Study of PF-06940434 in Patients With Advanced or Metastatic Solid Tumors.

Study Overview
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Brief Summary
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Open-label, multi-center, non-randomized, multiple dose, safety, tolerability, pharmacokinetic, and pharmacodynamics and clinical activity study of PF-06940434 (Integrin alpha-V/beta-8 Antagonist) in patients with SCCHN (Squamous Cell Carcinoma of the Head and Neck), renal cell carcinoma (RCC - clear cell and papillary), ovarian, gastric, esophageal, esophageal (adeno and squamous), lung squamous cell, pancreatic and biliary duct, endometrial, melanoma and urothelial tumors. This study contains two parts, single agent dose escalation (Part 1A), dose finding of PF 06940434 in combination with anti-PD-1 (Part 1B) and dose expansion (Part 2). Part 2 Dose Combination Expansion will enroll participants into 3 cohorts at doses determined from Part 1B in order to further evaluate the safety of PF-06940434 in combination with anti-PD-1.

Official Title
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A PHASE 1 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF ESCALATING DOSES OF PF-06940434 IN PATIENTS WITH ADVANCED OR METASTATIC SOLID TUMORS

Conditions
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Ovarian Cancer, Gastric Cancer, Esophageal Cancer, Squamous Cell Carcinoma of the Head and Neck, Renal Cell Carcinoma, Lung Squamous Cell Carcinoma, Pancreatic Cancer, Bile Duct Cancer, Endometrial Cancer, Melanoma Cancer, Urothelial Cancer

Intervention / Treatment
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* Drug: PF-06940434
* Drug: PF-06801591


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Histological or cytological diagnosis of SCCHN, RCC (clear cell and papillary cell), ovarian, gastric, esophageal (adeno and squamous), lung squamous cell, pancreatic and biliary duct, endometrial, melanoma, or urothelial cancer. Part 2: Arm A SCCHN: Primary tumor location of the oral cavity, oropharynx, hypopharynx or larynx. PDL-1 expression positive and CPS ≥1. No prior systemic therapy administered in the recurrent or metastatic setting (except for systemic therapy given as part of a multimodal treatment for locally advanced disease). Arm B RCC (clear cell): 1 or 2 prior lines of therapy including PD-L1/PD-1 immunotherapy in combination or sequentially with antiangiogenic directed treatment Adequate bone marrow, kidney and liver function. Performance status of 0 or 1. Exclusion Criteria: Participant disease status is suitable for local therapy administered with curative intent. Hypertension that cannot be controlled by medications. Active or prior autoimmune disease Active, uncontrolled bacterial, fungal, or viral infection, including (but not limited to) Hepatitis B, Hepatitis C, and known Human Immunodeficiency Virus infection or Acquired Immunodeficiency Syndrome-related illness

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: Dose Escalation<br>Single Agent Dose Escalation | Drug: PF-06940434<br>* PF-06940434 is given intravenously (IV) every 2 or 4 weeks in a 28 day cycle or every 3 weeks in a 21 day cycle. Multiple dose levels will be evaluated<br>|
| Experimental: Dose Finding Anti-PD-1 Combination 1<br>Part 1B PF-06940434 plus anti-PD-1 | Drug: PF-06940434<br>* PF-06940434 is given intravenously (IV) every 2 or 4 weeks in a 28 day cycle or every 3 weeks in a 21 day cycle. Multiple dose levels will be evaluated<br>Drug: PF-06801591<br>* PF-06801591 will be administered subcutaneously on Day 1 of each 28 day cycle or Day 1 of each 21 day cycle.<br>* Other names: Anti-PD-1;|
| Experimental: Dose Expansion Arm A<br>PF-06940434 with anti-PD-1 in SCCHN | Drug: PF-06940434<br>* PF-06940434 is given intravenously (IV) every 2 or 4 weeks in a 28 day cycle or every 3 weeks in a 21 day cycle. Multiple dose levels will be evaluated<br>Drug: PF-06801591<br>* PF-06801591 will be administered subcutaneously on Day 1 of each 28 day cycle or Day 1 of each 21 day cycle.<br>* Other names: Anti-PD-1;|
| Experimental: Dose Expansion Arm B<br>PF-06940434 with anti-PD-1 in RCC | Drug: PF-06940434<br>* PF-06940434 is given intravenously (IV) every 2 or 4 weeks in a 28 day cycle or every 3 weeks in a 21 day cycle. Multiple dose levels will be evaluated<br>Drug: PF-06801591<br>* PF-06801591 will be administered subcutaneously on Day 1 of each 28 day cycle or Day 1 of each 21 day cycle.<br>* Other names: Anti-PD-1;|
| Experimental: Dose Expansion, Arm C<br>PF-06940434 with anti-PD-1 (both Q3W) | Drug: PF-06940434<br>* PF-06940434 is given intravenously (IV) every 2 or 4 weeks in a 28 day cycle or every 3 weeks in a 21 day cycle. Multiple dose levels will be evaluated<br>Drug: PF-06801591<br>* PF-06801591 will be administered subcutaneously on Day 1 of each 28 day cycle or Day 1 of each 21 day cycle.<br>* Other names: Anti-PD-1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Dose-limiting toxicities (DLT) for Dose Escalation and Dose Finding |  | Baseline up to 28 Days (Cycle 1) | 
| Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities |  | Baseline up to approximately 24 months | 
| Number of Participants With Adverse Events (AEs) According to Severity |  | Baseline up to approximately 24 months | 
| Number of Participants With Adverse Events (AEs) According to Seriousness |  | Baseline up to up to approximately 24 months | 
| Number of Participants With Adverse Events (AEs) by Relationship |  | Baseline up to approximately 24 months | 
| Progression-Free Survival (PFS) for Dose Expansion | The period from study entry until disease progression, death or date of last contact. | Baseline up to 24 Months | 
| Objective Response Rate - Percentage of Participants With Objective Response in Dose Expansion |  | Baseline up to 24 months | 
| Duration of Response (DR) for Dose Expansion |  | Baseline up to 24 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PF-06940434 after multiple doses PK parameters (Cmax). | Maximum observed plasma concentration of PF-06940434. | Pre-dose on Cycle 1 Day 1 and on days 3, 8, and 15 of Cycle 1; Day 1 and Day 15 of Cycles 2 and 3; Days 1, 3, 8, and 15 of Cycle 4 and Pre-dose on Day 1 of every cycle thereafter and at end of treatment (each cycle is 28 days). | 
| Area under the curve from time zero extrapolated to the last quantifiable dose of PF-06940434. | Time zero extrapolated to the last quantifiable time point prior to the next dose. | Pre-dose on Cycle 1 Day 1 and on days 3, 8, and 15 of Cycle 1; Day 1 and Day 15 of Cycles 2 and 3; Days 1, 3, 8, and 15 of Cycle 4 and Pre-dose on Day 1 of every cycle thereafter and at end of treatment (each cycle is 28 days). | 
| Systemic Clearance (CL) | CL is a quantitative measure of the rate at which a drug substance is removed from the body. | Pre-dose on Cycle 1 Day 1 and on days 3, 8, and 15 of Cycle 1; Day 1 and Day 15 of Cycles 2 and 3; Days 1, 3, 8, and 15 of Cycle 4 and Pre-dose on Day 1 of every cycle thereafter and at end of treatment (each cycle is 28 days). | 
| Volume of Distribution (Vd) |  | Pre-dose on Cycle 1 Day 1 and on days 3, 8, and 15 of Cycle 1; Day 1 and Day 15 of Cycles 2 and 3; Days 1, 3, 8, and 15 of Cycle 4 and Pre-dose on Day 1 of every cycle thereafter and at end of treatment (each cycle is 28 days). | 
| Incidence and titers of anti-drug antibodies (ADA) against PF-06940434. |  | Pre-dose on Days 1 and 15 of Cycle 1, pre-dose on Day 1 of Cycles 2 and 3, pre-dose on Day 1 of Cycle 4, pre-dose on Day 1 of every cycle thereafter and at end of treatment (each cycle is 28 days). | 
| Incidence and titers of neutralizing antibodies (NAb) against PF-06940434. | Titers of neutralizing antibodies (NAb) against PF-06940434. | Pre-dose on Days 1 and 15 of Cycle 1, pre-dose on Day 1 of Cycles 2 and 3, pre-dose on Day 1 of Cycle 4, pre-dose on Day 1 of every cycle thereafter and at end of treatment (each cycle is 28 days). | 
| PK parameters of PF-06940434 and PF-06801591 (Cmax). | Maximum observed plasma concentration after multiple doses of PF-06940434 and PD-1 (PF-06801591). | Pre-dose on Cycle 1 Day 1 and on day 15 of Cycle 1; Day 1 of Cycles 2 and 3; Days 1, 3, 8, and 15 of Cycle 4 and Pre-dose on Day 1 of every cycle thereafter and at end of treatment (each cycle is 28 days) | 
| Area under the curve from time zero extrapolated to the last quantifiable dose of PF-06940434 and PF-06801591. | Area under the curve from time zero extrapolated to the last quantifiable dose of PF-06940434 and PF-06801591. | Pre-dose on Cycle 1 Day 1 and on day 15 of Cycle 1; Day 1 of Cycles 2 and 3; Days 1, 3, 8, and 15 of Cycle 4 and Pre-dose on Day 1 of every cycle thereafter and at end of treatment (each cycle is 28 days) | 
| Characterize the multiple dose PK of PF-06940434 following intravenous administration in combination with PF-06801591. | Maximum observed plasma concentration of PF-06940434. | Cycle 4 Day 1 (each cycle is 28 days) | 
| Area under the curve from time zero extrapolated to the last quantifiable dose of PF-06940434. | Time zero extrapolated to the last quantifiable time point prior to the next dose. | Cycle 4 Day 1 (each cycle is 28 days) | 
| Number of participants with increased T-cells after PF-06940434 treatment. |  | Pre-dose on Day 1 of Cycle 1; pre-dose on Day 1 of Cycles 2 and 3 (each cycle is 28 days) | 
| Progression-Free Survival (PFS) for Dose Expansion | The period from study entry until disease progression, death or date of last contact. | Baseline to measured progression (up to approximately 24 months) | 
| Duration of Response (DR) |  | Baseline up to approximately 24 Months | 
| Number of Participants With Objective Response for Dose Expansion portion |  | Baseline up to 24 months | 
| Disease Control Rate (DCR) | DCR is defined as the percent of participants with a confirmed complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1. | Every 8 weeks from the time of enrollment up to 2 years | 
| Trough concentrations of PF-06940434 and PF-06801591 in Dose Expansion |  | Day 1 of Cycle 1 though 4, Day 1 of every 2 Cycles starting from Cycle 5 up to 24 months (each cycle is 28 days). For Part 2 Cohort 3, Day 1 of Every Cycle (each cycle is 21 days) | 
| Plasma Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | Pre-dose on Cycle 1 Day 1 and on days 3, 8, and 15 of Cycle 1; Day 1 and Day 15 of Cycles 2 and 3; Days 1, 3, 8, and 15 of Cycle 4 and Pre-dose on Day 1 of every cycle thereafter and at end of treatment (up to 24 Months) [each cycle is 28 days] | 
| Incidence and titers of anti-drug antibodies (ADA) against PF-06801591 in Dose Finding and Dose Expansion | Incidence and titers of anti-drug antibodies (ADA) against PF-06801591. | Pre-dose on Days 1 and 15 of Cycle 1, pre-dose on Day 1 of Cycles 2 and 3, pre-dose on Day 1 of Cycle 4, pre-dose on Day 1 of every cycle thereafter and at end of treatment (up to 24 Months) [each cycle is 28 days]. | 
| Incidence and titers of neutralizing antibodies (NAb) against PF-06801591 in Dose Finding and Dose Expansion. | Incidence and titers of neutralizing antibodies (NAb) against PF-06801591. | Pre-dose on Days 1 and 15 of Cycle 1, pre-dose on Day 1 of Cycles 2 and 3, pre-dose on Day 1 of Cycle 4, pre-dose on Day 1 of every cycle thereafter and at end of treatment (up to 24 Months) [each cycle is 28 days]. | 
| Overall Survival | The period from study entry until death or date of last contact (24 months) | From baseline to up to 2 years after last dose of study drug |