Axelopran and Nivolumab in PD-1-Refractory Metastatic Melanoma

NCT07631325 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: HCC 26-041
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

This first-in-human study will evaluate the safety, clinical activity, and immunologic effects of combining axelopran with nivolumab in patients with PD-1-refractory unresectable or metastatic cutaneous melanoma. Exploratory analyses incorporating opioid exposure history and post-hoc OPRM1 genotyping will inform future precision immuno-oncology strategies.

Conditions

Unresectable Cutaneous Melanoma

Keywords

anti-PD-1; immune checkpoint inhibitors (ICIs); OPRM1-mu opioid receptor (MOR)

Outcome Measures

Primary Outcomes (2)

• Adverse Events Related to Treatment

  Adverse events (AEs), serious adverse events (SAEs), AEs leading to discontinuation or death, and severity of AEs as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) determined to be possibly, probably or definitely related to study treatment.

  Up to 30 days post end of treatment

• Best objective response rate (BORR)

  The proportion of subjects with a confirmed best objective response of Complete Response (CR) or Partial Response (PR) based on RECIST v1.1. CR: Disappearance of all target lesions. Pathological lymph nodes must decrease to a short axis of \< 10 mm. All non-target lesions must have disappeared, and tumor markers must have normalized. PR: At least a 30% decrease in the sum of diameters of target lesions, using baseline measurements as a reference.

  Up to 3 years

Secondary Outcomes (7)

• Duration of response (DOR)

  Up to 3 years

• Best Treatment Response in Target lesions

  Up to 3 years

• Progression-free Survival (PFS)

  Up to 3 years

• Overall survival (OS)

  Up to 4.5 years

• Immune best objective response rate (iBORR)

  Up to 3 years

Study Arms (1)

Axelopran + Nivolumab

EXPERIMENTAL

Run in (1 week): Days -6 to 0, Axelopran monotherapy with dose escalating to 15mg PO daily by day 0 Combination Phase: Axelopran: 15 mg PO daily Nivolumab: 480 mg IV q4w (until disease progression, up to 3 years)

Drug: Axelopran; Drug: Nivolumab

Interventions

Axelopran DRUG

A peripherally restricted mu-opioid receptor antagonist (PAMORA) designed to mitigate the undesirable peripheral effects of opioids without compromising their central analgesic action.

Axelopran + Nivolumab

Nivolumab DRUG

An immune checkpoint inhibitor that helps the immune system attack cancer cells by blocking PD-1 receptors.

Also known as: OPDIVO Qvantig

Axelopran + Nivolumab

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed, unresectable or metastatic cutaneous melanoma with documented PD-1-refractory disease, defined as disease progression during or after prior anti-PD-1-based therapy, meeting criteria for either primary or secondary (acquired) resistance, as follows57:
• Primary resistance: Disease progression as best response, or stable disease lasting \<6 months, following at least 6 weeks (approximately two cycles) of anti-PD-1-based therapy, with progression confirmed by RECIST v1.1.
• Secondary (acquired) resistance: Disease progression occurring after an initial objective response (complete or partial response) or durable stable disease (≥6 months) per RECIST v1.1 while receiving anti-PD-1-based therapy, or within 12 weeks of discontinuation of anti-PD-1 therapy following prior clinical benefit.
• Note: Disease must have been histologically confirmed through prior pathology assessment conducted as per SOC.
• Note: Prior anti-PD-1-based therapy may have been administered as monotherapy or in combination with other agents.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) Performance Scale (PS) 0-2
• Measurable disease using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Patients must have normal organ and marrow function as defined below:
• absolute neutrophil count ≥1,000/mcL
• platelets ≥75,000/mcL
• total bilirubin ≤1.5 × the institutional upper limit of normal (ULN)
• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN (≤5 × the institutional ULN for patients with liver metastasis)
• Creatinine clearance ≥40 mL/min/1.73 m2 for patients with a creatinine level above institutional normal.
• Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception prior to study entry, during the course of the study, and for 5 months after the last dose of treatment (whichever is later). In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods.

You may not qualify if:

• Participant is not a candidate to continue anti-PD-1 therapy due to unresolved toxicities resulting from previous treatment with anti-PD-1 therapy.
• Has an active autoimmune disease requiring systemic treatment within the past 3 months, or a syndrome that requires ongoing systemic steroids or immunosuppressive agents. Subjects with vitiligo, Graves' disease, or psoriasis not requiring systemic therapy or resolved childhood asthma/atopy would be an exception to this rule.
• i. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with stable hypothyroidism or Sjogren's syndrome will not be excluded from the study.
• ii. Physiological replacement doses of steroids are permitted.
• Participant is taking a daily dose of opioids that is \>30 morphine milligram equivalents (MME) i. Daily opioid doses ≤30 MME are allowed
• Has a history of non-infectious pneumonitis that required steroids, evidence of interstitial lung disease, or currently active non-infectious pneumonitis.
• Prior malignancy within 2 years that in the investigator's opinion would be likely to affect the outcomes of the patients with unresectable melanoma.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Known HIV or active Hepatitis B or C. Checking viral serology will not be mandated.
• Patients with major gastrointestinal surgery within 12 weeks prior to the first dose of study treatment. Patients who have a colostomy will be excluded from the trial.
• Are unable to swallow pills or have known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other condition that limits the ingestion or gastrointestinal absorption of drugs administered orally.
• i. Note: Gastroesophageal reflux disease under medical treatment is allowed (assuming no drug interaction potential).
• Subjects taking moderate to strong CYP3A inhibitors or P-gp inhibitors

Sponsors & Collaborators

• John Kirkwood: lead
• Glycyx MOR Inc.: collaborator

Study Sites (1)

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Interventions

Nivolumab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• John M Kirkwood, MD

  UPMC Hillman Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Danielle Bednarz, RN, BSN

CONTACT

412-623-1191; bednarzdl@upmc.edu

Amy Rose, RN, BSN

CONTACT

412-647-8587; kennaj@UPMC.EDU

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Medicine, Dermatology & Translational Science

Study Record Dates

• First Submitted: May 29, 2026
• First Posted: June 8, 2026
• Study Start (Estimated): October 31, 2026
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): July 31, 2030
• Last Updated: July 13, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)