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

Sponsor

Pfizer (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05905341

Collaborator

(none)

110

Enrollment

Arms

50.9

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer Ovarian Cancer Liposarcoma Non-small Cell Lung Cancer (NSCLC) Endometrial Solid Tumors	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	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

110 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jul 17, 2023

Anticipated Primary Completion Date :

Oct 14, 2025

Anticipated Study Completion Date :

Oct 14, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1 Dose Escalation-Dose Level 1 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 Small molecule cell cycle checkpoint inhibitor that targets CDK 2, 4, and 6, to be administered orally. Combination Product: Fulvestrant Competitive ER antagonist, to be administered by intramuscular injection (prefilled syringe).
Experimental: Part 1 Dose Escalation-Dose Level 2 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 Small molecule cell cycle checkpoint inhibitor that targets CDK 2, 4, and 6, to be administered orally. Combination Product: Fulvestrant Competitive ER antagonist, to be administered by intramuscular injection (prefilled syringe).
Experimental: Part 1 Dose Escalation-Dose Level 3 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 Small molecule cell cycle checkpoint inhibitor that targets CDK 2, 4, and 6, to be administered orally. Combination Product: Fulvestrant Competitive ER antagonist, to be administered by intramuscular injection (prefilled syringe).
Experimental: Part 1 Dose Escalation-Dose Level 4 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 Small molecule cell cycle checkpoint inhibitor that targets CDK 2, 4, and 6, to be administered orally. Combination Product: Fulvestrant Competitive ER antagonist, to be administered by intramuscular injection (prefilled syringe).
Experimental: Part 1 Dose Escalation-Dose Level 5 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 Small molecule cell cycle checkpoint inhibitor that targets CDK 2, 4, and 6, to be administered orally. Combination Product: Fulvestrant Competitive ER antagonist, to be administered by intramuscular injection (prefilled syringe).
Experimental: Part 2 - Arm A 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 Small molecule cell cycle checkpoint inhibitor that targets CDK 2, 4, and 6, to be administered orally. Combination Product: Fulvestrant Competitive ER antagonist, to be administered by intramuscular injection (prefilled syringe).
Experimental: Part 2 - Arm B 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 Small molecule cell cycle checkpoint inhibitor that targets CDK 2, 4, and 6, to be administered orally. Combination Product: Fulvestrant Competitive ER antagonist, to be administered by intramuscular injection (prefilled syringe).

Outcome Measures

Primary Outcome Measures

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

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 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: Duration of Response (DoR) of PF-07224826 alone or in combination with fulvestrant [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: Progression-Free Survival (PFS) of PF-07224826 alone or in combination with fulvestrant [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: Time to Response (TTR) of PF-07224826 alone or in combination with fulvestrant [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 2: Overall Survival (OS) of PF-07224826 with fulvestrant [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 2: Clinical benefit response (CBR) of PF-07224826 with fulvestrant [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.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.