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

• ClinicalTrials.gov Identifier: NCT05905341
• Recruitment Status: Withdrawn
• First Posted: June 15, 2023
• Last Update Posted: November 8, 2023
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

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	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 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
• Estimated Study Start Date: January 15, 2024
• Estimated Primary Completion Date: April 14, 2026
• Estimated Study Completion Date: April 13, 2028

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 :

1. Part 1: First cycle dose limiting toxicities (DLTs) [ Time Frame: Cycle 1 (28 days) ]
2. 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. [ Time Frame: From the first dose to earliest of 28 days post last dosing date or day of new anticancer therapy -1 day. ]
3. Part 1 and Part 2: Number of participants with Clinical Laboratory abnormalities [ Time Frame: From the first dose to earliest of 28 days post last dosing date or day of new anticancer therapy -1 day. ]
4. Part 1 and Part 2: Incidence of clinically significant abnormal vital signs. [ Time Frame: From the first dose to earliest of 28 days post last dosing date or day of new anticancer therapy -1 day. ]
5. Part 2: Preliminary antitumor activity measure for efficacy includes ORR, as assessed using RECIST version 1.1. [ Time Frame: 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. ]
6. Part 1 and Part 2: Incidence of clinically significant abnormal ECGs. [ Time Frame: From the first dose to earliest of 28 days post last dosing date or day of new anticancer therapy -1 day. ]

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT05905341
• Other Study ID Numbers: C5331001
• First Posted: June 15, 2023
• Last Update Posted: November 8, 2023
• Last Verified: November 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pfizer:

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-)

Additional relevant MeSH terms:

Breast Neoplasms; Liposarcoma; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Neoplasms, Adipose Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Sarcoma; Fulvestrant; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Estrogen Receptor Antagonists; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs