Pepinemab in Combination With Pembrolizumab in Advanced, Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
Pepinemab in Combination With Pembrolizumab in Advanced, Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
The purpose of the study is to evaluate the safety and tolerability of pepinemab in
 combination with pembrolizumab and determine a recommended Phase 2 dose (RP2D) in patients
 with advanced, recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC).
The purpose of the study is to evaluate the safety and tolerability of pepinemab in
 combination with pembrolizumab and determine a recommended Phase 2 dose (RP2D) in patients
 with advanced, 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 and determine a recommended Phase
 2 dose (RP2D) for the dose-expansion phase enrolling subjects in patients with advanced,
 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 advanced 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
 advanced 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).
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.