A Phase II Trial of MOR Antagonism With Axelopran and Nivolumab in PD-1-Refractory Metastatic Melanoma (MORALE-MM)
John Kirkwood
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.
Description
Immune checkpoint inhibitors have substantially improved outcomes in melanoma; however, resistance to PD-1 blockade remains a major clinical limitation. Approximately 60% of patients with metastatic melanoma fail to achieve an objective response to anti-PD-1 therapy, and many initial responders ultimately develop acquired resistance. These limitations highlight the need to identify additional, biologically grounded mechanisms of immune escape that can be therapeutically targeted. Importantly, pharmacologic inhibition of MOR with axelopran, a peripherally acting MOR antagonist restores T-cell e…
Eligibility
- Age range
- 18+ years
- Sex
- All
- Healthy volunteers
- No
Inclusion Criteria: 1. 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: 1. 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. 2. Secondary (acquired) resistance: Disease progression occurring af…
Interventions
- DrugAxelopran
A peripherally restricted mu-opioid receptor antagonist (PAMORA) designed to mitigate the undesirable peripheral effects of opioids without compromising their central analgesic action.
- DrugNivolumab
An immune checkpoint inhibitor that helps the immune system attack cancer cells by blocking PD-1 receptors.
Location
- UPMC Hillman Cancer CenterPittsburgh, Pennsylvania