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 <1.5 × ULN unless known liver metastasis where allowance up to 5 × ULN will be acceptable and for those with known Gilbert's Disease where total bilirubin up to 3.0 × ULN will be acceptable
   6. Calculated creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula) or normal creatinine.

10. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test prior to trial entry and must be willing to use a highly effective method of contraception throughout the trial and trial follow up or for at least 90 days after the last dose of study intervention. NOTE: A woman is considered to be of non-childbearing potential if she meets one of the following criteria: a) post-menopausal with at least 12 months of spontaneous amenorrhea; b) has had a bilateral oophorectomy; or c) has had a hysterectomy.

11. Males with female partners of childbearing potential must agree to use a highly effective method of contraception throughout the trial and trial follow up or for at least 90 days after the last dose of study intervention. All men with female partners of childbearing potential will be instructed to contact the investigator immediately if their partner becomes pregnant at any time during trial participation. All men must agree not to donate semen throughout the trial and for 90 days after the last dose of study intervention.

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Exclusion Criteria: Individuals will be excluded from the trial for any of the following reasons:

1. Previous severe hypersensitivity reaction to treatment with a monoclonal antibody, hypersensitivity to excipients components of drug product, or has a known sensitivity to any component of the anti-PD-1 antibody (if applicable).

2. Has received chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy that is considered to be investigational (i.e., used for nonapproved indications(s) and in the context of a research investigation) ≤ 14 days prior to the first dose of axelopran or within 5 drug half- lives (whichever is shorter) prior to the first dose of study intervention.

3. Has received any systemic therapy for recurrent/metastatic HNSCC.

4. Patients with any ongoing toxicity related to a prior cancer therapy that is Grade >2 and considered by the Sponsor to be a safety risk for the study will be excluded.

5. Rapid disease progression (within or at 3 months after definitive therapy)

6. Patients must not be under consideration for salvage surgery. This includes patients whose disease is deemed not resectable, in addition to patients who have declined salvage surgery.

7. Has received a live attenuated virus vaccine within 30 days of planned study intervention start Note: An individual may be eligible if they have an adequate white cell count such that an immune response can be mounted, at the discretion of the Investigator.

8. Confirmed HIV or active Hepatitis B or C as determined at baseline screening.

9. Active infection requiring anti-microbials within 2 weeks of start of trial therapy

10. Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension, and congestive heart failure (New York Heart Association (NYHA) class III or IV) related to primary cardiac disease, a history of a serious uncontrollable arrhythmia despite treatment, ischemic or severe valvular heart disease, a myocardial infarction within 6 months prior to the trial entry, or QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 msec at screening

11. Has not fully recovered from any effects of major surgery, including complications such as infection (Surgeries that required general anesthesia must be completed ≥ 2 weeks before first study intervention administration. Surgery requiring regional/epidural anesthesia must be completed ≥ 72 hours before first study intervention administration and subjects should be recovered).

12. Use of immunosuppressive medications within 4 weeks, or systemic corticosteroids within 2 weeks prior to first dose of study intervention (Topical, inhaled, or intranasal corticosteroids [with minimal systemic absorption] may be continued if the individual is on a stable dose. Non-absorbed intra-articular corticosteroid and replacement steroids [prednisone equivalent 10 mg or less] will be permitted.)

13. Underlying medical condition that, in the investigator's opinion, will make the administration of study intervention hazardous or obscure the interpretation of toxicity determination or AEs

14. Women who are pregnant or breastfeeding

15. Known alcohol or drug abuse or dependence

16. Subjects with known or suspected mechanical gastrointestinal obstruction and at increased risk of recurrent obstruction (i.e., Crohn's disease, peptic ulcer disease, Ogilvie's syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases).

17. Subjects with moderate or severe renal impairment (eGFR <60) or moderate and severe hepatic impairment (Child-Pugh Band C).

18. Subjects taking moderate to strong CYP3A inhibitors or P-gp inhibitors (see List in Appendix 5)

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