Overview

The investigational drug to be studied in this protocol, BCA101, is a first-in-class compound that targets both EGFR with TGFβ. Based on preclinical data, this bifunctional antibody may exert synergistic activity in patients with EGFR-driven tumors.

Eligibility

Inclusion Criteria:

• Patient must have measurable disease amendable to biopsy and be willing to undergo both a pre-treatment and on-treatment biopsy, as well as provide archival tumor if available from the primary tumor (a paraffin embedded tumor tissue block sufficient to obtain at least 10 sections of 4 to 5 micrometer thickness).
• Patient must have a performance status of ≤1 on the Eastern Cooperative Oncology Group Performance Scale.
• Patients must have evaluable or measurable disease (computed tomography [CT]/magnetic resonance imaging [MRI] scans performed within 21 days before the screening visit are acceptable) demonstrating measurable disease, i.e., at least 1 unidimensional measurable lesion as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) and Immune Response Evaluation Criteria in Solid Tumors (iRECIST).
• Tumor eligibility:

PART B (Cohort expansion):

i. Single agent BCA101 - patients with the following tumor type will be eligible:

        • Expansion Cohort 1: Cutaneous Squamous Cell Carcinoma (CSCC) - i. patients must have
        received (or been intolerant to or ineligible for) prior anti-PD-1 therapy in the
        metastatic or locally advanced setting.
        ii. No prior history of treatment with anti-EGFR antibodies in the unresectable/metastatic
        setting (prior treatment with radiotherapy in the adjuvant setting is allowed).
        ii. Combination BCA101 and pembrolizumab - patients with the following tumor types will be
        eligible:
        • Expansion Cohort 2: Head and Neck Squamous Cell Carcinoma (HNSCC), metastatic or
        unresectable, recurrent with a Combined Positive Score (CPS) equal to or greater than 1, as
        determined by an CLIA-approved laboratory test. Primary tumor locations of oropharynx, oral
        cavity, hypopharynx, or larynx. Participants may not have a primary tumor site of
        nasopharynx (any histology).
        i. Patients must have no prior systemic therapy administered in the recurrent or metastatic
        setting (with the exception of systemic therapy completed >6 months prior if given as part
        of multimodal treatment for locally advanced disease) or prior history of immune checkpoint
        inhibitors with the exception of neoadjuvant therapy (>6 months prior to study drug
        initiation). No prior history of anti-EGFR antibodies (with the exception of
        radiosensitizing agents and multimodal treatment for locally advanced disease).
        ii. Patients must provide tissue for PD-L1 biomarker analysis from a core or excisional
        biopsy (fine needle aspirate is not sufficient): A newly obtained biopsy (within 90 days
        prior to start of study treatment) is preferred but an archival sample is acceptable.
        iii. Patients must have results from testing of human papillomavirus (HPV) status for
        oropharyngeal cancer
          -  Expansion Cohort 3: Squamous Carcinoma of the Anal Canal (SCAC), locally
             advanced/unresectable or metastatic.
             i. Patients must have received (or been intolerant to or ineligible for) at least 1
             prior line of chemotherapy and received no more than 2 prior lines of systemic
             treatments for treatment of unresectable and/or metastatic disease. No prior history
             of immune checkpoint inhibitors.
          -  Expansion Cohort 5: Squamous Non-Small Cell Lung Cancer (SqNSCLC) i. Patients must
             have a histologically or cytologically confirmed diagnosis of stage IV (AJCC 8th
             edition) squamous NSCLC. Patients with mixed histology (e.g., adenosquamous) are not
             allowed.
        ii. Patients must have progressed on one prior systemic therapy in the metastatic setting.
        iii. No prior history of treatment with anti-EGFR antibodies in the metastatic setting.
        Exclusion Criteria:
          -  For Part A: Exposure to anti-EGFR antibodies within 4 weeks of the first dose of study
             drug.
          -  Prior treatment with any anti-TGFβ therapy.
          -  Prior history of Grade ≥ 2 intolerance or hypersensitivity reaction to cetuximab or
             other anti-EGFR therapy or other murine proteins or prior discontinuation of therapy
             in the setting of toxicity related to treatment.
          -  Pregnant or breastfeeding women.
          -  Any condition requiring systemic treatment with either corticosteroids (>10 mg daily
             of prednisone or equivalent) or other immunosuppressive medication within 14 days
             prior to the first dose of study drug, with the exception of topical, intranasal,
             intrabronchial, or ocular steroids.
          -  Known history of a hematologic malignancy (or solid tumor other than the ones
             indicated for this study), unless the patient has undergone potentially curative
             therapy with no evidence of that disease for 2 years. Does not include tumors with a
             negligible risk of metastasis or death (e.g. adequately treated basal or squamous cell
             carcinoma, stage 1 prostate cancer, or carcinoma in situ of the cervix or carcinoma in
             situ of the breast). Subjects enrolling in the CSCC cohort may have chronic
             lymphocytic leukemia as long as the patient is not on active treatment.
          -  Known cases of human immunodeficiency virus (HIV) are excluded if patients have a CD4+
             T-cell (CD4+) count <250 cells/uL. To ensure that effective antiretroviral therapy
             (ART) is tolerated and that toxicities are not confused with investigational drug
             toxicities, trial participants should be on established ART for at least four weeks
             and have an HIV viral load less than 400 copies/mL prior to enrollment.
          -  Patients with chronic HBV infection with active disease who meet the criteria for
             anti-HBV therapy and are not on a suppressive antiviral therapy prior to initiation of
             study treatment
          -  Patients with a known history of hepatitis C who have not completed curative antiviral
             treatment or have a HCV viral load above the limit of quantification