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

NCT07662720 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: Cx01261R44CA306565-01
• Study Type: interventional
• Target: 18
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Head and Neck Squamous Cell Carcinoma (HNSCC) - Recurrent/Metastatic (R/M)

Keywords

axelopran; opioids; immuno-oncology; Head and Neck Squamous Cell Carcinoma (HNSCC); PD-L1 Positive Tumors; Pembrolizumab; Immunotherapy; Opioid-Induced Immunodeficiency; Peripheral Mu-Opioid Receptor Antagonist; Immune Restoration; glycyx; MORALE-HN

Outcome Measures

Primary Outcomes (1)

• Safety and Tolerability

  To assess the safety of daily axelopran in combination with standard of care pembrolizumab in the first line treatment of R/M HNSCC patients with PD-L1 CPS ≥1 receiving opioids for pain control over a 12-week period.

  12 weeks

Secondary Outcomes (3)

• Spontaneous bowel motility (SBM)

  5 and 12 weeks

• Overall Response Rate (ORR)

  Approximately 18 months

• Duration of Response (DOR)

  Approximately 18 months

Study Arms (1)

Axelopran in combination with Pembrolizumab in PDL-1 positive patients with HNSCC

EXPERIMENTAL

Drug: axelopran; Drug: Pembolizumab

Interventions

axelopran DRUG

Axelopran is a investigational, orally administered, once daily, peripherally acting mu-opioid receptor antagonist administered in combination with pembrolizumab in patients with PD-L1 positive recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC).

Also known as: TD-1211, pembrolizumab

Axelopran in combination with Pembrolizumab in PDL-1 positive patients with HNSCC

Pembolizumab DRUG

Pembrolizumab will be given every 6 weeks for 18 cycles

Also known as: Keytruda, pembro

Axelopran in combination with Pembrolizumab in PDL-1 positive patients with HNSCC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Male or female ≥ 18 years of age
• 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.
• PD-L1 Combined positive score (CPS) \>1. PD-L1 can be done by local CLIA certified laboratory.
• 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.
• Is taking opioid therapy to control cancer pain or will initiate opioid therapy to control cancer pain during the screening period.
• Has a performance status of ≤ 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
• 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.)
• Adequate organ function as defined by:
• Neutrophils ≥ 1,000/mm3 granulocyte colony-stimulating factor (GCSF) transfusion within 14 days prior to screening is permittable
• Platelets ≥ 75,000/mm3
• Hemoglobin ≥ 8 g/dL
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN)
• 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
• Calculated creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula) or normal creatinine.

You may not qualify if:

• 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).
• 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.
• Has received any systemic therapy for recurrent/metastatic HNSCC.
• 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.
• Rapid disease progression (within or at 3 months after definitive therapy)
• 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.
• 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.
• Confirmed HIV or active Hepatitis B or C as determined at baseline screening.
• Active infection requiring anti-microbials within 2 weeks of start of trial therapy
• 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
• 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).
• 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.)
• 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
• Women who are pregnant or breastfeeding
• Known alcohol or drug abuse or dependence

Sponsors & Collaborators

• Glycyx Therapeutics: lead
• National Cancer Institute (NCI): collaborator
• University of Pittsburgh: collaborator
• Emory University: collaborator

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck; Recurrence; Neoplasm Metastasis

Interventions

3-(8-(2-(cyclohexylmethyl(2,3-dihydroxypropionyl)amino)ethyl)-8-azabicyclo(3.2.1)oct-3-yl)benzamide; pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplastic Processes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 12, 2026
• First Posted: June 23, 2026
• Study Start: July 15, 2026
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): August 31, 2028
• Last Updated: July 15, 2026

Record last verified: 2026-07