HK40110657A - Cdk4 inhibitor for the treatment of cancer - Google Patents

Description

CDK4 inhibitors used to treat cancer

Invention Field

This disclosure relates to the therapeutic treatment of cancer using the cyclin-dependent kinase (CDK) inhibitor 1,5-dehydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropyl-2-yl)-1-(propyl-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threopentanepentyl alcohol (hereinafter PF-07220060) or a pharmaceutically acceptable salt thereof, either alone as monotherapy or in combination with endocrine therapy agents. The invention also relates to related combination therapies, pharmaceutical compositions, and pharmaceutical uses.

introduce

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

Cancer arises from unregulated cell proliferation, which is reflected by unchecked progression of the cell cycle and subsequent loss of checkpoint control that permits uncontrolled cell proliferation. Retinoblastoma protein (Rb1) is a key negative regulator of the cell cycle's G1 and quiescent G0 phases, until and only when phosphorylated by CDK4 or CDK6 (Weinberg, R.A. Theretinoblastoma protein and cell cycle control. Cell, Vol. 81, 323-330, 1995). The idea of CDK4/6-retinoblastoma protein axis dysregulation in cancer is supported by gene alterations commonly identified in breast cancer, such as amplification of cyclin D1 (CCND1) and cyclin E1 (CCNE1) genes and alterations in endogenous CDK4-cyclin D1 inhibitor p16 (INK4a, encoded by the CDKN2A gene), TP53, and PIK3CA genes (Cancer Genome Atlas Network. Comprehensive genomic characterization of human breasttumours. 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 (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, abemaciclib, and ribociclib) in combination with endocrine therapy significantly improved progression-free survival and/or overall survival in patients with HR-positive/HER2-negative metastatic breast cancer (Spring, L.M. et al., Cyclin-dependent kinase 4 and 6 inhibitors 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+, HER2- breast cancer, they are associated with dose-limiting hematologic toxicities (primarily neutropenia).

PF-07220060 is a potent inhibitor of cyclin-dependent kinase 4 (CDK4). The preparation of PF-07220060 is described in International Patent Publication No. WO 2019/207463 and U.S. Patent No. 10,766,884. The entire contents of each of these documents are incorporated herein by reference. PF-07220060 differs from currently approved dual CDK4/6 inhibitors in that it exhibits greater selectivity for CDK4 than for CDK6. In in vivo models, PF-07220060 reduces dose-limiting neutropenia and is predicted to potentially achieve higher tolerable plasma concentrations than dual CDK4/6 inhibitors, thus potentially resulting in increased inhibition of CDK4 oncogenes in tumors.

Appropriate and effective dosing regimens are needed for PF-07220060, both as a single agent and in combination therapy, to treat cancer while minimizing adverse events.

Overview

This disclosure relates to both single-agent and combination therapies for the treatment of cancer, both of which contain the CDK4 inhibitor PF-07220060 or a pharmaceutically acceptable salt thereof.

In some embodiments, this disclosure provides a method of treating cancer comprising orally administering a therapeutically effective amount of PF-07220060 or a pharmaceutically acceptable salt thereof to an individual in need. Specifically, the method comprises administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of PF-07220060, wherein the total daily dose of PF-07220060 is from about 200 mg to about 1000 mg/day, and in some embodiments from about 100 mg to about 500 mg, twice daily (BID).

In some embodiments, this disclosure provides a method of treating cancer, comprising administering to an individual in need 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 degrader (SERD), or a selective estrogen receptor modulator (SERM). In embodiments, the endocrine therapeutic agent includes fulvestrant, tamoxifen, toremifene, anastrozole, exemestane, or letrozole.

Therefore, the implementation scheme described herein provides a dosing regimen for PF-07220060 in both single-dose and combination therapy for the treatment of cancer, thereby minimizing side effects in individuals during treatment.

Brief description of the attached diagram

Figure 1 shows a nominal time profile of PF-07220060 plasma concentrations following administration of an oral dose of PF-07220060 as monotherapy or in combination with letrozole or fulvestrant on day 1 of cycle 1.

Figure 2 shows a nominal time profile of PF-07220060 plasma concentrations following administration of PF-07220060 as monotherapy or in combination with letrozole or fulvestrant on day 15 of cycle 1.

Invention Details

This disclosure will be more readily understood by referring to the following detailed description of aspects and embodiments of the disclosure, as well as the examples included herein. It should be understood that the terminology used herein is for describing particular embodiments only and is not intended to be limiting. It should be further understood that, unless specifically limited herein, the terminology used herein has its conventional meaning as known in the related art.

definition:

As used herein, unless otherwise specified, the singular forms “a/an” and “the” include plural references. For example, an “a” substituent includes one or more substituents.

When considered by a person skilled in the art, the term "about" means a value that falls within an acceptable standard of average error. In some embodiments, the term "about" means within ±10% of the indicated value. For example, it should be understood that a dose of about 400 mg means that the dose may vary between 360 mg and 440 mg.

The invention described herein may be suitably practiced in the absence of any element not specifically disclosed herein. Thus, by way of example, in various contexts herein, any of the terms “comprising,” “consisting essentially of,” and “consisting of” may be replaced by any of the other two terms.

As used in this article, “dose-limiting toxicity” (DLT) refers to a further increase in the dose of PF-07220060 beyond the contraindicated dose.

As used in this article, "measurable lesion" refers to a lesion that can be accurately measured in at least one dimension, a lesion with a maximum diameter of at least 10 mm or more (with a slice thickness of 5 to 8 mm) that is twice the slice thickness when assessed by CT or MRI, a lesion with a maximum diameter of at least 20 mm when assessed by chest X-ray, a superficial lesion with a maximum diameter of 10 mm or more when assessed by calipers, or a malignant lymph node with a short axis of 15 mm 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 intolerable toxicities. MTD was assessed using mTPI based on the observed DLT rate, where the target DLT rate was 27.5% and the equivalent range was 22.5% to 32.5%.

As used herein, the terms “pharmaceuticalally acceptable carrier” or “pharmaceuticalally acceptable excipient” refer to components that may be included in the compositions described herein, are physiologically suitable for pharmaceutical use, and do not cause significant adverse effects in an individual.

As used in this article, "rest period" is the number of days between the administration of a full dose of the active agent and the next administration of a full dose of the active agent.

As used in this article, the term "week" refers to seven consecutive days. Therefore, a four-week period is 28 consecutive days that begin on any day of a calendar week.

As used herein, the term "individual" can be a mammal, referring to any animal species of the mammal class. Examples of mammals include humans; non-human primates such as monkeys; laboratory animals such as rats, mice, and guinea pigs; livestock such as cats, dogs, rabbits, cattle, sheep, goats, horses, and pigs; and captive wild animals such as lions and tigers. In some embodiments, the individual is a human. In some embodiments, the individual is female. In some embodiments, the individual is male.

As used herein, the term "therapeuticly effective amount" for use and/or treatment of an individual refers to an amount, alone or in combination with one or more other agents, treatments, regimens, or therapeutic regimens, administered in a single or multiple dose, that provides in an individual a detectable response, desired outcome, or objective or subjective benefit to the individual of any measurable or detectable degree or duration of remission or cure (e.g., hours, days, months, years). Such amounts are typically effective in improving the disease, or one, many, or all of the side effects/symptoms, consequences, or complications of the disease to a measurable degree, but are also considered satisfactory results if they reduce or inhibit the progression or worsening of the disease or provide a stable (i.e., non-worsening) state of the disease. The term "therapeuticly effective amount" also means the amount of an active agent that, upon administration to an individual, effectively produces the desired therapeutic effect, such as inhibiting the growth of a cancerous tumor or causing it to shrink.

Determining the therapeutically effective amount is entirely within the capabilities of those skilled in the art. In various embodiments, the dosage may vary within this range depending on the dosage form and route of administration. In some embodiments, the therapeutically effective amount of the compound described herein administered to an individual may be determined based on factors known to those skilled in the art, including the compound's biological activity and bioavailability (e.g., half-life and stability in vivo), the compound's chemical properties (e.g., molecular weight, hydrophobicity, and solubility), the route of administration, and frequency. Furthermore, it should be understood that the specific dosage of a pharmaceutical composition comprising compounds disclosed herein may be determined based on a variety of factors, including the individual's physical condition (e.g., age, sex, weight) and the individual's medical history (e.g., medications taken, health status, other diseases or conditions). The precise dosage of a pharmaceutical composition administered to an individual can be determined using methods known to those skilled in the art (such as pharmacologists or anesthesiologists).

As used herein, the term “improvement” refers to any reduction in the degree, severity, frequency, and/or likelihood of a particular disease’s symptoms or clinical signs. “Symptoms” refers to any subjective indication of a disease or individual condition.

As used herein, “treat” or “treating” cancer and/or cancer-related diseases refers to administering, according to the invention, a monotherapy or combination therapy 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 decrease in the rate of cancer cells infiltrating peripheral organs, or a decrease in tumor metastasis or tumor growth rate, reversal, relief, or inhibition of the progression of the disease or condition, or prevention of the disease or condition to which the term is applied, or one or more symptoms of the disease or condition. Unless otherwise indicated, the term “treat” as used herein means a therapeutic action as defined immediately preceding it. The term “treat” also includes adjuvant and neoadjuvant therapy for an individual. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reducing (or destroying) the proliferation of neoplastic or cancerous cells; inhibiting cancer metastases or neoplastic cells; reducing or decreasing tumor size; alleviating cancer; reducing symptoms caused by cancer; improving the quality of life of those patients with cancer; reducing the dosage of other medicines required to treat cancer; delaying cancer progression; curing cancer; overcoming one or more drug resistance mechanisms in cancer; and/or prolonging the survival of cancer patients. The positive therapeutic effect on cancer can be measured in various ways (see, for example, W.A. Weber, J. Nucl. Med. 50: 1S-10S (2009)).

When applied to an individual diagnosed with or suspected of having cancer, the term "tumor" refers to any malignant or potentially malignant growth or mass of tissue of any size, including primary and secondary tumors. Solid tumors are abnormal growths or masses of tissue that do not typically contain cysts or fluid-filled areas. Examples of solid tumors include sarcomas, carcinomas, and lymphomas. Leukemia (blood cancers) generally does not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

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

When a combination therapy of two or more agents is administered, the agents may be administered in the same treatment cycle or in different cycles. In a preferred embodiment, PF-07220060 is administered continuously in a 28-day cycle. Similarly, letrozole is typically administered continuously in a 28-day treatment cycle. Pabucixirib is typically administered in intermittent 28-day treatment cycles, comprising 21 days of drug administration with a 7-day break between cycles. Fulvestrant is typically administered intramuscularly on days 1, 15, and 29 of the first treatment cycle and then monthly thereafter.

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

The term "sequential" or "sequentially" refers to the individual therapeutic agents in a combination therapy, administered alone or in sequence within a drug regimen, wherein the therapeutic agents can be administered in any order. Sequential dosing may be particularly applicable when the therapeutic agents in a combination therapy are in different dosage forms (e.g., one agent is a tablet and another is a sterile liquid), and/or when the agents are administered according to different dosing schedules, such as one agent being administered daily and a second agent being administered at a lower frequency (e.g., weekly).

The term "in parallel" refers to the administration of individual therapeutic agents in a combination therapy, either alone or in separate dosage forms, wherein a 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 in parallel.

The term "simultaneously" refers to the administration of individual therapeutic agents of a combination therapy in the same dosage form, such as in a fixed-dose combination of two or more drugs in a single dosage form.

A "dosing regimen" refers to a period of time during which one or more drugs, compounds, or compositions are administered, comprising one or more treatment cycles, wherein each treatment cycle may include administration of one or more agents via the same or different routes of administration at different times, frequencies, or amounts. Dosing or dosing regimens may be repeated or adjusted as needed to achieve the desired therapeutic effect.

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

Therefore, certain embodiments of this disclosure provide therapeutic dosages and dosing regimens including administering a therapeutically effective amount of PF-07220060 to an individual.

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

In some implementations, the therapeutically effective dose of PF-07220060 is about 200 mg to about 1000 mg per day (i.e., total daily dose), for example, about 200 mg to about 500 mg per day, about 200 mg to about 450 mg per day, about 200 mg to about 400 mg per day, about 200 mg to about 350 mg per day, about 200 mg to about 300 mg per day, about 400 mg to about 950 mg per day, about 400 mg to about 900 mg per day, about 400 mg to about 850 mg per day, about 400 mg to about 800 mg per day, about 500 mg to about 950 mg per day, about 500 mg to about 900 mg per day, about 500 mg to about 850 mg per day, about 600 mg to about 950 mg per day, about 600 mg to about 900 mg per day, or about 600 mg to about 800 mg per day.

In some embodiments, PF-07220060 is administered in doses of about 200 mg to about 1000 mg once daily (QD), such as about 200 mg to about 500 mg QD, about 200 mg to about 450 mg QD, about 200 mg to about 400 mg QD, about 200 mg to about 350 mg QD, about 200 mg to about 300 mg QD, about 400 mg to about 950 mg QD, and about 400 mg to about 900 mg QD. Approximately 400 mg to approximately 850 mg QD, approximately 400 mg to approximately 800 mg QD, approximately 500 mg to approximately 950 mg QD, approximately 500 mg to approximately 900 mg QD, approximately 500 mg to approximately 850 mg QD, approximately 500 mg to approximately 800 mg QD, approximately 600 mg to approximately 950 mg QD, approximately 600 mg to approximately 900 mg QD, approximately 600 mg to approximately 850 mg QD, or approximately 600 mg to approximately 800 mg QD.

In some implementations, the therapeutically effective dose of PF-07220060 is about 100 mg to about 500 mg twice daily (BID), such as about 200 mg to about 500 mg BID, about 250 mg to about 500 mg BID, about 300 mg to about 500 mg BID, about 350 mg to about 500 mg BID, about 400 mg to about 500 mg BID, about 100 mg to about 450 mg BID, about 150 mg to about 450 mg BID, about 200 mg to about 450 mg BID, etc. 0 mg BID, about 250 mg to about 450 mg BID, about 300 mg to about 450 mg BID, about 350 mg to about 450 mg BID, about 400 mg to about 450 mg BID, about 100 mg to about 400 mg BID, about 150 mg to about 400 mg BID, about 200 mg to about 400 mg BID, about 250 mg to about 400 mg BID, about 300 mg to about 400 mg BID, about 350 mg to about 400 mg BID.

In some implementations, PF-07220060 is administered to an individual at any of the therapeutically effective doses disclosed herein.

The pharmaceutical composition containing a therapeutically effective amount of PF-07220060 as described herein may be administered once daily (QD) or twice daily (BID).

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

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

In some implementations, PF-07220060 is administered in the following doses: approximately 100 mg BID, approximately 200 mg BID, approximately 300 mg BID, approximately 400 mg BID, or approximately 500 mg BID.

The dosage of PF-07220060 can be increased or decreased based on an individual's weight, age, health condition, sex, or medical condition. Those skilled in the art can determine the appropriate dosage for an individual based on this disclosure.

PF-07220060 can be administered in treatment cycles, with or without a break between treatment cycles. A treatment cycle can be approximately 7 days, approximately 14 days, approximately 21 days, approximately 28 days, approximately 35 days, or any period in between. A break can 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 period in between (e.g., 1 week and 3 days). In some embodiments, PF-07220060 is administered continuously without any break (i.e., treatment continues until termination). In some embodiments, PF-07220060 is administered for one treatment cycle (e.g., approximately 28 days) with or without a break. In some embodiments, PF-07220060 is administered for approximately 28 days with an approximately one-week break. PF-07220060 can be administered for at least approximately 7 days, approximately 14 days, approximately 21 days, approximately 28 days, approximately 2 months, approximately 3 months, approximately 12 months, approximately 24 months and longer.

The pharmaceutical composition may be administered with or without food.

Pharmaceutical compositions may be administered via one or more routes deemed appropriate by those skilled in the art and based on dosage form. Pharmaceutical formulations are discussed in Remington's Pharmaceutical Sciences, 18th edition, (1995) Mack Publishing Co., Easton, Pa. Other examples of pharmaceutical formulations can be found in Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, Vol. 3, 2nd edition, New York, N.Y. If the compound is to be administered orally, it may be formulated into pills, capsules, tablets, etc., using pharmaceutically acceptable carriers, gliding agents, or excipients.

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

In some implementations, the pharmaceutical composition can be administered as an immediate release formulation or in a modified release formulation.

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

Treatment methods and uses

In some embodiments, this disclosure provides a method for treating cancer in an individual who requires it, comprising administering to said individual a therapeutically effective amount of PF-07220060 as described herein.

In some embodiments, this 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 some embodiments, this disclosure provides the use of PF-07220060 in the preparation of a medicament for treating cancer in an individual who requires it, wherein the medicament is administered in a therapeutically effective unit dose of PF-07220060 as described herein.

In some embodiments, this disclosure provides the use of PF-07220060 in conjunction with endocrine therapy in the preparation of a medicament for treating cancer in an individual who requires it, wherein the medicament is administered in a therapeutically effective unit dose of PF-07220060 as described herein.

In some embodiments, this disclosure provides a medicament comprising a therapeutically effective amount of PF-07220060 as described herein, for the treatment of cancer in an individual who requires it.

In its implementation, this disclosure provides a medicament comprising a therapeutically effective amount of PF-07220060 as described herein and an endocrine therapeutic agent for the treatment of cancer in an individual in need of it.

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

In some embodiments, the methods included herein include administering PF-07220060 to an individual suffering from CDK4-mediated cancer. In some embodiments, the cancer is characterized by amplification or overexpression of CDK4 and/or CCND1. In one embodiment, the cancer is characterized by amplification or overexpression of CDK4. In one embodiment, the cancer is characterized by amplification of the CCND1 gene or overexpression of cyclin D1.

In some embodiments, the methods disclosed herein include administering PF-07220060 to an individual suffering from cancer selected from breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer (PPC), bladder cancer, uterine cancer, prostate cancer, lung cancer (including non-small cell lung 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), kidney 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: breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, gastric cancer, or combinations thereof.

In some implementations, 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 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 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 or pertuzumab-resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer is resistant to treatment with standard-of-care agents; for example, the breast cancer may exhibit primary or acquired resistance to endocrine therapy, HER2-targeting agents (e.g., tamoxifen, trastuzumab emtansine, fam-trastuzumab deruxtecan, pertuzumab, lapatinib, neratinib, or tucatinib), or CDK4/6 inhibitors. In some embodiments, the individual is difficult to treat with endocrine therapy.

In some implementations, the breast cancer is difficult to treat with antitumor chemotherapy agents (such as platinum, taxanes, anthracycline antibiotics, or antimetabolites), or is resistant to their treatment, or progresses under their treatment.

In some embodiments, the breast cancer has progressed during treatment with an aromatase inhibitor or within 12 months of completing adjuvant therapy with an aromatase inhibitor. In some embodiments, the breast cancer has progressed during treatment with tamoxifen or within 12 months of completing 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-of-care therapy. In some embodiments, PF-07220060 is administered as a second (or subsequent) line-of-care therapy after treatment with an endocrine therapy agent and/or a CDK4/CDK6 inhibitor. In some embodiments, PF-07220060 is administered as a second (or subsequent) line-of-care therapy after treatment with an endocrine therapy agent (such as an aromatase inhibitor; a selective estrogen receptor modulator (SERM), such as tamoxifen; or a selective estrogen degrader/downregulator (SERD)). In some embodiments, PF-07220060 is administered as a second (or subsequent) line-of-care therapy after treatment with one or more chemotherapy regimens. In some embodiments, PF-07220060 is administered as a second (or subsequent) line-of-care therapy after HER2-targeted therapy.

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

In some embodiments, the endocrine therapeutic agent is an aromatase inhibitor, an androgen receptor inhibitor, a selective estrogen receptor degrader (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 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, elacestrant (RAD-1901, Radius Health/Menarini), amcenestrant (SAR439859, Sanofi), giredestrant (GDC9545, Roche), RG6171 (Roche), camizestrant (AZD9833, AstraZeneca), AZD9496 (AstraZeneca), rintodestrant (G1 Therapeutics), ZN-c5 (Zentalis), LSZ102 (Novartis), D-0502 (Inventisbio), LY3484356 (Eli Lilly), and SHR9549 (Jiansu Hengrui Medicine). 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, lasoxifene, bardoxifene, and aflixifen. In some such embodiments, the SERM is tamoxifen or raloxifene. In a preferred embodiment, the endocrine therapy agent is letrozole or fulvestrant.

The endocrine therapy agent may be administered according to the standards of care outlined in the product package insert or provided by a healthcare professional. The term "product package insert" refers to the information typically included in the commercial packaging of a therapeutic product, which contains information about indications, usage, dosage, administration, contraindications, and/or warnings related to the use of the therapeutic product.

In some embodiments, an endocrine therapy agent is administered to the individual during treatment with PF-07220060. In some embodiments, a first dose of the endocrine therapy agent is administered before administration of the first dose of PF-07220060. In some embodiments, a first dose of the endocrine therapy agent is administered on the same day as administration of the first dose of PF-07220060. In some embodiments, a first dose of the endocrine therapy agent is administered after the commencement of treatment with PF-07220060.

In some implementations, the individual has previously been treated with one or more lines of endocrine therapy before administering PF-07220060 to the individual.

In some implementations, the individual has previously been treated with chemotherapy, radiation therapy, and/or surgical resection before PF-07220060 is administered to the individual.

In some implementations, the individual has previously been treated with a CDK4/6 inhibitor before being given PF-07220060.

In some embodiments, the present invention treats a disease that elicits a complete response (CR), a partial response (PR), or a stable disease (SD) in an individual.

Treatment outcomes and tumor response assessment

The therapy of this invention can induce a complete response (CR), partial response (PR), progressive disease (PD), or stable disease (SD) in patients. Bioimaging can be used to assess the level of response to the therapy. Cytology and histology can also be used as needed (e.g., to locate any residual lesions). In some embodiments, the various levels of response can be assessed according to Table 1 below.

Table 1. Assessment of the target disease

This disclosure provides several exemplary embodiments. Non-limiting exemplary embodiments of this disclosure are shown below.

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

Implementation Scheme 2. The method as described in Implementation Scheme 1, wherein the therapeutically effective dose is about 300 mg to about 500 mg BID.

Implementation Scheme 3. The method as described in Implementation Scheme 1 or 2, wherein the therapeutically effective dose is approximately 300 mg BID.

Implementation Scheme 4. The method as described in Implementation Scheme 1 or 2, wherein the therapeutically effective dose is approximately 400 mg BID.

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

Implementation Scheme 6. The method of any one of Implementation Schemes 1 to 5, wherein PF-07220060 is administered in tablet or capsule form.

Implementation Scheme 7. A method of treating cancer, comprising administering to an individual in need 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 about 100 mg to about 500 mg BID.

Implementation Scheme 8. The method of Implementation Scheme 7, wherein the endocrine therapeutic agent is an aromatase inhibitor, an androgen receptor inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).

Implementation Scheme 9. The method as described in Implementation Scheme 7, wherein the endocrine therapy agent is selected from: letrozole, anastrozole, exemestane, fulvestrant, ellastrant, icrestriate, giretrestriate, RG6171, carmistren, AZD9496, reitressen, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549, tamoxifen, raloxifene, toremifene, lasoxifene, bardoxifene, and afoxifene.

Implementation Scheme 10. The method as described in Implementation Scheme 7, wherein the endocrine therapy agent is letrozole or fulvestrant.

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

Implementation Scheme 12. The method as described in Implementation Scheme 1 or 7, wherein the individual has previously been treated with chemotherapy, radiation therapy and/or surgical resection.

Implementation Scheme 13. The method as described in Implementation Scheme 1 or 7, wherein the individual has previously been treated with a CDK4/6 inhibitor.

Implementation Scheme 14. The method as described in Implementation Scheme 1 or 7, wherein the individual has previously been treated with an endocrine therapy agent.

Implementation Scheme 15. The method as described in Implementation Scheme 1 or 13, wherein the individual is a mammal.

Implementation Scheme 16. The method of any one of Implementation Schemes 1 to 15, wherein the individual 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, stomach cancer, and thyroid cancer.

Implementation Scheme 17. The method of any one of Implementation Schemes 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-), human epidermal growth factor receptor 2 negative (HER2-), human epidermal growth factor receptor 2 positive (HER2+), HR+/HER2-, ER-/HR+, ER+/HER2- and triple-negative breast cancer (TNBC).

Implementation Scheme 18. The method of any one of Implementation Schemes 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 CCND1.

Implementation scheme 19. Use of PF-07220060 in the preparation of a medicament for treating cancer in an individual who requires it, wherein the medicament is administered in a therapeutically effective unit dose of PF-07220060 in an amount of about 100 mg to about 500 mg BID.

Implementation Scheme 20. Use of PF-07220060 and an endocrine therapeutic agent in the preparation of a medicament for treating cancer in an individual who requires it, wherein the medicament is administered in a therapeutically effective unit dose of PF-07220060 in an amount of about 100 mg to about 500 mg BID.

Implementation Scheme 21. A medicine comprising a therapeutically effective amount of PF-07220060, used to treat cancer in an individual who requires it, wherein the therapeutically effective amount is about 100 mg to about 500 mg BID.

Implementation Scheme 22. A medicine comprising a therapeutically effective amount of PF-07220060 and an endocrine therapy agent, for treating cancer in an individual who requires it, wherein the therapeutically effective amount is about 100 mg to about 500 mg BID.

Example

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

Example 1

Inhibition of multicellular tumor spheroids growth via single agent PF-07220060 and in combination with fulvestrant

The purpose of this embodiment is to evaluate the combined effect of PF-07220060 and endocrine therapy in spheroid growth inhibition (SGI) of multicellular tumors.

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

1) In HR+, HER2-T47D breast cancer spheroids,

2) In HR+, HER2+ BT474 breast cancer spheroids,

3) In the BT474 sphere, and

4) In prostate cancer spheroids of AR+ prostate cancer cell line (LNCaP).

Spheroids were treated with escalating concentrations of 100, 300, or 1000 nM PF-07220060 and compared to the clinically relevant concentration of 30 nM pabuxirib. PF-07220060 monotherapy inhibited spheroid growth in a dose-dependent manner, with the highest efficacy observed in the T47DBC spheroid model (86% SGI over the duration of treatment with 1000 nM) (Table 1). Compared to monotherapy alone (57% to 67% SGI with 100 nM PF-07220060 or 79% SGI with fulvestrant), the combination of 100 nM PF-07220060 and 1 nM fulvestrant increased the SGI to 96% in T47D cells (Table 1). BT474 spheroids were relatively less sensitive to PF-07220060, yielding a 52% SGI at 1000 nM.

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

Overall, these data support the use of PF-07220060 in combination with endocrine therapy in HR+, HER2- breast cancer. The PF-07220060 combination exhibits additive or synergistic benefits across multiple tumor types. When used as a monotherapy, PF-07220060 inhibits spheroid growth in a dose-dependent manner, with the highest activity observed in the HR+, HER2- breast cancer spheroid model.

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

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

Example 2: Clinical Trial Protocol

A sustained open-label, non-randomized phase 1/1b dose-finding study was conducted to investigate the safety, tolerability, pharmacokinetic (PK) and drug-promoting (PD) outcomes of PF-07220060 when administered as a single agent and in combination with endocrine therapy.

Research Design

In Part 1A, a single escalation dose of PF-07220060 alone will be started at a 100 mg BID dose and administered on a continuous basis to determine the maximum tolerated dose (MTD) and/or to select PF-07220060 as the recommended Phase 2 dose (RP2D) for monotherapy.

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

Part 1D assesses the effect of food on the pharmacokinetics (PK) of PF-07220060 at or below the monotherapy MTD. In Part 1D, participants receive PF-07220060 in single-dose form on a continuous basis, starting on Day -7 and subsequently on Day 1, at or below the monotherapy MTD, to assess the effect of food.

Part 1E will assess the potential drug-drug interactions (DDIs) between PF-07220060 and midazolam, as established in Part 1A at or below the monotherapy MTD.

Part 2B is an expansion group of patients with HR-positive/HER2-negative advanced or metastatic breast cancer (mBC) who received combination therapy of PF-07220060 with letrozole and who had not received any prior systemic anticancer therapy for their advanced disease.

Part 2C is an expansion group of patients with HR-positive/HER2-negative advanced or mBC who have had disease progression on prior therapy and who have received combination therapy with PF-07220060 and fulvestrant (with or without goserelin).

Entering the study is defined as day 1 of dosing. All cycles are 28 days in length. Alternative dosing regimens (e.g., QD) may be evaluated based on newly emerging and available preliminary clinical data (including safety/tolerability, laboratory, PK, and PD study results) during dose escalation or after determining the MTD/RP2D of the BID regimen. If indicated, intermittent dosing schedules (e.g., 3 weeks dosing, 1 week off) may also be evaluated based on newly emerging clinical data, according to PF-07220060.

Participants experiencing toxicities, including DLT, can be managed through dose adjustments or treatment interruption. Proposed doses, schedules, and PK time points may be modified during the study based on emerging safety and PK data.

The study duration may vary depending on observed toxicities and the potential benefits experienced by individual participants. It is estimated that participants may maintain treatment for approximately 6 to 8 cycles, resulting in a total study duration of approximately 24 to 32 weeks. The actual duration could be longer if participants derive benefit from the study treatment.

Based on the progressed PK, PD, and safety profile assessed in Part 1A, the starting dose of PF-07220060 in Parts 1B and 1C can be initiated at or before reaching the MTD at a dose determined to be safe by a Bayesian Logistic Regression Model (BLRM), thus meeting the overdose control (EWOC) criteria in Part 1A for escalation (Rogatko, A. et al., Translation of Innovative Designs Into Phase Trials, J. Clin. Oncol., 25(31), 4982-6, 2007). The EWOC principle is used to limit the risk of treating participants at doses higher than the MTD. Additionally, more than one dosing regimen (e.g., different doses, dosing frequencies) of PF-07220060 can be investigated in Parts 1B and 1C.

research group

Inclusion criteria were designed to select participants deemed suitable for participation in the study. The inclusion criteria used for patient selection included the following:

All participants – those with histologically or cytologically confirmed locally advanced or metastatic solid tumors that are unrespectable and not intended for curative radiation.

For some of the disease requirements

Part 1B and Part 1C:

■ Refractory HR-positive/HER2-negative (2L+, prior to CDK4/6) breast cancer.

Parts 1A, 1D, and 1E:

■ Refractory HR-positive/HER2-positive breast cancer.

■ Tumors other than breast cancer: NSCLC, prostate, CRC, liposarcoma, or tumors that show previously confirmed CDK4 or CCND1 amplification according to local standards.

For some of the diseases in section 2, the requirements are as follows:

Part 2B and Part 2C:

■HR-positive/HER2-negative breast cancer

■The following participants:

Postmenopausal women defined by at least one of the following criteria:

■ Age ≥ 60 years;

■ Age <60 years and cessation of regular menstruation for at least 12 consecutive months without alternative pathological or physiological causes; and serum estradiol and follicle-stimulating hormone (FSH) levels within the laboratory reference range for postmenopausal women;

■ Bilateral oophorectomy is documented;

■ Ovarian failure is medically confirmed.

or

For some 2C cases: premenopause/menopause, i.e., those who do not meet the postmenopausal criteria.

■ Premenopausal/postmenopausal women are eligible for enrollment if they can be treated with the luteinizing hormone-releasing hormone (LHRH) agonist goserelin. Participants must have started treatment with goserelin or an alternative LHRH agonist at least 4 weeks prior to enrollment. If a participant is already receiving an alternative LHRH agonist prior to enrollment, switching to goserelin is preferred for use during the trial. However, other LHRH antagonists, such as leuprolide, are also acceptable.

Requirements for lesions:

■ For Part 1: Participants must have evaluable lesions (including skin or bone lesions only).

■ For Part 2B and Part 2C: Participants must have measurable disease as defined in RECIST (Response Assessment Criteria for Solid Tumors) Version 1.1 (Eisenhauer et al., European Journal of Cancer, 2009, 45(2):228-47). Tumor lesions previously irradiated or treated locally will be considered measurable only if clearly documented as having progressed at the treatment site after completion of therapy.

Previous systemic treatment:

For part 1:

HR-positive/HER2-negative breast cancer (partial 1A/partial 1B/partial 1C/partial 1D/partial 1E). Participants should have already received:

■ At least one line of care standard (SOC), including CDK4/6 inhibitor therapy for advanced or metastatic disease, or, where a CDK4/6 inhibitor is available but deemed unsuitable by the investigator, may be enrolled if the investigator provides a strong clinical basis and the trial commissioner approves; or

■ In countries where CDK4/6 inhibitors are not approved or reimbursed, at least one line of antiendocrine therapy is used for advanced or metastatic disease.

Prior chemotherapy is permitted in two cases in the context of advanced disease.

■HR-positive/HER2-positive breast cancer (part 1A/part 1D): Participants should have received prior treatment with at least one approved HER2-targeted therapy.

■ Tumors other than breast cancer (Part 1A/Part 1D): Tumors that are resistant to at least two 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 prior systemic anticancer therapy for advanced/metastatic breast cancer.

Partial 2C:

■ Progression during treatment or within 12 months of completing adjuvant therapy with aromatase inhibitors (if postmenopausal) or tamoxifen (if premenopausal or during menopause), or

■ Progression has occurred within 1 month or 1 month after the termination of previous aromatase inhibitor therapy for advanced/metastatic breast cancer (if postmenopausal) or previous endocrine therapy for advanced/metastatic breast cancer (if premenopausal or postmenopausal).

■ In addition to endocrine therapy, it allows for a pre-chemotherapy line for advanced/metastatic disease.

Inclusion criteria

The inclusion criteria for the two parts of the study are as follows:

1. Participants in both Part 1 and Part 2 (except Part 2B) must be unable to be treated with existing therapies that are known to provide clinical benefit for their condition or are intolerant of them.

2. Participants must be 18 years of age or older.

3. Performance status of 0 or 1 in the Eastern Cooperative Oncology Group (ECOG).

4. Sufficient bone marrow function, as demonstrated by the following:

a. ANC ≥ 1,500/ ^mm³ or ≥ 1.5 × ^10⁹ /L;

b. Platelet count ≥100,000/ ^mm³ or ≥100× ^10⁹ /L;

c. Heme ≥ 9 g/dL. Limited transfusions are permitted once this value is reached, following discussion with the client's medical monitor. There should be no long-term need for transfusions in the near term (approximately 3 months).

5. Adequate renal function is defined as a creatinine clearance ≥50 mL/min, calculated using the institution's methodological standards for part 1. In cases of unknown origin, a 24-hour urine collection test can be used for a more accurate estimate of creatinine clearance.

6. Sufficient liver function, as demonstrated by the following:

a. Total serum bilirubin ≤1.5×ULN, unless the participant has Gilbert syndrome (in which case a maximum total serum bilirubin ≤3.0×ULN will be allowed).

b. AST and ALT ≤ 2.5 × ULN; ≤ 5.0 × ULN when the tumor involves the liver;

c. ALKP ≤ 2.5 × ULN (≤ 5.0 × ULN in the case of bone or liver metastases).

Exclusion criteria

Participants are excluded from the study if they meet any of the following criteria:

1. For part 1D: Participants who have undergone gastrectomy or have other restrictions such as dietary restrictions or exclusion of 10-hour overnight fasting (with water allowed) or consumption of high-fat, high-calorie meals.

2. For part 2B: In cases of disease relapse within 12 months of completion of treatment, prior neoadjuvant or adjuvant therapy with a nonsteroidal aromatase inhibitor (i.e., anastrozole or letrozole) or prior therapy with any CDK4/6 inhibitor.

3. For part 2C: Prior treatment with any CDK inhibitor or fulvestrant or everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway.

4. Known uncontrolled or symptomatic CNS cancer metastases, carcinomatous meningitis, or leptomeningeal disease, cerebral edema, and/or progressive growth as indicated by clinical symptoms. Participants with CNS cancer metastases or umbilical cord compression are eligible if they have received definite treatment (e.g., radiation therapy, stereotactic surgery) and have been clinically stable for at least 4 weeks prior to enrollment after discontinuation of anticonvulsants and steroids, and show no signs of progression at study enrollment.

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

6. Have any other active malignant disease within the 3 years prior to selection, except for basal cell or squamous cell skin cancer or carcinoma in situ that has been adequately treated.

7. Had major surgery within 4 weeks prior to entering the study.

8. Radiation therapy intended for therapeutic use within 4 weeks prior to enrollment in the study. Any palliative radiation therapy must be completed within 7 days prior to day 1 of the study intervention administration.

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

10. For part 1C, participants who received fulvestrant as part of their last prior therapy are eligible.

11. The aforementioned high-dose chemotherapy that requires stem cell rescue.

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

13. Baseline 12-lead ECG confirms clinically relevant abnormalities that could potentially affect participant safety or study outcome interpretation (e.g., baseline QTc interval >470 ms, complete LBBB, signs of acute or age-unknown myocardial infarction, ST-T interval changes indicating active myocardial ischemia, grade II or III AV block, or severe bradycardia or tachyarrhythmias). If the uncorrected baseline QT interval is >470 ms, this interval should be rate-corrected using the Fridericia method, and the resulting QTcF should be used for decision-making and reporting. If the QTc exceeds 470 ms or the QRS exceeds 120 ms, the ECG should be repeated twice, and the average of the three QTc or QRS values should be used to determine participant eligibility. Computer-interpreted ECGs should be reread by a physician experienced in ECG interpretation before excluding participants. Cases must be discussed in detail with the trial sponsor's medical monitor to determine eligibility.

14. Any of the following conditions within the previous 6 months: myocardial infarction, congenital long QT syndrome, torsades de pointes, arrhythmia (including persistent ventricular tachyarrhythmias and ventricular fibrillation), severe conduction system abnormalities (e.g., bifascicular block (defined as right bundle branch and left anterior or posterior branch block), grade 3 AV block), unstable angina, coronary/peripheral artery bypass graft, symptomatic CHF, New York Heart Association class III or IV, cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism; deep vein thrombosis; arterial occlusive disease; persistent arrhythmia with NCITCCAE grade ≥2, uncontrolled atrial fibrillation of any grade, or QTcF interval >470 ms at screening.

15. Uncontrollable blood pressure (≥150/100 mmHg, despite the best medical treatment).

16. Therapeutic doses of anticoagulants are prohibited (prophylactic doses of anticoagulants are permitted).

17. Known coagulation disorders, such as bleeding diathesis.

18. Known or suspected hypersensitivity to the active ingredient/excipient of PF-07220060, letrozole, fulvestrant, enzalutamide and/or goserelin (or equivalent agents for inducing chemical menopause/castration).

19. Active inflammatory bowel disease (GI), known diverticulosis, or previous gastrectomy or banding surgery. Impairment of GI function or GI disease can significantly alter the absorption of PF-07220060, such as a history of GI surgery, which can cause intestinal blind loops and clinically significant gastric myoparalysis, short bowel syndrome, persistent nausea, vomiting, active inflammatory bowel disease, or diarrhea with a CTCAE grade >1.

20. Currently using medications that carry the risk of QTc prolongation.

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

22. Treat with a proton pump inhibitor (e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) for 7 days prior to the first dose of the study intervention.

23. Other medical or psychiatric conditions, including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormalities, may increase the risk of participation in the study or, in the researcher's judgment, render the participant unsuitable for participation in the study.

24. Pregnancy or breastfeeding.

Example 3: Clinical Trial Results

The Phase 1/1b clinical trial of PF-07220060 is ongoing. As of September 2, 2022, a total of 66 participants (43 women and 23 men) have been treated with PF-07220060 in Parts 1A, 1B, 1C, and 1D. The mean age was 61.4 years (range 36 to 82 years), and the cohort included participants with HR+HER2- advanced or mBC and other tumors that potentially grow in a CDK4-dependent manner, including NSCLC adenocarcinoma, prostate cancer, CRC, liposarcoma, and tumors with previously confirmed CDK4 or CCND1 amplification according to local criteria. Demographics of these 66 participants are provided in Table 2.

Table 2: Demographic characteristics categorized by treatment group

N = Number of participants.

patient group

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

Table 3. Overview of disease types and prior treatments used for registration

Partial 1A-PF-07220060 Single-dose escalation

The objective of Part 1A is to assess the safety and tolerability of PF-07220060 as a single agent in a sequentially escalating dose cohort of participants in any postmenopausal women and men with HR-positive HER2-negative or HR-positive HER2-positive advanced or metastatic bronchitis (whose disease has progressed after at least one standard of care treatment (i.e., 2L and beyond)) and 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 criteria). Patients with advanced or metastatic HR-positive bronchitis may receive additional endocrine therapy (letrozole or fulvestrant) after at least two cycles of PF-07220060 monotherapy under certain criteria.

In Part 1A, a single escalation dose of PF-07220060 is initiated on a continuous basis at a BID of 100 mg to determine the MTD and/or RP2D of PF-07220060 as monotherapy. Dosing continues in the sequential dose escalation group until the MTD/RP2D can be estimated.

In part 1A (five dose groups), thirty-four participants (n=34) were treated with a single dose of PF-07220060 at BID of 100 mg (n=3), 200 mg (n=8), 300 mg (n=10), 400 mg (n=9) and 500 mg (n=4).

Part 1B and Part 1C -PF-07220060 Dosage Exploration and Endocrine Therapy

The purpose of Part 1B and Part 1C is to determine the MTD/RP2D of PF-07220060 in combination with letrozole (Part 1B) or fulvestrant (Part 1C) in any postmenopausal woman and a man with HR-positive HER2-negative late or mBC, against a 2L+ background.

In Part 1B, participants received the approved dose of letrozole at a 2.5 mg QD, taken continuously with PF-07220060. In Part 1B (two dose groups), thirteen participants (n=13) were treated with 300 mg (n=6) and 400 mg (n=7) BID of PF-07220060 in combination with letrozole.

In Part 1C, participants received fulvestrant via two intramuscular (IM) injections (250 mg each) prior to oral administration of PF-07220060. Fulvestrant was administered in the field by a qualified healthcare professional on days 1 and 15 of Cycle 1, and on day 1 of each subsequent 28-day cycle (±1 to 5 days depending on the cycle number). In Part 1B (two dose groups), thirteen participants (n=13) were treated with a combination of 300 mg (n=6) and 400 mg (n=7) BID PF-07220060 with fulvestrant.

Partial 1D-PF-07220060 Food Effects

The purpose of Part 1D was to evaluate the effects of food on the pharmacokinetics (PK) of a single dose of PF-07220060 in participants.

Six participants (n=6) were treated with a single 400 mg BID of PF-07220060 in the morning under the "feeding condition" on Day 7 of Cycle 1 and under the "fasting condition" on Day 1 of Cycle 1. To assess the effect of food, plasma concentration-time data of PF-07220060 were compared between Day 7 of Cycle 1 and Day 1 of Cycle 1. Analysis of variance (ANOVA) models with treatments as fixed effects were used to analyze the AUC and _Cmax values of the natural logarithmic transformation. The mean difference (feeding-fasting) and its corresponding 90% CI were estimated from the model. The mean difference and its 90% CI were indexed to obtain the geometric mean ratio (feeding/fasting) and its 90% CI.

Partial list of 1E-midazolam drug interactions

The objective of Part 1E was to evaluate the pharmacokinetic (PK) effect of repeated administration of PF-07220060 as monotherapy MTD in participants with advanced solid tumors. In Part 1E, midazolam 2 mg was administered orally to participants alone on day (-1) of cycle 1 and together with PF-07220060 on day 15 of cycle 1. Only two doses of midazolam will be administered.

Part 2B and Part 2C -PF-07220060 Dosage Expansion and Endocrine Therapy

The purpose of Part 2B was to evaluate the tolerability, safety, and preliminary antitumor activity of PF-07220060 in combination with letrozole. Part 2B was a dose extension of PF-07220060 in combination with letrozole at the dose identified in Part 1B in participants with HR-positive/HER2-negative advanced/metastatic breast cancer who had not received any prior systemic anticancer therapy for their advanced disease. In Part 2B, participants received the approved dose of letrozole at a continuous 2.5 mg QD with PF-07220060.

The purpose of Part 2C was to evaluate the tolerability, safety, and preliminary antitumor activity of the combination of PF-07220060 and fulvestrant. Part 2C was a dose extension of the combination of PF-07220060 and fulvestrant at the dose identified in Part 1C in participants with HR-positive/HER2-negative advanced/metastatic breast cancer whose disease had progressed on prior therapy. Participants who had previously been treated with any agent that inhibited the PI3k-mTOR pathway, such as CDK4/6 inhibitors, fulvestrant, everolimus, or their MOA, were excluded. In Part 2C, participants received fulvestrant via two intramuscular injections (250 mg each) prior to oral administration of PF-07220060.

To achieve the optimal dosing regimen for the identified PF-07220060 in combination with letrozole or fulvestrant (e.g., different starting doses or different schedules), additional dosing regimens that have been identified as safe by BLRM in Parts 1B and 1C may be explored in Parts 2B and 2C.

Administration method :

PF-07220060

PF-07220060 should be administered orally on an empty stomach (except during the food effect assessment period on day -7 in part 1D) with at least 8 oz (240 mL) of water. During the entire study period with BID dosing, no food or fluids other than water should be consumed for 2 hours before and 1 hour after each dose. During the entire study period with QD dosing, no food or fluids other than water should be consumed for 2 hours before and 2 hours after each dose.

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

For part 1D only, PF-07220060 is administered on Day 7 of Cycle 1 and after a fast of at least 10 hours overnight on Day 1 of Cycle 1. On Day 7 of Cycle 1 (while eating), a test breakfast meal (described below) is provided and must be consumed within 30 minutes. PF-07220060 is administered with approximately 8 oz of water 30 minutes after the start of the meal. No additional food is permitted until at least 4 hours after administration. On Day 1 of Cycle 1, participants receive another single oral dose of PF-07220060 after a fast of at least 10 hours overnight. PF-07220060 is administered with 8 oz of water. No food is permitted for an additional 4 hours after administration. For any treatment day, free access to water is permitted except for 1 hour before and 1 hour after drug administration. Starting from day 1 of cycle 1, PF-07220060 is administered on an empty stomach with at least 8 oz of water. Food or liquids other than water are not permitted for 2 hours before and 2 hours after administration.

The test breakfast meal to be consumed was a high-fat (approximately 50% of the total calories) and high-calorie (approximately 800 to 1000 calories) meal. This test meal provided approximately 150, 250, and 500 to 600 calories from protein, carbohydrates, and fat, respectively.

Fulvestrant

Fulvestrant is available in two 5-mL clear neutral glass (Type 1) syringes, each containing 250 mg/5 mL of fulvestrant solution for intramuscular injection and fitted with an tamper-evident seal. The syringe is presented in a holder with a polystyrene plunger and a SafetyGlide™ needle for connection to the syringe.

The fulvestrant injection was performed prior to the administration of PF-07220060. On day 1 and day 15 of cycle 1, and on day 1 (±3) of each subsequent 28-day cycle, fulvestrant was administered intramuscularly in two slow 5 mL injections (1 to 2 minutes per injection) over the buttock area, according to the instructions for use provided on the label.

Part of participant 1C who received fulvestrant as part of their last prior therapy only needed to dosing on day 1 of cycle 1 (i.e., day 15 was not required). Day 1 of cycle 1 was approximately 28 days after the last dose of fulvestrant.

Letrozole

Letrozole is available in 2.5 mg tablet form.

Letrozole is administered orally once daily (2.5 mg QD) together with PF-07220060. Letrozole does not need to be administered concurrently with PF-07220060.

Midazolam

Midazolam is a benzodiazepine used clinically for conscious sedation. It is specifically metabolized by CYP3A and widely used as an in vivo probe of CYP3A activity. This study uses an oral formulation of midazolam to evaluate its effects on CYP3A activity in the GI tract and liver. The information obtained will be used to determine whether any limitations or dosage adjustments to concomitant medications are appropriate in future studies.

Participants should avoid food and fluids other than water for 2 hours before and 1 hour after administration of midazolam. On Day-1 and Day 15 of Cycle 1, a 2 mg dose of midazolam was administered orally to participants with 8 oz (240 mL) of water for DDI assessment. Only two doses of midazolam were administered.

I. Pharmacokinetic (pk) Studies

In the ongoing Phase 1/1b study, as of August 30, 2022, preliminary pharmacokinetic (PK) data for PF-07220060 as monotherapy (part 1A) and in combination with endocrine therapy (parts 1B and 1C) were obtained from 60 participants with advanced solid tumors. PF-07220060 was administered orally as a monotherapy at doses ranging from 100 to 500 mg BID, and in combination with letrozole or fulvestrant at doses ranging from 300 to 400 mg BID. Available plasma concentration-time data for PF-07220060 were analyzed using non-compartmental methods.

Preliminary non-compartmental PK analysis was performed based on available samples collected from participants in the study. Figure 1 shows the plasma concentration-time profile of PF-07220060 on day 1 after oral BID administration. Figure 2 shows the plasma concentration-time profile of PF-07220060 on day 15 after oral BID administration. Table 4 provides an overview of the PK parameters of PF-07220060 as monotherapy and in combination with letrozole or fulvestrant.

Table 4: Preliminary plasma pharmacokinetic parameters of PF-07220060 after administration as monotherapy and in combination with letrozole or fulvestrant at a BID oral dose.

^a n=1; ^b n=2

Abbreviations: CV = Coefficient of variation; N = Number of participants in the treatment group whose PK parameters could be assessed; ND = Not measured; n = Number of participants whose AUC _tau , R _ac , t _1/2 , CL/F were measured; PK = Pharmacokinetics; SD = Standard deviation.

Note: Except for _Tmax being the median (min-max) and T1 _/2 and R _ac being the arithmetic mean (SD), all parameters are geometric means (geometric %CV); when the number of individuals with available parameters is <3, SD and %CV are not reported; ND = not determined.

Preliminary pharmacokinetic (PK) results showed that PF-07220060 was rapidly absorbed after oral administration, with a median _Tmax of 1 to 4 hours. For Day 1 and Day 15 of Cycle 1, exposure parameters (including _Cmax , AUC, and _Cmin ) of PF-07220060 generally increased with doses from 100 to 300 mg BID. No further increase in exposure parameters was observed at doses above 300 mg BID. Moderate accumulation of AUC was observed after repeated BID administration. Generally, PF-07220060 exhibited moderate inter-individual variability in exposure parameters. The pharmacokinetic profiles of PF-07220060 were generally comparable as monotherapy and in combination with letrozole or fulvestrant.

II. Safety

Dose-limiting toxicities (DLT)

As of September 2, 2022, among 55 evaluable participants, 4 (7.3%) experienced DLT. In the single-dose 500 mg BID PF-07220060 group, two participants experienced DLT with grade 3 thrombocytopenia. In the single-dose 200 mg BID PF-07220060 group, one participant experienced DLT with grade 3 neutropenia, and in the 400 mg BID PF-07220060 + fulvestrant combination group, one participant experienced DLT with grade 3 neutropenia ≥5 days.

Adverse events

Adverse events in patients who received PF-07220060 in the Phase 1/1b clinical trial were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. The following adverse event data were obtained as of September 2, 2022.

Treatment-induced adverse events (TEAEs) caused by whole-cause therapy

Of the 66 participants who received PF-07220060 in Parts 1A, 1B, 1C, and 1D, 59 (89.4%) reported a total of 375 whole-cause TEAEs.

In Part 1A (single-dose PF-07220060), 32 out of 34 participants (94.1%) reported all-cause TEAEs. The most frequently reported (≥20%) all-cause TEAEs across all dose levels were neutropenia (41.2%), anemia, diarrhea, leukopenia (35.3% each), nausea (29.4%), increased aspartate aminotransferase (AST), and vomiting (20.6% each). A total of 15 grade 3 or higher all-cause TEAEs were reported across all dose levels. The most frequently reported (≥5%) grade 3 or higher all-cause TEAEs were neutropenia (14.7%), anemia, increased AST, COVID-19, diarrhea, leukopenia, thrombocytopenia, and syncope (5.9% each). No grade 4 TEAEs were reported. One participant in the 400mg BID group experienced a grade 5 all-cause TEAE (respiratory failure; not related to the study drug PF-07220060).

In Part 1B (PF-07220060 in combination with letrozole), 10 out of 13 participants (76.9%) reported all-cause TEAEs. The most frequently reported (≥20%) all-cause TEAEs were diarrhea (38.5%), fatigue (30.8%), nausea, neutropenia, and sinusitis (23.1% each). At all dose levels, one participant (7.7%) reported a Grade 3 all-cause TEAE, including anemia, leukopenia, and neutropenia (7.7% each). No Grade 4 or 5 all-cause TEAEs were reported.

In part 1C (PF-07220060 in combination with fulvestrant), 13 out of 13 (100%) participants experienced at least one all-cause TEAE. The most frequently reported (≥20%) all-cause TEAEs were neutropenia (53.8%), diarrhea, leukopenia, and nausea (46.2% each), thrombocytopenia and hyperglycemia (30.8% each), and anemia, fatigue, and vomiting (23.1% each). A total of seven grade 3 all-cause TEAEs were reported across all dose levels, including neutropenia (23.1%), leukopenia (15.4%), and anemia, nausea, and biliary tract infection (7.7% each). No grade 4 or 5 TEAEs were reported.

In the 1D portion (single-dose PF-07220060, 400 mg BID food group), 4 out of 6 participants (66.7%) reported TEAEs. The most frequently reported (≥20%) all-cause TEAEs were diarrhea, leukopenia, and neutropenia (50.0% each). No grade 3 or 5 TEAEs were reported. One participant reported a grade 4 all-cause TEAE (respiratory failure).

Treatment-related adverse events

Of the 66 participants who received a single-dose formulation of PF-07220060 in a dose-escalation regimen, 54 (81.8%) reported any treatment-related TEAEs. Overall, the most frequently 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-drug PF-07220060), 27 out of 34 participants (79.4%) experienced at least one treatment-related TEAE.

The most frequently reported (≥10%) treatment-related TEAEs across all dose levels were neutropenia (41.2%), anemia 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 participants (26.5%) had grade 3 treatment-related TEAEs. The most frequently reported (≥5%) grade 3 treatment-related TEAEs were neutropenia (14.7%), anemia, diarrhea, leukopenia, and thrombocytopenia (5.9% each). No grade 4 or 5 treatment-related TEAEs were reported.

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

In part 1C (PF-07220060 in combination with fulvestrant), all 13 participants (100%) experienced at least one treatment-related TEAE. The most frequently reported (≥20%) treatment-related TEAEs 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 participants (46.2%) had a grade 3 treatment-related TEAE. The 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 TEAEs were reported.

In the partial 1D (single-dose PF-07220060, 400 mg BID food group) regimen, a total of 4 out of 6 participants (66.7%) reported treatment-related TEAEs. The most frequently reported (≥20%) treatment-related TEAEs were diarrhea, leukopenia, and neutropenia (50.0% each). No grade 3, 4, or 5 treatment-related TEAEs were reported.

Security Summary:

The available safety results support the ongoing clinical development of PF-07220060 for the treatment of HR+, HER2- advanced or mBC and other tumors that potentially grow in a CDK4-dependent manner, including NSCLC adenocarcinoma, prostate cancer, CRC, liposarcoma, and tumors that have previously confirmed CDK4 or CCND1 amplification according to local standards.

III. Efficacy

Efficacy data were obtained from 70 evaluable patients. As of October 15, 2022, PF-06873600 demonstrated a disease control rate of 65.7% (n = 65.7/100) in all evaluable patients across all cohorts. This included one participant with a confirmed complete response and six participants with a confirmed partial response. Among evaluable patients assessed according to RECIST version 1.1 (Table 5), the disease control rate was 57.9% (n = 22/38) in the single-agent PF-07220060 group (total part 1A) and 80.8% (n = 21/26) in the combination cohort PF-07220060 + endocrine therapy (part 1B + part 1C).

Table 5: Optimal Overall Response

n = number of participants

PF-07220060 shows early indications of antitumor activity in combination with endocrine therapy in a HR+/Her2- metastatic breast cancer patient population. Efficacy evaluation is underway in a dose-expansion group under RDE in combination with fulvestrant and letrozole.

Claims (22)

1. A method of treating cancer, comprising orally administering to an individual in need a therapeutically effective amount of PF-07220060 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is about 100 mg to about 500 mg, twice daily (BID). 2. The method of claim 1, wherein the therapeutically effective dose is about 300 mg to about 500 mg BID. 3. The method of claim 1 or 2, wherein the therapeutically effective dose is about 300 mg BID. 4. The method of claim 1 or 2, wherein the therapeutically effective dose is about 400 mg 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 tablet or capsule form. 7. A method of treating cancer, comprising administering to an individual in need 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 about 100 mg to about 500 mg BID. 8. The method of claim 7, wherein the endocrine therapeutic agent is an aromatase inhibitor, an androgen receptor inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM). 9. The method of claim 7, wherein the endocrine therapy agent is selected from: letrozole, anastrozole, exemestane, fulvestrant, ellastrant, icrestriate, giretrestriate, RG6171, carmistren, AZD9496, reitressen, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549, tamoxifen, raloxifene, toremifene, lasoxifene, bardoxifene, and afoxifene. 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 PF-07220060 is subsequently administered. 12. The method of claim 1 or 7, wherein the individual has previously been treated with chemotherapy, radiation therapy and/or surgical resection. 13. The method of claim 1 or 7, wherein the individual has previously been treated with a CDK4/6 inhibitor. 14. The method of claim 1 or 7, wherein the individual has previously been treated with an endocrine therapy agent. 15. The method of claim 1 or 13, wherein the individual is a mammal. 16. The method of any one of claims 1 to 15, wherein the individual 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, stomach 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 the following: hormone receptor positive (HR+), hormone receptor negative (HR-), human epidermal growth factor receptor 2 negative (HER2-), human epidermal growth factor receptor 2 positive (HER2+), HR+/HER2-, ER-/HR+, ER+/HER2- and triple-negative breast cancer (TNBC). 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 CCND1. 19. Use of PF-07220060 in the preparation of a medicament for treating cancer in an individual who requires it, wherein the medicament is administered in a therapeutically effective unit dose of PF-07220060 in an amount of about 100 mg to about 500 mg BID. 20. Use of PF-07220060 and endocrine therapeutic agents in the preparation of a medicament for treating cancer in an individual who requires it, wherein the medicament is administered in a therapeutically effective unit dose of PF-07220060 in an amount of about 100 mg to about 500 mg BID. 21. A medicine comprising a therapeutically effective amount of PF-07220060, used to treat cancer in an individual who requires it, wherein the therapeutically effective amount is about 100 mg to about 500 mg BID. 22. A medicine comprising a therapeutically effective amount of PF-07220060 and an endocrine therapy agent, for the treatment of cancer in an individual in need of it, wherein the therapeutically effective amount is about 100 mg to about 500 mg BID.