Study to Test the Safety and Tolerability of PF-07257876 in Participants With Selected Advanced Tumors.

Study Overview
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Brief Summary
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This is a first-in-human, Phase 1, open label, multicenter, multiple dose, dose escalation and dose expansion study intended to evaluate the safety, pharmacokinetic, pharmacodynamic and potential clinical benefit of PF-07257876, a CD47-PD-L1 bispecific antibody, in participants with selected advanced or metastatic tumors for whom no standard therapy is available. The study contains 2 parts, single agent Dose Escalation (Part 1) to determine the recommended dose of PF-07257876, followed by Dose Expansion (Part 2) in selected tumor types at the recommended dose.

Official Title
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A PHASE 1 DOSE ESCALATION AND EXPANSION STUDY EVALUATING THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND ANTITUMOR ACTIVITY OF PF-07257876 IN PATIENTS WITH ADVANCED OR METASTATIC TUMORS

Conditions
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Non-Small Cell Lung Cancer, Squamous Cell Carcinoma of the Head and Neck, Ovarian Cancer

Intervention / Treatment
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* Biological: PF-07257876


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological/cytological diagnosis of selected advanced or metastatic tumor Prior treatment with PD-1 (Programmed cell death 1) or PD-L1 (programmed death-ligand 1) in NSCLC and SCCHN or platinum-based therapy in Ovarian cancer Confirmed radiographic progression of disease PD-L1 IHC positivity ≥1% Have ≥1 measurable lesion as defined by RECIST 1.1 that has not been previously irradiated Eastern Cooperative Oncology Group performance status 0-1 Adequate hematologic, renal and liver functions Resolved acute effects of any prior therapy Participants in Part 1 must be able to provide archival tumor tissue collected within the prior 6 months or consent to undergo a fresh biopsy during screening. Participants enrolled to the MTD (Maximum Tolerated Dose) cohort in Part 1 must consent to mandatory paired pre-treatment and on-treatment biopsies. Participants in Part 2 must consent to a pre-treatment biopsy and a subset of patients must consent to a paired on-study biopsy as well until the Sponsor deems an adequate number have been received. Exclusion Criteria: Participants with known brain metastasis larger than 4 cm or that is symptomatic. New brain metastases detected at screening. Participants with previously diagnosed brain metastases are eligible if they have completed treatment and recovered from acute effects prior to study entry. Abnormal neurological assessment by investigator Other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ Major surgery or radiation therapy within 4 weeks prior to planned first dose Last systemic anti-cancer therapy within 28 days or 5 half-lives (whichever is shorter) prior to planned first dose (6 weeks for mitomycin C or nitrosoureas) Active bleeding disorder in the past 6 months prior to first dose History of clinically significant severe immune mediated adverse event that was considered related to prior immune modulatory therapy and required immunosuppressive therapy (other than hormone replacement therapy) History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (ie, bronchiolitis obliterans, cryptogenic organizing pneumonia), evidence of active pneumonitis on screening chest CT(computer tomography) scan Anticoagulation with vitamin K antagonists or factor Xa inhibitors is not allowed Treatment with chronic systemic corticosteroids or other immunosuppressive medications Participation in other studies involving investigational drug(s) within 4 weeks prior to planned first dose Active, uncontrolled bacterial, fungal, or viral infection, Hepatitis B, Hepatitis C, or Human immunodeficiency virus (HIV) infection Active COVID-19/SARS-CoV2 Pregnant or breastfeeding female participant Organ transplant requiring immunosuppressive treatment or prior allogeneic bone marrow or hematopoietic stem cell transplant Significant cardiac or pulmonary conditions or events within previous 6 months

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 (Part 1)<br>Participants will receive PF-07257876 at escalating dose levels. | Biological: PF-07257876<br>* CD47-PDL-1 bispecific antibody<br>|
| Experimental: Dose Expansion (Part 2) - Cohort 1 (NSCLC)<br>Participants with non-small cell lung cancer (NSCLC) will receive PF-07257876 at the recommended dose from Part 1. | Biological: PF-07257876<br>* CD47-PDL-1 bispecific antibody<br>|
| Experimental: Dose Expansion (Part 2) - Cohort 2 (SCCHN)<br>Participants with squamous cell carcinoma of the head and neck (SCCHN) will receive PF-07257876 at the recommended dose from Part 1. | Biological: PF-07257876<br>* CD47-PDL-1 bispecific antibody<br>|

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 (DLTs) in Dose Escalation (Part 1) | DLTs will be evaluated during Cycle 1 (a cycle is 28 days) in Part 1. The number of DLTs will be used to determine the optimal dose | Baseline through end of Cycle 1 (each cycle is 28 days) | 
| Number of participants with adverse events (AEs) | AEs characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 5.0), timing, seriousness, and relationship to study therapy. | Baseline through up to 2 years | 
| Number of participants with clinically significant laboratory abnormalities | Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing. | Baseline through up to 2 years | 
| Objective response rate (ORR) in the Expansion cohorts (Part 2) | Tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Baseline through up to 2 years or until disease progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single dose Pharmacokinetics (PK) parameter: Maximal concentration (Cmax) in Part 1 | Maximum observed plasma concentration of PF-07257876 (Cmax) | Cycle 1, Cycle 2, Cycle 3, Cycle 4, and pre-dose on Day 1 at Cycle 5 and every third cycle thereafter (all cycles are 28 days) and at End of Treatment, up to 2 years | 
| Single dose PK parameter: Time to maximal plasma concentration (Tmax) in Part 1 | Time to maximal observed plasma concentration of PF-07257876 (Tmax) | Cycle 1, Cycle 2, Cycle 3, Cycle 4, and pre-dose on Day 1 at Cycle 5 and every third cycle thereafter (all cycles are 28 days) and at End of Treatment, up to 2 years | 
| Single dose PK parameter: Area under the Curve (AUClast) in Part 1 | Area under the concentration-time curve from time zero to the last quantifiable time point prior to the next dose. | Cycle 1, Cycle 2, Cycle 3, Cycle 4, and pre-dose on Day 1 at Cycle 5 and every third cycle thereafter (all cycles are 28 days) and at End of Treatment, up to 2 years | 
| Multiple dose PK parameter: Maximal concentration (Cmax, ss) in Part 1 | Maximum observed steady state plasma concentration of PF-07257876 (Cmax, ss) | Cycle 1, Cycle 2, Cycle 3, Cycle 4, and pre-dose on Day 1 at Cycle 5 and every third cycle thereafter (all cycles are 28 days) and at End of Treatment, up to 2 years | 
| Multiple dose PK parameter: Time to maximal plasma concentration (Tmax, ss) in Part 1 | Time to reach Maximum Observed Steady State Plasma Concentration (Tmax,ss). | Cycle 1, Cycle 2, Cycle 3, Cycle 4, and pre-dose on Day 1 at Cycle 5 and every third cycle thereafter (all cycles are 28 days) and at End of Treatment, up to 2 years | 
| Multiple dose PK parameter: Area under the Curve (AUCtau, ss) in Part 1 | Area Under the curve within one dose interval at steady state (AUCtau,ss) | Cycle 1, Cycle 2, Cycle 3, Cycle 4, and pre-dose on Day 1 at Cycle 5 and every third cycle thereafter (all cycles are 28 days) and at End of Treatment, up to 2 years | 
| Immunogenicity of PF-07257876 | Incidence, titers, and duration (if data permit) of antidrug antibodies (ADA) and neutralizing antibodies against PF-07257876 | Cycle 1, Cycle 2, Cycle 3, Cycle 4, and pre-dose on Day 1 at Cycle 5 and every third cycle thereafter (all cycles are 28 days) and at End of Treatment, up to 2 years | 
| Intratumor T cell levels | Immune biomarker levels in archival biopsies and/or de novo and on-treatment tumor biopsies. | Baseline through Cycle 2 Day 15 (each cycle is 28 days) | 
| Intratumor PD-L1 expression | PD-L1 expression levels in pretreatment tumor biopsies | Baseline through Cycle 2 Day 15 (each cycle is 28 days) | 
| ORR in Dose Escalation (Part 1) | Tumor response assessment based on RECIST 1.1 | Baseline through up to 2 years or until disease progression | 
| Duration of response (DOR) | DOR as assessed using RECIST 1.1 | Baseline through up to 2 years or until disease progression | 
| Progression free survival (PFS) | PFS as assessed using RECIST 1.1 | Baseline through up to 2 years or until disease progression | 
| Time to progression (TTP) | TTP as assessed using RECIST 1.1 | Baseline through up to 2 years or until disease progression | 
| Lowest concentration (Ctrough) reached before the next dose is administered in Part 2 | PK assessment for PF-07257876 | Pre-dose on Day 1 at Cycles 1, 2, 3, 4, 5 and every third cycle thereafter (each cycle is 28 days) and End of Treatment visit, up to 2 years | 
| Overall Survival (OS) in the Expansion Cohorts (Part 2) | Proportion of patients alive | Baseline through up to 2 years or until disease progression | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SCCHN, NSCLC, PD-L1 (Programmed death-ligand 1), CD47 (cluster of differentiation 47), immunotherapy, macrophage checkpoint inhibitor, advanced solid tumor, metastatic solid tumor, Ovarian Cancer, Lung Cancer, Non-small cell lung cancer, Head and Neck cancer, solid tumor, advanced cancer, metastatic cancer, Squamous cell carcinoma of the head and neck, Squamous cell head and neck cancer