Although advances in treatment with immune checkpoint inhibitors (CPI) have greatly improved the survival for pts with metastatic melanoma (MM), many still progress and ultimately die from this disease. Metastases to the Central Nervous System (CNS) are one of the most common and devastating complications of MM, occurring in up to 60% of pts and those with LMD have the worst prognosis (overall survival only weeks) and limited treatment options. Our program has demonstrated that IT administration of interleukin-2 (IL2) induces durable disease control and prolonged survival in pts with LMD, with 1, 2, 5- year survival rates of 36%, 26%, and 13% respectively. Given the favorable clinical activity and safety compared to systemic IL2 and supported by pre-clinical data, we hypothesize that IT administration of nivo is safe and will induce CNS immune responses in pts with LMD.
This single center Phase I/Ib trial (NCT03025256) will treat MM LMD pts with concurrent IT (via Ommaya) and IV nivo. The initial dose escalation phase (up to 18pts) will determine the safety and recommended dose (primary objective) followed by an expansion cohort (12 pts) at the recommended dose to assess overall survival (secondary objective). Cycle 1 will consist of IT nivo only at a starting flat dose of 5mg. In subsequent cycles, IT nivo will be followed the next day by IV nivo 240mg Q2W. Pts will be hospitalized overnight for the IT dosing and monitored for neurotoxicity, including signs of elevated intracranial pressure. We will use the Bayesian mTPI method to determine the recommended dose. Pts must have radiographic and/or CSF cytopathologic (CSF) confirmed LMD. Prior therapy with systemic CPI and steroid use (≤ 4 mg / 24 hrs of dexamethasone or equivalent) to control CNS symptoms is allowed. Exploratory objectives include the evaluation of immunological effects of this treatment on immune cells in the CSF versus peripheral blood and non-LMD tumors. This is the first in human study for LMD pts to receive CPI via IT and systemic administration concurrently. This approach has great potential to be a safe and more efficacious therapy in MM patients with LMD for which there is an urgent unmet need.
Clinical trial identification
Legal entity responsible for the study
University of Texas MD Anderson Cancer Center.
I.C. Glitza: Research trial funding: BMS. W-J. Hwu: Research grant: BMS. M. Wong: Advisory board: EMD-Serono, Pfizer, Merck. R. Amaria: Research trial funding: BMS. H. Tawbi: Consulting/participated advisory boards: Merck, BMS, Genentech, Novartis; Research funding (institution): Merck, GSK, BMS, Genentech, Celgene. M. Davies: Advisory board, BMS. All other authors have declared no conflicts of interest.