A Study to Learn About the Study Medicine (Called PF-07220060 in Combination With PF-07104091) In Participants With Breast Cancer and Solid Tumors

Study Overview
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Brief Summary
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The purpose of this clinical trial is to learn about the safety and effects of the study medicine (called PF-07220060 and PF-07104091) in people with breast cancer. This clinical study consists of 2 parts (part 1 and part 2). In part 1, we are seeking participants who: Have been diagnosed with Breast Cancer (BC) of either types: Have HR+, HER2- BC Refractory HR-positive/HER2-positive BC Have other solid tumors other than BC In part 2, we are seeking participants who: -Have HR-positive/HER2-negative BC Part 1 will include increasing doses of PF-07220060 with PF-07104091. In part 2, participants will take 1 of 2 study medicine combinations. This will help us decide the highest amount of study medicines that can be safety given to people. All participants in this study will receive PF-07220060 with PF-07104091 by mouth. We will compare participant experiences to help us determine if PF-07220060 with PF-07104091 is safe and effective. Participants will take part in this study for about 2 years. During this time, they will receive the study medicine, an x-ray imaging, and will be observed for safety and effects of the study medicines.

Official Title
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A PHASE 1B/2, OPEN-LABEL, MULTICENTER, DOSE ESCALATION AND DOSE EXPANSION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND ANTITUMOR ACTIVITY OF PF-07220060 IN COMBINATION WITH PF-07104091 PLUS ENDOCRINE THERAPY IN PARTICIPANTS WITH ADVANCED SOLID TUMORS

Conditions
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Breast Cancer, Solid Tumors

Intervention / Treatment
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* Drug: PF-07220060 + PF-07104091 combination dose escalation
* Drug: PF-07220060 + PF-07104091 combination dose escalation
* Drug: PF-07220060 + PF-07104091 combination dose escalation
* Drug: PF-07220060 + PF-07104091 combination dose escalation
* Drug: PF-07220060 + PF-07104091 combination dose escalation
* Drug: PF-07104091 + PF-07220060 + fulvestrant dose expansion
* Drug: PF-07104091 + PF-07220060 + fulvestrant dose expansion
* Drug: PF-07104091 + PF-07220060 + letrozole dose expansion
* Drug: PF-07220060 + PF-07104091 combination dose escalation
* Drug: PF-07220060 + PF-07104091 combination dose escalation
* Drug: PF-07220060 + PF-07104091 combination dose escalation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Part 1: Breast Cancer (BC) HR+, HER2- BC Refractory HR-positive/HER2-positive BC Part 1: Solid Tumors other than BC Part 2: HR-positive/HER2-negative BC Lesion: Part 1: evaluable lesion (including skin or bone lesion only) Part 2: measurable lesion per RECIST v1.1 Prior systemic Treatment Part 1: HR-positive/HER2-negative BC At least 1 line of SOC, including CDK4/6 inhibitor therapy and Endocrine Therapy, for advanced or metastatic disease. Prior chemotherapy in the metastatic setting is allowed. Part 1: HR-positive/HER2-positive BC At least 1 prior treatment of approved HER2 targeting therapy. Part 1: Solid Tumors other than BC Participants with no standard therapy available or for which no local regulatory approved standard therapy is available that would confer significant clinical benefit in the medical judgement of the investigator. Part 2A: At least 1 prior systemic therapy for advanced or metastatic disease, including CDK4/6 inhibitor treatment and ET. Parts 2B: At least 1 prior endocrine therapy for advanced or metastatic disease. Progression during treatment or within 12 months of completion of adjuvant endocrine therapy is acceptable. Part 2B: Up to 1 prior line of chemotherapy for advanced/metastatic disease is allowed. General Inclusion Criteria Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 Adequate renal, liver, and bone marrow function Resolved acute effects of any prior therapy to baseline severity Exclusion Criteria: All Study Parts: Permanent treatment discontinuation from prior CDK 4 and/or CDK2 inhibitor due to treatment related toxicity. Part 2B and 1C: Prior treatment with any CDK 4/6 inhibitor, or SERDs (e.g. fulvestrant), or everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway for advanced disease. Parts 2B and 2C: Prior treatment with any CDK4/6 inhibitor for advanced disease. Parts 2B and 2C: Prior treatment with an investigational endocrine therapy for advanced disease. Part 2C: Prior neoadjuvant or adjuvant treatment with a nonsteroidal aromatase inhibitor AI (ie, anastrozole or letrozole) with disease recurrence while on or within 12 months of completing treatment. Part 2C: Any prior systemic treatment for advanced disease. Prior irradiation to >25% of the bone marrow Current use of drugs which have a risk for QTc prolongation Current use or anticipated need for food or drugs that are known strong CYP3A4/5, strong UGT2B7 or UGT1A9 inhibitors or inducers Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry Participants with 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 of the cervix, Bowen's disease Major surgery within 4 weeks prior to study entry Radiation therapy within 4 weeks prior to study entry. Clinically important hypertension Known or suspected hypersensitivity to PF-07220060, PF-07104091, letrozole, fulvestrant, or goserelin (or equivalent to induce chemical menopause if applicable) Known abnormalities in coagulation. Anticoagulation with subcutaneous heparin or prophylactic doses of anticoagulant are allowed Known active uncontrolled or symptomatic central nervous system (CNS) metastases Active inflammatory GI disease Current use or anticipated need for Proton Pump Inhibitors (PPI) within 14 days prior to first dose of the study intervention Previous high-dose chemotherapy requiring stem cell rescue Participants with active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), and known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness Other protocol specific exclusion criteria may apply

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>PF-07220060 + PF-07104091 dose escalation (Breast Cancer or solid tumors) | Drug: PF-07220060 + PF-07104091 combination dose escalation<br>* PF-07104091 and PF-07220060 will be administered orally<br>|
| Experimental: Part 1 Dose Escalation - Dose Level 2<br>PF-07220060 + PF-07104091 dose escalation (Breast Cancer or solid tumors) | Drug: PF-07220060 + PF-07104091 combination dose escalation<br>* PF-07104091 and PF-07220060 will be administered orally<br>|
| Experimental: Part 1 Dose Escalation - Dose Level 3<br>PF-07220060 + PF-07104091 dose escalation (Breast Cancer or solid tumors) | Drug: PF-07220060 + PF-07104091 combination dose escalation<br>* PF-07104091 and PF-07220060 will be administered orally<br>|
| Experimental: Part 1 Dose Escalation - Dose Level 4<br>PF-07220060 + PF-07104091 dose escalation (Breast Cancer or solid tumors) | Drug: PF-07220060 + PF-07104091 combination dose escalation<br>* PF-07104091 and PF-07220060 will be administered orally<br>|
| Experimental: Part 1 Dose Escalation - Dose Level 5<br>PF-07220060 + PF-07104091 dose escalation (Breast Cancer or solid tumors) | Drug: PF-07220060 + PF-07104091 combination dose escalation<br>* PF-07104091 and PF-07220060 will be administered orally<br>|
| Experimental: Part 2A<br>PF-07220060 + PF-07104091 + Fulvestrant (ER+/HER2- Breast Cancer with at least 1 prior systemic therapy for advanced or metastatic disease, including CDK4/6 inhibitor treatment and Endocrine Therapy) | Drug: PF-07104091 + PF-07220060 + fulvestrant dose expansion<br>* PF-07104091 and PF-07220060 will be administered orally in combination with fulvestrant<br>|
| Experimental: Part 2B<br>PF-07220060 + PF-07104091 + Fulvestrant (ER+/HER2- Breast Cancer with at least 1 prior endocrine therapy and up to 1 prior line of chemotherapy for advanced or metastatic disease and no prior treatment with any CDK4/6 inhibitor for advanced disease) | Drug: PF-07104091 + PF-07220060 + fulvestrant dose expansion<br>* PF-07104091 and PF-07220060 will be administered orally in combination with fulvestrant<br>|
| Experimental: Part 2C<br>PF-07220060 + PF-07104091 + Letrozole (ER+/HER2- Breast Cancer with no prior treatment with any CDK4/6 inhibitor for advanced disease) | Drug: PF-07104091 + PF-07220060 + letrozole dose expansion<br>* PF-07104091 and PF-07220060 will be administered orally in combination with letrozole<br>|
| Experimental: Part 1 Dose Escalation - Dose Level 6<br>PF-07220060 + PF-07104091 dose escalation (Breast Cancer or solid tumors) | Drug: PF-07220060 + PF-07104091 combination dose escalation<br>* PF-07104091 and PF-07220060 will be administered orally<br>|
| Experimental: Part 1 Dose Escalation - Dose Level 7<br>PF-07220060 + PF-07104091 dose escalation (Breast Cancer or solid tumors) | Drug: PF-07220060 + PF-07104091 combination dose escalation<br>* PF-07104091 and PF-07220060 will be administered orally<br>|
| Experimental: Part 1 Dose Escalation - Dose Level 8<br>PF-07220060 + PF-07104091 dose escalation (Breast Cancer or solid tumors) | Drug: PF-07220060 + PF-07104091 combination dose escalation<br>* PF-07104091 and PF-07220060 will be administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation: Number of participants with Dose-limiting toxicities (DLT) during first cycle | Number of participants with DLTs, which are typically Grade 3 or higher adverse events will be summarized by dose level | Cycle 1 (28 days) | 
| Number of participants with treatment emergent adverse events (AEs) |  | From baseline until end of study treatment or study completion (approximately 2 years) | 
| Incidence of participants with clinical laboratory abnormalities |  | From baseline until end of study treatment or study completion (approximately 2 years) | 
| Number of participants with vital signs abnormalities |  | From baseline until end of study treatment or study completion (approximately 2 years) | 
| Number of participants with corrected QT (QTc) interval | Determine the effect of the drug on QT prolongation. The number and percentage of participants who experienced QT interval prolongation will be summarized by dose level | From baseline until end of study treatment or study completion (approximately 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) of PF-07220060 and PF-07104091 together after a single dose and multiple dose |  | Day 1 and Day 15 of Cycle 1 (each cycle is 28 days) | 
| Time to maximum plasma concentration (Tmax) of PF-07220060 and PF-07104091 together after a single dose and multiple dose |  | Day 1 and Day 15 of Cycle 1 (each cycle is 28 days) | 
| Area under the concentration versus time curve from time zero to the last quantifiable time point prior to the next dose (AUClast) of PF-07220060 and PF-07104091 together |  | Day 1 and Day 15 of Cycle 1 (each cycle is 28 days) | 
| Objective response rate (ORR) of PF-07220060 and PF-07104091 together in dose escalation and together in combination with fulvestrant or letrozole | Percentage of participants with a best ORR of complete response (CR) or partial response (PR) using RECIST 1. | From baseline through disease progression or study completion (approximately 2 years) | 
| To evaluate the preliminary antitumor activity of PF-07220060 and PF-07104091 together in dose escalation and together in combination with fulvestrant or letrozole by time to event endpoints | Time from first assessment of event endpoint to last assessment of using RECIST 1.1 | From baseline through time to event on study or study completion (approximately 2 years) | 
| Duration of Response (DoR) of PF-07220060 and PF-07104091 together in dose escalation and together in combination with fulvestrant or letrozole | DoR is defined as the time from first documentation of CR or PR to date of first documentation of progressive disease/pharmacodynamic (PD) or death due to any cause, whichever occurs first | From baseline through time to event on study or study completion (approximately 2 years) | 
| Progression-Free Survival (PFS) of PF-07220060 and PF-07104091 together in dose escalation and together in combination with fulvestrant or letrozole | PFS is defined as time from start date of treatment to the date of first documentation of PD or death due to any cause | From baseline through time to event on study or study completion (approximately 2 years) | 
| Time to Progression (TTP) of PF-07220060 and PF-07104091 together in dose escalation and together in combination with fulvestrant or letrozole | TTP is defined as the time from start date of treatment to the date of the first documentation of PD | From baseline through time to event on study or study completion (approximately 2 years) | 

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