Testing Whether Cemiplimab (REGN2810) Plus CDX-1140 Given Prior to Surgery Are Better Than Cemiplimab (REGN2810) Alone in Patients With Stage III-IV Head and Neck Cancer

This phase II trial compares the effectiveness of cemiplimab with CDX-1140 to cemiplimab without CDX-1140 prior to surgery in treating patients with stage III-IV head and neck cancer. Immunotherapy with monoclonal antibodies, such as cemiplimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. CDX-1140 is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Giving cemiplimab with CDX-1140 versus cemiplimab alone before surgery may make the tumor smaller and may reduce the amount of normal tissue that needs to be removed for patients with stage III-IV head and neck cancer.

PRIMARY OBJECTIVE: I. To evaluate major pathologic response rate (defined as ≤ 10% of residual viable tumor) of anti-CD40 agonist monoclonal antibody CDX-1140 (CDX-1140) combined with cemiplimab (REGN2810) compared with cemiplimab (REGN2810) alone. SECONDARY OBJECTIVES: I. Evaluate the rate of any pathologic response of CDX-1140 in combination with cemiplimab (REGN2810). II. To evaluate toxicity and tolerability of CDX-1140 and programmed cell death protein 1 (PD-1) blockade combination in neoadjuvant (pre-surgical) setting. III. To compare gene expression profiles by ribonucleic acid (RNA) sequencing (RNAseq) between CDX-1140 and control groups as well as correlate gene expression with pathologic response. IV. To evaluate circulating tumor deoxyribonucleic acid (DNA) (ctCNA) as a biomarker of response to neoadjuvant immunotherapy V. To evaluate the pharmacokinetics (PK) of CDX-1140 and cemiplimab (REGN2810) used in combination (arm 2) and the relationship of outcomes to baseline and time-varying clearance of both agents. EXPLORATORY OBJECTIVES: I. To evaluate dynamic changes in tumor microenvironment (TME) and circulating immune cell populations. Ia. To compare dynamic changes in TME while on treatment with subsequent pathologic response in the final specimen. II. To evaluate changes in circulating plasma cytokines pre and post neoadjuvant immunotherapy with CDX-1140 and cemiplimab (REGN2810). III. To correlate major pathologic response with the level of programmed cell death ligand 1 (PD-L1) expression. IV. To explore the correlation of pathologic response to disease free recurrence and overall survival at 2 years after surgery. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive cemiplimab intravenously (IV) over 30 minutes on day 1. Patients then undergo standard of care surgical resection on day 29-36 and receive standard of care adjuvant therapy. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, positron emission tomography (PET) during screening and tumor biopsy and blood sample collection throughout the study. ARM II: Patients receive CDX-1140 IV over 90 minutes on day 1 and cemiplimab IV over 30 minutes on day 4. Patients then undergo standard of care surgical resection on day 29-36 and receive standard of care adjuvant therapy. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, PET during screening and tumor biopsy and blood sample collection throughout the study. After completion of study treatment, patients are followed up at week 9-10, week 18, at 6 months and every 3-6 months for 2 years after surgery.