OGCT-03 PHASE I/IB STUDY OF CONCURRENT INTRAVENOUS (IV) AND INTRATHECAL (IT) NIVOLUMAB (N) AND RELATLIMAB (R) FOR METASTATIC MELANOMA (MM) PATIENTS (PTS) WITH LEPTOMENINGEAL DISEASE (LMD)

Abstract LMD patients are faced with dismal overall survival (OS) . Our previously reported phase 1/1b trial using IT/IV N (n=50) showed a median OS of 7.5 months, with no unexpected toxicities. N (anti-PD1) and R (anti-LAG3) represents a fixed- dose combination (FDC) approved for the treatment of unresectable MM. We therefore amended this trial using the combination of IT/IV N/R, as we identified LAG-3 on T cells within the cerebrospinal fluid (CSF). Preclinical models confirmed that the combined treatment with IT/IV anti-PD1/anti-LAG3 achieved highly significant improvement in OS. Based on the prior tolerated dose of IT N 50mg, and the approved FDC ratio for IV N/R, we chose a FDC of IT N/R 50mg/16.7mg with concurrent with IT N/R at 480mg/160mg. We hypothesize that IT/IV N/R will be safe and an effective treatment for MM patients with LMD. Methods: This is a Phase Ib, non- randomized, single center trial of concurrent IT/IV N/R in adult (≥18 years) MM pts with LMD (NCT03025256). Up to 20 patients will receive IT N/R every 28 days, and Cycle 1 (C1) will consist of IT N/R only. Subsequently, IT dose will be followed by IV N/R. Most pertinent inclusion criteria are radiographic and/or CSF cytological evidence of LMD, ECOG PS of ≤ 2, with adequate organ function. Prior radiation and immunotherapy is allowed, as is the use of concurrent BRAF/MEK inhibitors and dexamethasone (≤ 4 mg per day). Primary endpoint is safety, and Bayesian toxicity monitoring rule will be used. Secondary endpoints are OS, survival rates at 3,6 and 12 months, and median duration of treatment. CSF, blood and microbiome samples will be collected at various time points. The first patient was enrolled in October 2024 and accrual is ongoing (NCT03025256).