PF-07104091 as a Single Agent and in Combination Therapy

Study Overview
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Brief Summary
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To assess the safety and tolerability of increasing doses of PF-07104091 and to estimate the Maximum Tolerated Dose (MTD) and/or select the Recommended Phase 2 dose (RP2D) for PF-07104091 as a single agent in participants with advanced or metastatic small cell lung, breast and ovarian cancers.

Detailed Description
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Study C4161001 is a Phase 1, open label, multi dose, multi center, dose escalation, safety, pharmacokinetic (PK) and pharmacodynamic study of PF-07104091 in adult patients with advanced or metastatic small cell lung cancer (SCLC), advanced platinum resistant epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer, locally recurrent/advanced or metastatic triple negative breast cancer (TNBC), HR-positive HER2-negative advanced or mBC, advanced or metastatic non-small cell lung cancer (NSCLC). This two part study will assess the safety and tolerability of increasing dose levels of PF-07104091 in Part 1, and establish the recommended Phase 2 dose (RP2D) in Part 2.

Official Title
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PHASE 1/2A DOSE ESCALATION, FINDING AND EXPANSION STUDY EVALUATING SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS AND ANTI TUMOR ACTIVITY OF PF-07104091 AS A SINGLE AGENT AND IN COMBINATION THERAPY

Conditions
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Small Cell Lung Cancer, Ovarian Cancer, Breast Cancer

Intervention / Treatment
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* Drug: PF-07104091 monotherapy dose escalation
* Drug: PF-07104091 + palbociclib + fulvestrant
* Drug: PF-07104091 + palbociclib + letrozole
* Drug: PF-07104091 monotherapy dose expansion (ovarian)
* Drug: PF-07104091 monotherapy dose expansion (SCLC)
* Drug: PF-07104091 + Fulvestrant (post CDK4/6)
* Drug: PF-0704091 + Fulvestrant (post CDK4/6)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with HR-positive HER2-negative advanced or metastatic breast cancer (received at least two prior lines in the advanced or metastatic setting including one prior line of combined CDK4/6 inhibitor and endocrine therapy and no more than two prior lines of cytotoxic chemotherapy) Participants with locally recurrent/advanced or metastatic TNBC who have received up to 2 prior lines of chemotherapy in the advanced or metastatic setting Participants with advanced platinum resistant epithelial ovarian cancer (EOC)/fallopian tube cancer/primary peritoneal cancer (PPC) (histologically or cytologically proven) who have received at least 1 systemic anti-cancer therapy containing a platinum analog Participants with cytological diagnosis of advanced/metastatic SCLC Participants with or cytological diagnosis of advanced/metastatic NSCLC Participants with HR-positive HER2-negative advanced or metastatic breast cancer (second line plus setting) (histologically or cytologically proven). Participants entering the study in the expansion cohort have at least one measurable lesion as defined by RECIST version 1.1 that has not been previously irradiated Performance Status 0 or 1 Adequate bone marrow, hematological, kidney and liver function Resolved acute effects of any prior therapy to baseline severity Exclusion Criteria: Participants with known symptomatic brain metastases requiring steroids Participants with any other active malignancy within 3 years prior to enrollment Major surgery within 3 weeks prior to study entry Radiation therapy within 3 weeks prior to study entry. Systemic anti cancer therapy within 4 weeks prior to study Prior irradiation to >25% of the bone marrow Participants with active, uncontrolled bacterial, fungal, or viral infection, including HBV, HCV, and known HIV or AIDS related illness Active COVID-19/SARS-CoV2 infection Baseline 12 lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results Any of the following in the previous 6 months: myocardial infarction, long QT syndrome, Torsade de Pointes, arrhythmias, serious conduction system abnormalities, unstable angina, coronary/peripheral artery bypass graft, symptomatic CHF, New York Heart Association class III or IV, cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism, and/or other clinical significant episode of thrombo embolic disease. Anticoagulation with vitamin K antagonists or factor Xa inhibitors is not allowed. Hypertension that cannot be controlled by medications Participation in other studies involving investigational drug(s) within 2 weeks prior to study entry. Known or suspected hypersensitivity to active ingredient/excipients in PF 07104091. Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease or previous gastric resection or lap band surgery. Participants with advanced/metastatic, symptomatic, visceral spread, that are at risk of life threatening complications in the short Participants with an indwelling catheter that has an external component such as those used for drainage of effusion(s) or central venous catheter that is externally Previous high dose chemotherapy requiring stem cell rescue Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of goserelin (if applicable). Current use or anticipated need for food or drugs that are known strong CYP3A4/5 or UGT1A9 inhibitors or inducers Current use or anticipated need for drugs that are known sensitive UGT1A1 substrates with narrow therapeutic Serum pregnancy test positive at screening Other medical or psychiatric condition

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: PF-07104091<br>CDK2 monotherapy dose escalation | Drug: PF-07104091 monotherapy dose escalation<br>* PF-07104091 will be administered orally<br>|
| Experimental: PF-07104091 + palbociclib + fulvestrant<br>CDK2 + palbociclib + fulvestrant | Drug: PF-07104091 + palbociclib + fulvestrant<br>* PF-07104091 will be administered orally in combination with palbociclib and fulvestrant<br>|
| Experimental: PF-07104091 + palbociclib + letrozole<br>CDK2 + palbociclib + letrozole | Drug: PF-07104091 + palbociclib + letrozole<br>* PF-07104091 will be administered orally in combination with palbociclib and letrozole<br>|
| Experimental: PF-07104091 monotherapy dose expansion (SCLC)<br>PF-07104091 monotherapy dose expansion (SCLC) | Drug: PF-07104091 monotherapy dose expansion (SCLC)<br>* PF-07104091 will be administered orally<br>|
| Experimental: PF-07104091 monotherapy dose expansion (ovarian)<br>PF-07104091 monotherapy dose expansion (ovarian) | Drug: PF-07104091 monotherapy dose expansion (ovarian)<br>* PF-07104091 will be administered orally<br>|
| Experimental: PF-07104091 + fulvestrant (post CDK4/6) dose expansion<br>PF-07104091 + fulvestrant (post CDK4/6) dose expansion | Drug: PF-0704091 + Fulvestrant (post CDK4/6)<br>* PF-07104091 + fulvestrant (post 4/6) dose expansion<br>|
| Experimental: PF-07104091 + fulvestrant (post CDK 4/6) dose escalation<br>CDK2+ fulvestrant (post CDK 4/6) dose escalation | Drug: PF-07104091 + Fulvestrant (post CDK4/6)<br>* PF-07104091 will be administered orally in combination with fulvestrant<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 | 28 days | 
| To evaluate incidence of treatment emergent adverse events and laboratory abnormalities | Type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and any laboratory abnormalities will be summarized by dose level | From baseline until end of study treatment or study completion (approximately 2 years) | 
| Evaluate pulse rate that is out of normal range and changes in pulse rate as compared to baseline | Identify pulse rate readings that are outside the normal range. The number and percentage of participants who experienced significant pulse rate change from baseline will be summarized by dose level | From baseline until end of study treatment or study completion (approximately 2 years) | 
| Evaluate blood pressure that is out of normal range and changes in blood pressure as compared to baseline | Identify systolic and diastolic readings that are outside the normal range. The number and percentage of participants who experienced significant blood pressure change from baseline will be summarized by dose level | From baseline until end of study treatment or study completion (approximately 2 years) | 
| To evaluate heart rate corrected QT interval and changes in corrected QT interval as compared to baseline | 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) | 
| To evaluate the preliminary antitumor activity of PF-07104091 as a single agent and in combination with palbociclib and in combination with letrozole or fulvestrant or fulvestrant alone by objective response rate (ORR) in dose expansion | Percentage of participants with a best overall response of complete response (CR) or partial response (PR) using RECIST 1.1 | From baseline through disease progression or study completion (approximately 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) of PF-07104091 after a single dose and multiple dose | Peak concentration of PF-07104091 during selected cycles | Day 1 and Day 15 of Cycle 1 (each cycle is 28 days) | 
| Time to maximum plasma concentration (Tmax) of PF-07104091 after a single dose and multiple dose | Time to peak concentration of PF-07104091 during selected cycles | 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-07104091 | AUC of PF-07104091 will be calculated at selected cycles | Day 1 and Day 15 of Cycle 1 (each cycle is 28 days) | 
| Area under the curve of PF-07104091 with or without food | AUC of PF-07104091 in plasma and whether absorption of the drug is affected when taken by food | From baseline through time to event on study or study completion (approximately 2 years) | 
| Maximum plasma concentration of PF-07104091 with or without food | Peak concentrations of PF-07104091 in plasma and whether absorption of the drug is affected when taken by food | From baseline through time to event on study or study completion (approximately 2 years) | 
| To document any preliminary evidence of antitumor activity of PF-07104091 as a single agent and in combination with palbociclib and in combination with letrozole or fulvestrant or fulvestrant alone by objective response rate (ORR) in dose escalation | Percentage of participants with a best overall response of CR or PR using RECIST 1.1 | From baseline and every 8 weeks through disease progression or study completion (approximately 2 years) | 
| To document any preliminary evidence of antitumor activity of PF-07104091 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hormone receptor-positive human epidermal growth factor receptor 2 negative breast cancer, Cyclin-Dependent Kinase 2 Inhibitor, PF-07104091, palbociclib, letrozole, cyclin-dependent kinase, Ibrance