoprazole), rabeprazole (rabeprazole) was performed 7 days prior to the first dose of study intervention.

23. Other medical or mental conditions, including recent (over the past year) or active suicidal thoughts/behaviors or laboratory abnormalities, may increase the risk of study participation or, at the discretion of the researcher, make the participant unsuitable for participation in the study.

24. Pregnancy or lactation.

Example 3: results of clinical trials

A phase 1/1b PF-07220060 clinical trial is underway. By day 9 of 2022, a total of 66 participants (43 females and 23 males) in section 1A, section 1B, section 1C and section 1D had been treated with PF-07220060. The mean age was 61.4 years (ranging from 36 to 82 years) and the population included participants with hr+her2-advanced or mBC and other tumors potentially growing in CDK 4-dependent fashion, including NSCLC adenocarcinoma, prostate cancer, CRC, liposarcoma and tumors with previously confirmed CDK4 or CCND1 amplification according to local standard tests. Demographics of these 66 participants are provided in table 2.

Table 2: demographic characteristics categorized by treatment group

N = number of participants.

Patient population

An overview of patient populations in each part of the study is described in table 3:

TABLE 3 overview of disease types and previous treatments for registration

Part 1A-PF-07220060 Single agent dose escalation

The purpose of part 1A was to achieve the safety and tolerability of increasing doses of PF-07220060 as a single agent in sequentially increasing dose groups of any of the female in the stopped state and of the male with advanced or mBC HR positive HER2 negative or HR positive HER2 positive, who had progressed after (i.e., 2L and after) at least one standard of care treatment, and of the participants with other solid tumors such as NSCLC adenocarcinoma, prostate cancer, colorectal cancer, liposarcoma and tumors with previously confirmed CDK4 or CCND1 amplification according to local standard tests. Patients with advanced or metastatic HR positivity mBC may receive endocrine increasing therapy (letrozole or fulvestrant) after at least two cycles of PF-07220060 monotherapy under certain criteria.

In part 1A, single ascending doses of PF-07220060 alone were administered on a continuous basis beginning with a BID dose of 100mg to determine the MTD of PF-07220060 as monotherapy and/or to select RP2D. Dosing will continue in sequential dose escalation groups until MTD/RP2D can be estimated.

Thirty-four participants (n=34) were treated with 100mg (n=3), 200mg (n=8), 300mg (n=10), 400mg (n=9), and 500mg (n=4) BID single agent PF-07220060 in part 1A (five dose group).

Dose discovery and endocrine therapy of part 1B and part 1C-PF-07220060

The purpose of parts 1B and 1C is to determine the MTD/RP2D of PF-07220060 when administered in combination with letrozole (part 1B) or fulvestrant (part 1C), respectively, in a 2l+ background in any of the female in the withdrawal state and in men with HR positive HER2 negative advanced or mBC.

In part 1B, participants received an approved dose of letrozole with 2.5mg QD taken consecutively with PF-07220060. Thirteen participants (n=13) were treated in part 1B (two dose groups) with 300mg (n=6) and 400mg (n=7) BID PF-07220060 in combination with letrozole.

In part 1C, participants received fulvestrant in the form of two Intramuscular (IM) injections (250 mg each) prior to oral administration of PF-07220060. Fulvestrant is administered on site by qualified medical personnel on days 1 and 15 of cycle 1, and on day 1 (from 1 to 5 days, depending on the number of cycles) of each subsequent 28-day cycle. Thirteen participants (n=13) were treated in part 1B (2 dose groups) with 300mg (n=6) and 400mg (n=7) BID PF-07220060 in combination with fulvestrant.

Part 1D-PF-07220060 food influence

The purpose of section 1D was to evaluate the food impact on the single dose Pharmacokinetic (PK) of PF-07220060 alone in participants.

Six participants (n=6) were treated with 400mg BID single agent PF-07220060 in the morning on cycle 1, day 7 under "fed" conditions and on cycle 1, day 1 under "fasted" conditions. To assess food effects, the plasma concentration-time data of PF-07220060 of the participants were compared from day-7 of cycle 1 to day 1 of cycle 1. The AUC and C _max values of the natural logarithmic transformation were analyzed using the analysis of variance model and the treatment as a fixed effect. An estimate of the mean difference (fed-fasted) and corresponding 90% CI was obtained from this model. The average difference and 90% CI of the difference are indexed to yield a geometrically averaged ratio (fed/fasted) and an estimate of 90% CI of the ratio.

Partial 1E-midazolam drug-drug interaction

The purpose of section 1E was to assess the effect of repeated administration of PF-07220060 at the monotherapy MTD on PK for oral midazolam in participants with advanced solid tumors. In part 1E, 2mg of midazolam was administered orally to the participants on day 1 (-1) alone and with PF-07220060 on day 15 of cycle 1. Only two doses of midazolam will be administered.

Dose extension and endocrine therapy of part 2B and part 2C-PF-07220060

The purpose of section 2B was to evaluate the tolerability, safety and primary antitumor activity of PF-07220060 in combination with letrozole. Part 2B is the dose expansion of PF-07220060 in combination with letrozole at the dose identified in part 1B in the participants with HR positive/HER 2 negative advanced/metastatic breast cancer who have not received any prior systemic anti-cancer therapy for their advanced disease. In part 2B, participants received an approved dose of letrozole with 2.5mg QD taken consecutively with PF-07220060.

The purpose of section 2C was to evaluate the tolerability, safety and primary antitumor activity of PF-07220060 in combination with fulvestrant. Part 2C is the dose spread of PF-07220060 in combination with fulvestrant at the dose identified in part 1C in the participants with HR positive/HER 2 negative advanced/metastatic breast cancer whose disease has progressed on previous therapies. Participants previously treated with any agent that inhibits the PI3k-mTOR pathway with CDK4/6 inhibitors, fulvestrant, everolimus, and MOAs thereof are excluded. In part 2C, participants received fulvestrant in the form of two IM injections (250 mg each) prior to oral administration of PF-07220060.

To achieve the best dosing regimen (e.g., different initial doses or different schedules) of the identified PF-07220060 in combination with letrozole or fulvestrant, additional dosing regimens identified as safe by BLRM in part 1B and part 1C can be explored in part 2B and part 2C.

The administration method comprises the following steps:

PF-07220060

Oral PF-07220060 was administered on an empty stomach (except in part 1D at the food impact evaluation period of day-7) with at least 8oz (240 mL) of water. No food or liquids other than water were consumed 2 hours before and 1 hour after each dose throughout the study of BID dosing. No food or liquids other than water were consumed 2 hours before and 2 hours after each dose throughout the study of QD dosing.

PF-07220060 is provided in tablet form for oral administration in the form of 5mg, 25mg, 100mg, 125mg and 200mg immediate release tablets.

For only part 1D, PF-07220060 was administered after cycle 1, day-7 and overnight fast on cycle 1, day 1 for at least 10 hours. On cycle 1, days 7 (fed state), a test breakfast meal (described below) is provided and must be consumed within 30 minutes. PF-07220060 was administered with about 8oz of water 30 minutes after beginning a meal. No additional food was allowed until at least 4 hours after administration. On cycle 1, day 1, participants received another single oral dose of PF-07220060 under fasted conditions after at least 10 hours of overnight fast. PF-07220060 was administered with 8oz water. No food was allowed for another 4 hours after dosing. For either treatment day, ad libitum drinking was allowed except for 1 hour before and 1 hour after drug administration. PF-07220060 was administered with at least 8oz of water on an empty stomach starting on cycle 1, day 1, and no food or liquids other than water were allowed 2 hours before and 2 hours after administration.

The test breakfast meal to be consumed is a high fat (about 50% of the total calories of the meal) and high calorie (about 800 to 1000 calories) meal. The test meal resulted in about 150, 250 and 500 to 600 calories from protein, carbohydrate and fat, respectively.

Fulvestrant

FulvestrantAvailable as two 5-mL clear neutral glass (type 1) syringes, each containing 250mg/5mL fulvestrant solution for intramuscular injection and fitted with an anti-opening seal. The syringe is presented in a cradle with a polystyrene plunger rod and a safety needle (SAFETYGLIDETM) for connection to the barrel.

Fulvestrant injection was completed prior to PF-07220060 administration. On days 1 and 15 of cycle 1 and 1 day (+ -3 days) of each subsequent 28-day cycle, according toInstructions for administration provided in the label fulvestrant was administered intramuscularly slowly (1 to 2 minutes/injection) in two 5mL injections at the buttock area.

The participants in fraction 1C who received fulvestrant as part of the last previous therapy only needed to be administered on day 1 of cycle 1 (i.e., no day 15). Cycle 1 day 1 is about 28 days from the last administration of fulvestrant.

Letrozole

LetrozoleAvailable in the form of 2.5mg tablets.

Letrozole was continuously orally administered with PF-07220060 once daily (2.5 mg QD). Letrozole need not be administered simultaneously with PF-07220060.

Midazolam

Midazolam is benzodiazepine which is clinically used for conscious sedationIt is metabolized specifically by CYP3A and is widely used as an in vivo probe for CYP3A activity. Oral formulations of midazolam were used to assess the effect on CYP3A activity in the GI tract and liver. The information obtained will be used to determine if any restrictions or dose adjustments accompanying the drug are appropriate in future studies.

Participants were prevented from taking food and liquids other than water 2 hours before and 1 hour after the administration of midazolam. On day-1 and day 15 of cycle 1, 2mg dose of midazolam was orally administered to the participants with 8oz (240 mL) water for DDI evaluation. Only two doses of midazolam were administered.

I. pharmacokinetic (pk) study

In ongoing phase 1/1B studies, PF-07220060 was obtained as monotherapy (part 1A) and in combination with endocrine therapy (part 1B and part 1C) as preliminary PK data from 60 participants with advanced solid tumors by day 8 of 2022. PF-07220060 is orally administered in a single dosage form at a dose in the range of 100 to 500mg BID and 300 to 400mg BID in combination with letrozole or fulvestrant. Available plasma concentration-time data for PF-07220060 were analyzed using a non-compartmental method.

Preliminary non-compartmental PK analysis was performed based on available samples collected from participants in the study. FIG. 1 shows a plasma concentration-time profile of PF-07220060 following oral BID administration on day 1. FIG. 2 shows the plasma concentration-time profile of PF-07220060 following oral BID administration on day 15. Table 4 shows a summary of PF-07220060 in monotherapy form, and PK parameters in combination with letrozole or fulvestrant.

Table 4: preliminary plasma pharmacokinetic parameters of PF-07220060 following administration of PF-07220060 as a monotherapy and BID oral doses in combination with letrozole or fulvestrant.

^a n＝1;^b n＝2

Abbreviations: CV = coefficient of variation; n = number of participants in the treatment group who can evaluate PK parameters; ND = not measured; n = AUC _tau、R_ac、t_1/2, number of participants determined CL/F; PK = pharmacokinetics; sd=standard deviation.

Note that: all parameters are geometric averages (geometric% CV) except T _max is the median (min-max) and T _1/2 and R _ac are the arithmetic mean (SD); SD and% CV were not reported when the number of individuals with available parameters was < 3; nd=not measured.

Preliminary PK results showed that PF-07220060 was rapidly absorbed following oral dosing, with median T _max values of 1 to 4 hours. For cycle 1, day 1 and cycle 1, day 15, exposure parameters of PF-07220060 (including C _max, AUC, and C _min) generally increased with doses from 100 to 300mg BID. No further increase in exposure parameters was observed at doses above 300mg BID. Moderate accumulation of AUC was observed after repeated BID dosing. In general, PF-07220060 exhibited moderate inter-individual variability in exposure parameters. PF-07220060 is generally equivalent to PK in combination with letrozole or fulvestrant in monotherapy.

II safety of

Dose Limiting Toxicity (DLT)

By day 2 of 9 of 2022, 4 (7.3%) of the 55 evaluable participants experienced DLT. In the 500mg BID PF-07220060 group of single agent, two participants experienced grade 3 thrombocytopenic DLT. One participant experienced a DLT of grade 3 neutropenia in the 200mg BID PF-07220060 group of single agents, and one participant experienced a DLT of grade 3 neutropenia of > 5 days in the 400mg BID PF-07220060 and fulvestrant group.

Adverse events

Adverse events were assessed in phase 1/1b clinical trials with patients given PF-07220060 using the national cancer institute adverse events common terminology standard (NCI CTCAE) version 4.03. By day 2 of 9 of 2022, the following adverse event data were obtained.

Total causal treatment triggers adverse events (TEAE)

A total of 375 total causal TEAE was reported in part 1A, part 1B, part 1C and part 1D to 59 (89.4%) of the 66 participants with PF-07220060.

In part 1A (single agent PF-07220060), total 32 (94.1%) of 34 participants reported total causal TEAE. The most commonly reported (> 20%) all-causal TEAE at all dose levels were neutropenia (41.2%), anemia, diarrhea, leukopenia (35.3% each), nausea (29.4% each), increased aspartate aminotransferase and emesis (20.6% each). Total 15 total grade 3 or higher total causal TEAEs were reported at all dose levels. The most commonly reported (5% or more) all-causal TEAEs of grade 3 or higher are neutropenia (14.7%), anemia, increased aspartate aminotransferase, COVID-19, diarrhea, leukopenia, thrombocytopenia and syncope (5.9% each). No grade 4 TEAE was reported. One participant in the 400mg BID group experienced grade 5 all-causal TEAE (respiratory failure; unrelated to study drug PF-07220060).

In part 1B (PF-07220060 in combination with letrozole), 10 of 13 participants (76.9%) reported total causal TEAE. The most commonly reported (.gtoreq.20%) all-causal TEAE is diarrhea (38.5%), fatigue (30.8%), nausea, neutropenia and sinusitis (23.1% each). At all dose levels, one participant (7.7%) reported grade 3 all-causal TEAE, including anemia, leukopenia, and neutropenia (7.7% each). No grade 4 and 5 all-cause TEAE was reported.

In part 1C (PF-07220060 in combination with fulvestrant), 13/13 (100%) of the participants experienced at least 1 total causal TEAE. The most commonly reported (. Gtoreq.20%) all-causal TEAE was neutropenia (53.8%), diarrhea, leukopenia and nausea (46.2% each), thrombocytopenia and hyperglycemia (30.8% each), anemia, fatigue and vomiting (23.1% each). At all dose levels, a total of 7 grade 3 total causal TEAEs were reported, including neutropenia (23.1%), leukopenia (15.4%), and anaemia, nausea and biliary tract infections (7.7% each). No grade 4 or 5 TEAE was reported.

In part 1D (single agent PF-07220060, 400mg BID food group), TEAE was reported in a total of 4 out of 6 participants (66.7%). The most commonly reported (> 20%) all-causal TEAE is diarrhea, leukopenia and neutropenia (50.0% each). No grade 3 or 5 TEAE was reported. One participant reported grade 4 all-causal TEAE (respiratory failure).

Treatment-related therapies trigger adverse events

Of the 66 participants given PF-07220060 in a single dose escalation of part 1, 54 (81.8%) reported any treatment-related TEAE. Overall, the most commonly reported (> 20%) treatment-related TEAEs were neutropenia (40.9%), diarrhea (33.3%), leukopenia (30.3%), nausea (27.3%) and anemia (21.2%).

In part 1A (single agent PF-07220060), 27 out of 34 participants (79.4%) experienced at least one treatment-related TEAE.

The most commonly reported (> 10%) treatment-related TEAEs at all dose levels were neutropenia (41.2%), anaemia and leukopenia (29.4% each), nausea (26.5%), diarrhea (23.5%), thrombocytopenia (20.6%), vomiting (14.7%) and fatigue (11.8%). A total of 9 (26.5%) participants had a grade 3 treatment-related TEAE. The most commonly reported (. Gtoreq.5%) grade 3 treatment-related TEAE was neutropenia (14.7%), anemia, diarrhea, leukopenia, and thrombocytopenia (5.9% each). No grade 4 and grade 5 treatment related TEAE was reported.

In part 1B (PF-07220060 in combination with letrozole), a total of 10 out of 13 participants (76.9%) reported treatment-related TEAE. The most commonly reported (.gtoreq.20%) treatment-related TEAE were diarrhea (38.5%), fatigue (30.8%), nausea and neutropenia (23.1% each). One participant in the cohort (7.7%) reported grade 3 treatment-related TEAEs including anemia, leukopenia, and neutropenia (7.7% each). No grade 4 and grade 5 TEAE were reported.

In part 1C (PF-07220060 in combination with fulvestrant), all 13 participants (100%) experienced at least one treatment-related TEAE. The most commonly reported (.gtoreq.20%) treatment-related TEAE were neutropenia (53.8%), diarrhea and leukopenia (46.2% each), nausea (38.5%), hyperglycemia (30.8% each), anemia, fatigue, vomiting, and thrombocytopenia (23.1% each). A total of 6/13 (46.2%) participants had grade 3 treatment-related TEAE. Reported grade 3 treatment-related TEAEs were neutropenia (23.1%), leukopenia (15.4%), and anemia and nausea (7.7% each). No grade 4 or 5 TEAE was reported.

In part 1D (single agent PF-07220060, 400mg BID food group), a total of 4 out of 6 participants (66.7%) reported treatment-related TEAE. The most commonly reported (> 20%) treatment-related TEAE is diarrhea, leukopenia and neutropenia (50.0% each). No grade 3, grade 4 or grade 5 treatment related TEAE was reported.

Summary of security:

The safety results available support the clinical development of ongoing PF-07220060 for the treatment of hr+, HER 2-advanced or mBC and other tumors potentially growing in CDK 4-dependent manner, including NSCLC adenocarcinoma, prostate cancer, CRC, liposarcoma and tumors with previously confirmed CDK4 or CCND1 amplification according to local standard tests.

III efficacy

Efficacy data were obtained from 70 evaluable patients. By day 10 and 15 of 2022, PF-06873600 exhibited a disease control rate of 65.7% in the evaluable patients in all groups (n=65.7/100). This includes one participant who demonstrated a complete response, and six participants who demonstrated a partial response. In evaluable patients assessed according to RECIST version 1.1 (table 5), disease control rate was 57.9% (n=22/38) in the single agent PF-07220060 group (overall part 1A) and 80.8% (n=21/26) in the combined group PF-07220060+ endocrine therapy (part 1b+ part 1C).

Table 5: optimal overall response

N = number of participants

PF-07220060 shows early signs of anti-tumor activity in combination with endocrine therapy in the HR+/Her 2-metastatic breast cancer patient population. Efficacy assessment in a dose extended group combined with fulvestrant and letrozole at RDE is ongoing.

Claims (22)

1. A method of treating cancer comprising orally administering to a subject in need thereof a therapeutically effective amount of PF-07220060, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is about 100mg to about 500mg twice daily (BID).

2. The method of claim 1, wherein the therapeutically effective amount is from about 300mg to about 500mg BID.

3. The method of claim 1 or 2, wherein the therapeutically effective amount is about 300mg BID.

4. The method of claim 1 or 2, wherein the therapeutically effective amount is about 400mg BID.

5. The method of any one of claims 1 to 4, wherein PF-07220060 is administered continuously.

6. The method of any one of claims 1 to 5, wherein PF-07220060 is administered in the form of a tablet or capsule.

7. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising PF-07220060 and an endocrine therapeutic agent, wherein the therapeutically effective amount of PF-07220060 is from about 100mg to about 500mg BID.

8. The method of claim 7, wherein the endocrine therapeutic agent is an aromatase inhibitor, an androgen receptor inhibitor, a selective estrogen receptor degradation agent (SERD), or a Selective Estrogen Receptor Modulator (SERM).

9. The method of claim 7, wherein the endocrine therapeutic agent is selected from the group consisting of: letrozole, anastrozole, exemestane, fulvestrant, ilast, axletree, ji Leisi, RG6171, ka Mi Siqun, AZD9496, rituximab, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549, tamoxifen, raloxifene, toremifene, lasofoxifene, bazedoxifene, and alfexifene.

10. The method of claim 7, wherein the endocrine therapeutic agent is letrozole or fulvestrant.

11. The method of any one of claims 7 to 10, wherein the endocrine therapeutic agent is administered to the individual and subsequently PF-07220060 is administered.

12. The method of claim 1 or 7, wherein the subject has been previously treated with chemotherapy, radiation therapy, and/or surgical excision.

13. The method of claim 1 or 7, wherein the subject has been previously treated with a CDK4/6 inhibitor.

14. The method of claim 1 or 7, wherein the individual has been previously treated with an endocrine therapeutic agent.

15. The method of claim 1 or 13, wherein the subject is a mammal.

16. The method of any one of claims 1-15, wherein the subject suffers from breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, and thyroid cancer.

17. The method of any one of claims 1 to 16, wherein the cancer is breast cancer selected from any one or more of: hormone receptor positive (HR+), hormone receptor negative (HR-), HER2 negative (HER 2-), HER2 positive (HER2+), HR+/HER2-, ER-/HR+, ER+/HER2-, and Triple Negative Breast Cancer (TNBC).

18. The method of any one of claims 1 to 16, wherein the cancer is NSCLC, prostate cancer, colorectal cancer, liposarcoma or a tumor characterized by amplification or overexpression of CDK4 and/or CCND 1.

Use of PF-07220060 in the manufacture of a medicament for treating cancer in an individual in need thereof, wherein the medicament is administered in a therapeutically effective unit dose of PF-07220060 in an amount of from about 100mg to about 500mg BID.

Use of PF-07220060 and an endocrine therapeutic agent in the manufacture of a medicament for treating cancer in an individual in need thereof, wherein the medicament is administered in a therapeutically effective unit dose of PF-07220060 in an amount of from about 100mg to about 500mg BID.

21. A medicament comprising a therapeutically effective amount of PF-07220060 for treating cancer in an individual in need thereof, wherein the therapeutically effective amount is from about 100mg to about 500mg BID.

22. A medicament comprising a therapeutically effective amount of PF-07220060 and an endocrine therapeutic agent for treating cancer in an individual in need thereof, wherein the therapeutically effective amount is from about 100mg to about 500mg BID.