Clinical trial NCT04815720: Pepinemab in Combination With Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck (HNSCC)
Keywords: 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®
MK3475-B84
Lead sponsor: Vaccinex Inc.
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2021-03-25
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: Inclusion Criteria:

1. Subjects must be ≥18 years of age.
2. 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.
3. Subjects must have histologically or cytologically confirmed HNSCC; eligible histologies include SCC of the oropharynx, oral cavity, hypopharynx, and larynx.
4. Subjects must have PD-L1 IHC (including CPS score using an FDA approved test) testing completed within 6 months of screening or at screening.
5. 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.
6. Subjects must have locally advanced, recurrent or metastatic neoplastic disease that is not curable by currently available local therapies.
7. Subjects must have an Eastern Cooperative Oncology Group (ECOG) PS of 0 or1.
8. Subjects must have a life expectancy of at least 12 weeks.
9. Subjects must have adequate hematologic reserve based on the following:

   1. ANC ≥1,500/μL
   2. Platelet count \>100,000/μL
   3. Hemoglobin \>9 g/dL
10. Subjects must have adequate hepatic function based on the following:

    1. Total bilirubin \<1.5 × upper limit of normal (ULN)
    2. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 x ULN (≤5 x ULN for subjects with known hepatic metastases).
11. Subjects must have adequate renal function based on the following:

    1. Serum creatinine ≤1.5 × ULN; or
    2. Calculated creatinine clearance of \>30 mL/min.
12. Human immunodeficiency virus (HIV) infected subjects must be on antiretroviral therapy (ART) and have a well-controlled HIV infection/disease defined as:

    1. Subjects on ART must have a CD4+ T cell count 350 cells/mm3 at time of screening
    2. 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
    3. 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).
13. 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.
14. All subjects must have archival or recently obtained tissue available for biomarker analysis.
15. 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:

1. Subjects with SCC of the nasopharynx.
2. 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.
3. Subjects must have recovered from the effects of any prior radiation therapy or surgery.
4. Subjects who have received investigational therapy within 5 half-lives of the investigational agent or 4 weeks, whichever is shorter.
5. Subjects with primary immunodeficiency.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. Subjects with prior allogenic transplants.
12. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
13. Subjects with an active infection requiring treatment with systemic antibiotics.
14. Subjects who are pregnant or lactating.
15. 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.
16. HIV-infected subjects with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
17. 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:
    1. Known history of HBV infection
    2. As mandated by local health authority.
18. 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:
    1. Known history of HCV infection
    2. As mandated by local health authority.
19. Subjects who have received a live vaccine within 30 days of study enrollment.
20. Current alcohol or drug abuse.
21. 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.
22. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the investigator (or designee).
23. Inability to comply with visit schedule or other protocol requirements.

Primary outcomes:
measure: Number of Subjects with Treatment Emergent Adverse Events (TEAE's).
timeFrame: 2 Years
measure: Evaluation of RP2D
timeFrame: 2 Years
measure: Efficacy Endpoint
timeFrame: 2 Years
Secondary outcomes:
measure: Duration of Response (DoR)
timeFrame: 2 Years
measure: Overall Survival (OS)
timeFrame: 2 Years
measure: Progression Free Survival (PFS)
timeFrame: 2 Years
measure: Extent of Disease (EOD)
timeFrame: 2 Years
measure: Pharmacokinetic (PK) Endpoints
timeFrame: 2 Years
measure: Pharmacokinetic (PK) Endpoints
timeFrame: 2 Years
measure: Pharmacokinetic (PK) Endpoints
timeFrame: 2 Years
measure: Pharmacokinetic (PK) Endpoints
timeFrame: 2 Years
measure: Pharmacokinetic (PK) Endpoints
timeFrame: 2 Years
measure: Pharmacokinetic (PK) Endpoints
timeFrame: 2 Years
measure: Pharmacokinetic (PK) Endpoints
timeFrame: 2 Years
measure: Immunogenicity Endpoint
timeFrame: 2 Years
measure: Pharmacodynamic (PD) Endpoint
timeFrame: 2 Years
Other outcomes:
measure: On-Treatment Tumor Biopsies
timeFrame: 2 Years
measure: Serum and CSF Levels of Neuroinflammatory Cytokines
timeFrame: 2 Years
measure: T- and B-Cell Quantitation by Flow Cytometry (TBNK)
timeFrame: 2 Years
Locations:
city: Springdale
country: United States
facility: Highlands Oncology Group, PA - North Hills
state: Arkansas
city: Fresno
country: United States
facility: California Cancer Associates for Research and Excellence (CCARE)-Fresno
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center at Mission Bay
state: California
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Celebration
country: United States
facility: AdventHealth Celebration
state: Florida
city: Orlando
country: United States
facility: AdventHealth Orlando
state: Florida
city: Atlanta
country: United States
facility: Emory Saint Joseph's Hospital
state: Georgia
city: Bethesda
country: United States
facility: American Oncology Partners of Maryland, PA
state: Maryland
city: Saint Louis
country: United States
facility: Siteman Cancer Center - Washington University Medical Campus
state: Missouri
city: Lake Success
country: United States
facility: Northwell Health - Centers for Advanced Medicine
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Asheville
country: United States
facility: Messino Cancer Centers
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Research Center
state: Ohio
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Fairfax
country: United States
facility: Virginia Cancer Specialists - Fairfax
state: Virginia
Study officials:
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