A Phase II Trial for MOR Antagonism With Axelopran to Enhance Immunotherapy in Head and Neck Cancer

This Phase 2, open-label, multicenter study will evaluate the safety and preliminary efficacy of axelopran in combination with pembrolizumab in patients with PD-L1 positive recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Axelopran is a peripherally acting mu-opioid receptor antagonist being developed to address opioid-induced immunodeficiency, a condition that may impair anti-tumor immune responses and reduce the effectiveness of immune checkpoint inhibitors. Many patients with advanced HNSCC require opioid analgesics for cancer-related pain management. Emerging evidence suggests that opioid signaling may suppress immune function and diminish the therapeutic activity of PD-1/PD-L1 inhibitors. By blocking peripheral mu-opioid receptor signaling without affecting central analgesia, axelopran may restore immune competence and enhance response to pembrolizumab. Approximately 18 patients with PD-L1 positive recurrent or metastatic HNSCC will be enrolled in a two-stage design consisting of an initial futility assessment cohort followed by expansion to the full study population. Participants will receive axelopran in combination with standard pembrolizumab therapy and will be followed for efficacy, safety, and survival outcomes. The estimated study duration is approximately 36 months, including enrollment, treatment, and follow-up. The primary objectives are to evaluate objective response rate and assess the safety and tolerability of the combination regimen. Secondary and exploratory objectives include progression-free survival, overall survival, duration of response, and assessment of biomarkers related to immune activation and opioid-induced immunosuppression. This study aims to determine whether targeting opioid-mediated immune suppression can improve clinical outcomes in patients receiving immune checkpoint inhibitor therapy for advanced head and neck cancer.

Inclusion Criteria: Individuals may be included in the trial only if they meet all of the following inclusion criteria prior to administration of investigational product: 1. Read, understood, and provided written informed consent and, if applicable, Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the trial has been fully explained and must be willing to comply with all trial requirements and procedures 2. Male or female ≥ 18 years of age 3. Recurrent/Metastatic Squamous cell carcinoma of the head and neck (oral cavity, oropharynx, larynx, hypopharynx) that is considered incurable by local therapies, who are planning to receive pembrolizumab as first line therapy or for platinum failure. Platinum Failure is defined as recurrence/progression between 3-6 months from definitive platinum based chemoradiation therapy. 4. PD-L1 Combined positive score (CPS) \>1. PD-L1 can be done by local CLIA certified laboratory. 5. Has not received anti-PD-1 or Anti-PD-L1 mAb therapy for recurrent/metastatic disease. A patient that received anti-PD-1 or Anti-PD-L1 mAb therapy as part of upfront curative intent therapy is eligible as long as it has been at least 1 year since the last dose of anti-PD-1 or anti-PD-L1 mAb therapy. 6. Is taking opioid therapy to control cancer pain or will initiate opioid therapy to control cancer pain during the screening period. 7. Has a performance status of ≤ 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale 8. Measurable disease by RECIST v1.1 that meets the criteria for selection as a target lesion according to RECIST v1.1 (The presence of measurable disease per RECIST v1.1 must be confirmed by local radiology prior to subject entry.) 9. Adequate organ function as defined by: 1. Neutrophils ≥ 1,000/mm3 granulocyte colony-stimulating factor (GCSF) transfusion within 14 days prior to screening is permittable 2. Platelets ≥ 75,000/mm3 3. Hemoglobin ≥ 8 g/dL 4. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN) 5. Total bilirubin \