Axelopran and Nivolumab in PD-1-Refractory Metastatic Melanoma
ConditionUnresectable Cutaneous Melanoma
Trial statusNot yet recruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorJohn Kirkwood
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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.
Disqualifiers
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.
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.
Trial design
Design model
Single group
Treatments tested in this trial
Axelopran
DrugA peripherally restricted mu-opioid receptor antagonist (PAMORA) designed to mitigate the undesirable peripheral effects of opioids without compromising their central analgesic action.
Nivolumab
DrugAn immune checkpoint inhibitor that helps the immune system attack cancer cells by blocking PD-1 receptors.
Treatment groups
28 Participants
are divided into 1 treatment groupGroup A: Axelopran + NivolumabExperimental treatment 2 interventions
Trial outcomes
Primary outcomes
1
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.
Time frame
Up to 30 days post end of treatment2
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.
Time frame
Up to 3 yearsSecondary outcomes
1
Duration of response (DOR)
Time from date of first documented response Complete Response (CR) or Partial Response (PR) to date of documented Progressive Disease (PD) or death from any cause, 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. PD: At least 20% increase in the sum of diameters of target lesions, taking the smallest sum on study (nadir) as the reference. In addition to the 20% relative increase, the sum must also show an absolute increase of at least 5 mm. The unequivocal progression of non-target lesions or the appearance of any new lesion also classifies as PD.
Time frame
Up to 3 years2
Best Treatment Response in Target lesions
Best treatment response in target lesions 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.
Time frame
Up to 3 years3
Progression-free Survival (PFS)
Time from date of first dose of study treatment to date of first documented Progressive Disease (PD) based on RECIST v1.1, or death from any cause, whichever occurs first. PD: At least 20% increase in the sum of diameters of target lesions, taking the smallest sum on study (nadir) as the reference. In addition to the 20% relative increase, the sum must also show an absolute increase of at least 5 mm. The unequivocal progression of non-target lesions or the appearance of any new lesion also classifies as PD. iUPD (Unconfirmed Progressive Disease) requires a follow-up scan to confirm whether it is true tumor growth or temporary.
Time frame
Up to 3 years4
Overall survival (OS)
Overall survival, defined as the time from date of first dose of study treatment to date of death from any cause.
Time frame
Up to 4.5 yearsSponsors and contacts
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Source ClinicalTrials.gov
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