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
Trial Snapshot
- Phase
- Phase 1
- Status
- Withdrawn
- Sponsor
- Pfizer
- Primary Endpoint
- Part 1: First cycle dose limiting toxicities (DLTs)
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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
- •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.
Arms & Interventions
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.
Intervention: PF-07224826 (Drug)
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.
Intervention: Fulvestrant (Combination Product)
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.
Intervention: PF-07224826 (Drug)
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.
Intervention: Fulvestrant (Combination Product)
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.
Intervention: PF-07224826 (Drug)
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.
Intervention: Fulvestrant (Combination Product)
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.
Intervention: PF-07224826 (Drug)
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.
Intervention: Fulvestrant (Combination Product)
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.
Intervention: PF-07224826 (Drug)
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.
Intervention: Fulvestrant (Combination Product)
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.
Intervention: PF-07224826 (Drug)
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.
Intervention: Fulvestrant (Combination Product)
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.
Intervention: PF-07224826 (Drug)
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.
Intervention: Fulvestrant (Combination Product)
Outcomes
Primary Outcomes
Part 1: First cycle dose limiting toxicities (DLTs)
Time Frame: 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.
Time Frame: 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
Time Frame: 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.
Time Frame: 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.
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.
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 Outcomes
- 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: 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 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: 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 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: 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: 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)