Study of PF-07224826, as a Single Agent or in Combination With Endocrine Therapy in Participants With Breast Cancer and Other Advanced Solid Tumors.

Study Overview
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Brief Summary
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This is a Phase 1, open-label, multicenter, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of PF-07224826, as a single agent or in combination with endocrine therapy in participants with advanced solid tumors. This study will be divided into dose escalation/finding (Part 1) and dose expansion (Part 2). In Part 1, participants with locally recurrent/advanced or metastatic Triple Negative Breast Cancer (TNBC), platinum resistant ovarian cancer and other advanced solid tumors will receive PF-07224826 as a single agent. Participants with HR-positive HER2-negative advanced or mBC will receive PF-07224826 in combination with endocrine therapy. In Part 2 (Arm A), PF-07224826 will be evaluated in combination with fulvestrant in HR-positive HER2-negative advanced or mBC participants who have received prior CDK4/6 inhibitor. In Part 2 (Arm B), PF-07224826 will be evaluated in combination with fulvestrant in HR-positive HER2-negative locally advanced or mBC participants whose disease has progressed on prior endocrine therapy and is naïve to CDK4/6 inhibitors.

Official Title
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A PHASE 1, OPEN-LABEL, MULTICENTER, DOSE ESCALATION AND DOSE EXPANSION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND ANTITUMOR ACTIVITY OF PF-07224826, AS A SINGLE AGENT AND IN COMBINATION WITH ENDOCRINE THERAPY IN PARTICIPANTS WITH ADVANCED SOLID TUMORS

Conditions
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Ovarian Cancer, Breast Cancer, Liposarcoma, Non-small Cell Lung Cancer (NSCLC), Endometrial, Solid Tumors

Intervention / Treatment
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* Drug: PF-07224826
* Combination Product: Fulvestrant
* Drug: PF-07224826
* Combination Product: Fulvestrant
* Drug: PF-07224826
* Combination Product: Fulvestrant
* Drug: PF-07224826
* Combination Product: Fulvestrant
* Drug: PF-07224826
* Combination Product: Fulvestrant
* Drug: PF-07224826
* Combination Product: Fulvestrant
* Drug: PF-07224826
* Combination Product: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1: Participants with HR-positive HER2-negative locally advanced or metastatic breast cancer. Participants with locally recurrent/advanced or metastatic TNBC. Participants with advanced platinum resistant epithelial ovarian cancer (EOC)/fallopian tube cancer/primary peritoneal cancer (PPC). Other advanced solid tumor types: Tumors other than BC or Ovarian: NSCLC, prostate, endometrial, liposarcoma, or other tumors with cyclin D (CCND) and cyclin E (CCNE) implicated in pathogenesis either by gene amplification or overexpression. Part 2 (Arm A): Participants with HR positive HER2 negative locally advanced or mBC (post CDK4/6 inhibitors). Part 2 (Arm B): Participants with HR positive HER2 negative locally advanced or mBC (naïve to CDK4/6 inhibitors). Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. Adequate Bone Marrow Function Exclusion Criteria: Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, Cerebral edema, and/or progressive growth. Participants with a history of CNS metastases or cord compression are eligible if they have been definitively treated (eg, radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before enrollment and have no evidence of progression at time of study enrollment. Participants with advanced/metastatic, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term (eg, including participants with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement). Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ. Last anticancer treatment within 2 weeks (or 5 half-lives, whichever is shorter), unless the last immediate anticancer treatment contained an antibody-based agent(s) (approved or investigational), then the interval of 4 weeks or 5 half-lives (whichever is shorter) is required prior to receiving the study intervention.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Dose Escalation-Dose Level 1<br>In Part 1, participants with locally recurrent/advanced or metastatic TNBC, platinum resistant ovarian cancer and other advanced solid tumors will receive PF-07224826 as a single agent. Participants with HR-positive HER2-negative advanced or mBC will receive PF-07224826 in combination with endocrine therapy. PF-07224826 will be administered orally, once daily, on a continuous basis. | Drug: PF-07224826<br>* Small molecule cell cycle checkpoint inhibitor that targets CDK 2, 4, and 6, to be administered orally.<br>Combination Product: Fulvestrant<br>* Competitive ER antagonist, to be administered by intramuscular injection (prefilled syringe).<br>|
| Experimental: Part 1 Dose Escalation-Dose Level 2<br>In Part 1, participants with locally recurrent/advanced or metastatic TNBC, platinum resistant ovarian cancer and other advanced solid tumors will receive PF-07224826 as a single agent. Participants with HR-positive HER2-negative advanced or mBC will receive PF-07224826 in combination with endocrine therapy. PF-07224826 will be administered orally, once daily, on a continuous basis. | Drug: PF-07224826<br>* Small molecule cell cycle checkpoint inhibitor that targets CDK 2, 4, and 6, to be administered orally.<br>Combination Product: Fulvestrant<br>* Competitive ER antagonist, to be administered by intramuscular injection (prefilled syringe).<br>|
| Experimental: Part 1 Dose Escalation-Dose Level 3<br>In Part 1, participants with locally recurrent/advanced or metastatic TNBC, platinum resistant ovarian cancer and other advanced solid tumors will receive PF-07224826 as a single agent. Participants with HR-positive HER2-negative advanced or mBC will receive PF-07224826 in combination with endocrine therapy. PF-07224826 will be administered orally, once daily, on a continuous basis. | Drug: PF-07224826<br>* Small molecule cell cycle checkpoint inhibitor that targets CDK 2, 4, and 6, to be administered orally.<br>Combination Product: Fulvestrant<br>* Competitive ER antagonist, to be administered by intramuscular injection (prefilled syringe).<br>|
| Experimental: Part 1 Dose Escalation-Dose Level 4<br>In Part 1, participants with locally recurrent/advanced or metastatic TNBC, platinum resistant ovarian cancer and other advanced solid tumors will receive PF-07224826 as a single agent. Participants with HR-positive HER2-negative advanced or mBC will receive PF-07224826 in combination with endocrine therapy. PF-07224826 will be administered orally, once daily, on a continuous basis. | Drug: PF-07224826<br>* Small molecule cell cycle checkpoint inhibitor that targets CDK 2, 4, and 6, to be administered orally.<br>Combination Product: Fulvestrant<br>* Competitive ER antagonist, to be administered by intramuscular injection (prefilled syringe).<br>|
| Experimental: Part 1 Dose Escalation-Dose Level 5<br>In Part 1, participants with locally recurrent/advanced or metastatic TNBC, platinum resistant ovarian cancer and other advanced solid tumors will receive PF-07224826 as a single agent. Participants with HR-positive HER2-negative advanced or mBC will receive PF-07224826 in combination with endocrine therapy. PF-07224826 will be administered orally, once daily, on a continuous basis. | Drug: PF-07224826<br>* Small molecule cell cycle checkpoint inhibitor that targets CDK 2, 4, and 6, to be administered orally.<br>Combination Product: Fulvestrant<br>* Competitive ER antagonist, to be administered by intramuscular injection (prefilled syringe).<br>|
| Experimental: Part 2 - Arm A<br>In Part 2 Arm A, PF-07224826 will be evaluated in combination with fulvestrant in HR positive HER2 negative advanced or mBC participants who have received prior CDK4/6 inhibitor. PF-07224826 will be administered orally, once daily, on a continuous basis. | Drug: PF-07224826<br>* Small molecule cell cycle checkpoint inhibitor that targets CDK 2, 4, and 6, to be administered orally.<br>Combination Product: Fulvestrant<br>* Competitive ER antagonist, to be administered by intramuscular injection (prefilled syringe).<br>|
| Experimental: Part 2 - Arm B<br>In Part 2 Arm B, PF-07224826 will be evaluated in combination with fulvestrant in HR-positive HER2-negative locally advanced or mBC participants whose disease has progressed on prior endocrine therapy and is naïve to CDK4/6 inhibitors. PF-07224826 will be administered orally, once daily, on a continuous basis. | Drug: PF-07224826<br>* Small molecule cell cycle checkpoint inhibitor that targets CDK 2, 4, and 6, to be administered orally.<br>Combination Product: Fulvestrant<br>* Competitive ER antagonist, to be administered by intramuscular injection (prefilled syringe).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: First cycle dose limiting toxicities (DLTs) |  | Cycle 1 (28 days) | 
| Part 1 and Part 2: Adverse events (AEs) as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 5.0), timing, seriousness and relationship to study therapy. |  | From the first dose to earliest of 28 days post last dosing date or day of new anticancer therapy -1 day. | 
| Part 1 and Part 2: Number of participants with Clinical Laboratory abnormalities |  | From the first dose to earliest of 28 days post last dosing date or day of new anticancer therapy -1 day. | 
| Part 1 and Part 2: Incidence of clinically significant abnormal vital signs. |  | From the first dose to earliest of 28 days post last dosing date or day of new anticancer therapy -1 day. | 
| Part 2: Preliminary antitumor activity measure for efficacy includes ORR, as assessed using RECIST version 1.1. |  | From baseline until the date of first documented progression, or date of death of any cause, or date of withdrawal of consent, or date of lost to follow-up, whichever came first. | 
| Part 1 and Part 2: Incidence of clinically significant abnormal ECGs. |  | From the first dose to earliest of 28 days post last dosing date or day of new anticancer therapy -1 day. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part1 and Part 2: Maximum Observed Plasma Concentration (Cmax); Single Dose (SD) |  | Cycle 1 (Pre-dose, Day 1, 8, and 15) and Cycle 2 (Day 1). Each cycle is 28 days. | 
| Part 1 and Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax); Single Dose (SD) |  | Cycle 1 (Pre-dose, Day 1, 8, and 15) and Cycle 2 (Day 1). Each cycle is 28 days. | 
| Part 1: Area under the concentration-time curve from 0 to time of last measurable concentration (AUClast) |  | Cycle 1 (Pre-dose, Day 1, 8, and 15) and Cycle 2 (Day 1). Each cycle is 28 days. | 
| Part 1 and Part 2: Maximum Observed Plasma concentration (Cmax,ss), steady state |  | Cycle 1 (Pre-dose, Day 1, 8, and 15) and Cycle 2 (Day 1). Each cycle is 28 days. | 
| Part 1 and Part 2: Time to Reach Maximum Observed Plasma Concentration steady state (Tmax, ss) |  | Cycle 1 (Pre-dose, Day 1, 8, and 15) and Cycle 2 (Day 1). Each cycle is 28 days. | 
| Part 1 and Part 2: Minimum Observed Plasma Concentration (Cmin, ss), steady state |  | Cycle 1 (Pre-dose, Day 1, 8, and 15) and Cycle 2 (Day 1). Each cycle is 28 days. | 
| Part 1: Area Under the concentration-time curve from 0 to time the end of the dosing interval (AUCtau,ss), steady state |  | Cycle 1 (Pre-dose, Day 1, 8, and 15) and Cycle 2 (Day 1). Each cycle is 28 days. | 
| Part 2: Accumulation ratio (Rac) |  | Cycle 1 (Pre-dose, Day 1, 8, and 15) and Cycle 2 (Day 1). Each cycle is 28 days. | 
| Part 1: Objective Response, as assessed using RECIST version 1.1. |  | From baseline and up to approximately 24 months | 
| Part 1 and Part 2: Duration of Response (DoR) of PF-07224826 alone or in combination with fulvestrant |  | From baseline and up to approximately 24 months | 
| Part 1 and Part 2: Progression-Free Survival (PFS) of PF-07224826 alone or in combination with fulvestrant |  | From baseline and up to approximately 24 months | 
| Part 1 and Part 2: Time to Response (TTR) of PF-07224826 alone or in combination with fulvestrant |  | From baseline and up to approximately 24 months | 
| Part 2: Overall Survival (OS) of PF-07224826 with fulvestrant |  | From baseline and up to approximately 24 months | 
| Part 2: Clinical benefit response (CBR) of PF-07224826 with fulvestrant |  | From baseline and up to approximately 24 months | 
| Part 1 and Part 2: Expression of Pharmacodynamic (PD) biomarkers in tumor tissue |  | From baseline and up to approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), cyclin-dependent kinase 6 (CDK6), hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-)