Pepinemab in Combination With Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the safety and tolerability of pepinemab in combination with pembrolizumab as first-line treatment and determine a recommended Phase 2 dose (RP2D) in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC).

Detailed Description
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The purpose of the study is to evaluate the safety and tolerability of pepinemab in combination with pembrolizumab as first-line treatment and determine a recommended Phase 2 dose (RP2D) in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). The study will consist of a safety run in phase and a dose expansion phase. The primary objective of the Safety Run-in phase of the study is to evaluate the safety and tolerability of pepinemab in combination with pembrolizumab as first-line treatment and determine a recommended Phase 2 dose (RP2D) for the dose-expansion phase enrolling subjects in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). The primary objective of the Dose Expansion phase of the study is to evaluate objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of the combination of pepinemab/pembrolizumab in immunotherapy naïve patients with R/M HNSCC. The secondary objectives of the study are to evaluate progression-free survival (PFS) by RECIST 1.1 of the combination of pepinemab/pembrolizumab in immunotherapy naïve patients with R/M HNSCC, to evaluate the overall survival (OS), and to evaluate the duration of response (DOR). The exploratory objectives of the study are to evaluate PFS, ORR, and DOR via the iRECIST criteria, to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of the combination, to investigate the relationship between treatment with pepinemab and pembrolizumab and certain biomarkers and the genomic signatures of baseline or archival tumor samples. The Safety Run-in phase will enroll a minimum of 3 subject and a maximum of 18 subjects who will be treated with intravenous pepinemab IV (starting at 20 mg/kg, with potential dose modifications to 15 mg/kg or 10 mg/kg) and pembrolizumab at 200 mg IV, Q3W. The Dose Expansion phase of the study will enroll a maximum of approximately 62 subjects who will be treated with intravenous pepinemab administered IV at the RP2D, plus pembrolizumab 200 mg IV, Q3W. Subjects will undergo evaluation for extent of disease (EOD) at baseline, week 9, every 6 weeks through year 1, and every 9 weeks thereafter. Subjects who discontinue study treatment will continue to be followed for survival every 12 weeks after safety follow-up (for up to approximately 2 years).

Official Title
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A Phase 1b/2 Study of the Combination of Pepinemab and Pembrolizumab in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

Conditions
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Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck (HNSCC)

Intervention / Treatment
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* Drug: pepinemab + pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be ≥18 years of age. Subjects or their legal representative must be able to provide written informed consent to participate in the trial prior to the performance of any study-specific procedures. Subjects must have histologically or cytologically confirmed HNSCC; eligible histologies include SCC of the oropharynx, oral cavity, hypopharynx, and larynx. Subjects must have PD-L1 IHC (including CPS score using an FDA approved test) testing completed within 6 months of screening or at screening. Have measurable disease per RECIST 1.1 as assessed by the central imaging vendor or the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Subjects must have locally advanced, recurrent or metastatic neoplastic disease that is not curable by currently available local therapies. Subjects must have an Eastern Cooperative Oncology Group (ECOG) PS of 0 or1. Subjects must have a life expectancy of at least 12 weeks. Subjects must have adequate hematologic reserve based on the following: ANC ≥1,500/μL Platelet count >100,000/μL Hemoglobin >9 g/dL Subjects must have adequate hepatic function based on the following: Total bilirubin <1.5 × upper limit of normal (ULN) Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 x ULN (≤5 x ULN for subjects with known hepatic metastases). Subjects must have adequate renal function based on the following: Serum creatinine ≤1.5 × ULN; or Calculated creatinine clearance of >30 mL/min. Human immunodeficiency virus (HIV) infected subjects must be on antiretroviral therapy (ART) and have a well-controlled HIV infection/disease defined as: Subjects on ART must have a CD4+ T cell count 350 cells/mm3 at time of screening Subjects on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening Subjects on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1). Subjects with oropharyngeal cancer must have archival tissue available for p16 testing or be willing to undergo pre-study biopsy to obtain tissue for p16 testing. All subjects must have archival or recently obtained tissue available for biomarker analysis. Female subjects of childbearing potential must have a negative pregnancy test within 72 hours of first dose of study treatment. Female subjects of childbearing potential must use a highly effective mode of contraception or abstain from heterosexual activity for the duration of the trial and for 120 days following the last dose of study medication. A female is NOT of childbearing potential if she has undergone bilateral salpingoophorectomy or is menopausal, defined as an absence of menses for 12 consecutive months. Male subjects must agree to use highly effective contraception. Exclusion Criteria: Subjects with SCC of the nasopharynx. Subjects who have received systemic treatment for recurrent or metastatic HNSCC; however, subjects who have received adjuvant systemic therapy or systemic therapy for locally advanced disease which was completed more than 6 months prior to study enrollment are eligible. Subjects must have recovered from the effects of any prior radiation therapy or surgery. Subjects who have received investigational therapy within 5 half-lives of the investigational agent or 4 weeks, whichever is shorter. Subjects with primary immunodeficiency. Subjects who require immunosuppressive therapy including, but not limited to, treatment with corticosteroids in pharmacologic doses (equivalent to ≥10 mg prednisone daily), cyclosporine, mycophenolate, azathioprine, methotrexate, adalimumab, infliximab, vedolizumab, tofacitinib, dupilumab, rituximab, etc. Subjects with autoimmune conditions requiring treatment in the previous 2 years; however, subjects on replacement hormonal therapy alone for autoimmune endocrinopathies are eligible for enrollment. Subjects with active central nervous system (CNS) metastases; however, subjects who have undergone radiation and/or surgery for the treatment of CNS metastases, who are neurologically stable and who are no longer taking pharmacologic doses of corticosteroids are eligible; subjects with leptomeningeal metastases are not eligible. Has received prior radiotherapy within 2 weeks of start of study treatment. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. Subjects with a prior malignancy (other than the malignancy under study) in the 2 years prior to enrollment; however, subjects with curatively treated nonmelanoma skin cancers, intra-epithelial cervical neoplasia or in situ carcinoma of the breast are eligible for enrollment. Subjects with prior allogenic transplants. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis. Subjects with an active infection requiring treatment with systemic antibiotics. Subjects who are pregnant or lactating. Subjects who have received treatment with a prior anti-PD-1 or anti-PD-L1, anti-CTLA-4, or anti-LAG3 agent or who have received prior treatment with pepinemab. HIV-infected subjects with a history of Kaposi sarcoma and/or Multicentric Castleman Disease. Subjects who are hepatitis B surface antigen positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to enrollment. Note: Subjects should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention. Hepatitis B screening tests are not required unless: Known history of HBV infection As mandated by local health authority. Subjects with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening. Note: Subjects must have completed curative antiviral therapy at least 4 weeks prior to enrollment. Hepatitis C screening tests are not required unless: Known history of HCV infection As mandated by local health authority. Subjects who have received a live vaccine within 30 days of study enrollment. Current alcohol or drug abuse. Subjects with any intercurrent medical condition where the known risks of participation in the trial outweigh any potential benefits; subjects with psychiatric or social circumstances that preclude responsible participation in the trial; subjects with severe nutritional deficiencies or marked hypoalbuminemia. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the investigator (or designee). Inability to comply with visit schedule or other protocol requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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
Intervention Model: Single Group Assignment
Interventional Model Description: This study will be conducted in 2 parts: a Safety Run-in phase and a Dose Expansion phase. The Safety Run-in phase will be based on the starting dose of 20 mg/kg pepinemab and a fixed dose of pembrolizumab (200 mg Q3W); 3 to 6 subjects will be treated at this pepinemab dose level. If the initial 20-mg/kg dose of pepinemab in combination with pembrolizumab is determined not to be well tolerated, the dose of pepinemab will be reduced to 15 mg/kg for an additional 3 subjects and a maximum of 6 subjects and then, potentially, to 10 mg/kg for a third group of 3 subjects and a maximum of 6 subjects. Once the recommended Dose Expansion phase dose is determined, a maximum of approximately 62 subjects will be treated with that dose of pepinemab combined with pembrolizumab.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pepinemab + pembrolizumab<br>Pepinemab will be administered at 20 mg/kg (with possible dose modifications to 15 mg/kg or 10 mg/kg, if the initial 20 mg/kg dose of pepinemab is determined not to be well tolerated) in combination with a fixed dose of 200 mg pembrolizumab, administered in separate IV infusions, Q3W. | Drug: pepinemab + pembrolizumab<br>* The Safety Run-in phase will begin at 20 mg/kg pepinemab with a fixed dose of 200 mg pembrolizumab. The dose of pepinemab may be reduced to 15 mg/kg or 10 mg/kg with a fixed dose of 200 mg pembrolizumab if the initial pepinemab dose of 20 mg/kg is found to not be well tolerated. Once a recommended phase II dose of pepinemab is determined it will be utilized in the Dose Expansion phase in combination with 200 mg pembrolizumab.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects with Treatment Emergent Adverse Events (TEAE's). | TEAE's are defined as Adverse Events (AEs) with onset after date-time of first dose, or medical conditions present prior to the start of IMP but increased in severity or relationship after date-time of first dose of IMP. | 2 Years | 
| Evaluation of RP2D | Review number of subjects with incidence of laboratory abnormalities based on hematology, clinical chemistry, and urinalysis test results with consideration to ECG, vital sign measurements and physical examinations. | 2 Years | 
| Efficacy Endpoint | To be determined by the ORR of the combination pepinemab and pembrolizumab first-line treatment in patients with R/M HNSCC. This is defined as complete response (CR) or PR according to RECIST 1.1 from the first dose until documented confirmed disease progression. | 2 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DoR) | To be measured from the first date of response (CR or PR) until the development of progressive neoplastic disease or death from any cause. | 2 Years | 
| Overall Survival (OS) | To be measured from the date of the first dose (Day 1 of Cycle 1) until death from any cause. | 2 Years | 
| Progression Free Survival (PFS) | To will be measured based on the RECIST 1.1 criteria from the date of enrollment until the development of progressive neoplastic disease or death from any cause. | 2 Years | 
| Extent of Disease (EOD) | To based on radiographic findings on computed tomography (CT) or magnetic resonance imaging (MRI) scan. | 2 Years | 
| Pharmacokinetic (PK) Endpoints | Area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC0-∞). | 2 Years | 
| Pharmacokinetic (PK) Endpoints | AUC from time zero to the time of the last quantifiable concentration (AUC0-tlast). | 2 Years | 
| Pharmacokinetic (PK) Endpoints | Maximum observed plasma concentration (Cmax). | 2 Years | 
| Pharmacokinetic (PK) Endpoints | Time of the maximum observed plasma concentration (tmax). | 2 Years | 
| Pharmacokinetic (PK) Endpoints | Apparent plasma terminal elimination half-life (t1/2). | 2 Years | 
| Pharmacokinetic (PK) Endpoints | Apparent total plasma clearance (CL/F). | 2 Years | 
| Pharmacokinetic (PK) Endpoints | Apparent volume of distribution (Vz/F). | 2 Years | 
| Immunogenicity Endpoint | The incidence and severity of specific antidrug antibodies (ADA) to pepinemab. | 2 Years | 
| Pharmacodynamic (PD) Endpoint | Include receptor occupancy, cellular SEMA4D levels, and total soluble SEMA4D levels. | 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic, Squamous Cell, Carcinoma, Recurrent, Pepinemab, Pembrolizumab, Head, Neck, VX15/2503, Solid Tumors, Immunotherapy, Progression-Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR), Pharmacokinetics (PK), Pharmacodynamics (PD), Immunogenicity, Biomarkers, Overall Survival (OS), Extent of Disease (EOD), Exploratory, Biopsy, T-Cell, Myeloid Suppressor Cells, ECG, KEYTRUDA