CTIM-17. INTRA-CRANIAL ADMINISTRATION OF CTLA-4 AND PD-1 IMMUNE CHECKPOINT-INHIBITING MONOCLONAL ANTIBODIES IN RECURRENT GLIOBLASTOMA PATIENTS: A MULTI-COHORT ADAPTIVE PHASE I CLINICAL TRIAL

Abstract

Abstract BACKGROUND: Intracerebral (iCE) administration of nivolumab (NIVO) and ipilimumab (IPI) after resection of recurrent glioblastoma (rGB), followed by repeated intravenous(IV) NIVO was recently shown to be feasible, safe and associated with encouraging survival. Subsequent cohorts were defined to investigate the addition of biweekly intracavitary (iCA) or intrathecal (iTH) NIVO +/- IPI administrations. METHODS Four groups were defined according to rGB resectability and postoperative treatment schedule. Group A and D underwent biopsy, B and C maximal safe resection. All patients received iCE injections of 10 mg/1ml NIVO + 5 mg/1ml IPI at the end of surgery, after which an Ommaya catheter was implanted iCA (A, B and C) or iTH (D). Following surgery, all patients received biweekly IV low-dose NIVO(10mg) combined with iCA/iTH 10 mg NIVO (A and B) + 1, 5 or 10 mg IPI (C and D) for up to 24 weeks. NIVO/IPI concentrations were dosed in the cerebrospinal fluid (CSF). Gene sequencing and RNA gene expression profiling were performed on all tissue samples RESULTS 39pts(27 male; 16 in A, 16 in B, 4 in C, 3 in D; recruitment ongoing in C+D) were enrolled. All patients received the predefined dose of iCE IPI/NIVO. Most frequent AEs were fatigue (n=30), headache (n=19), confusion (n=14), dysphasia (n=13), and fever (n=10). Ommaya infection occurred in 5patients, subacute neurological deterioration requiring corticosteroids in 6patients. There were no G5 AEs. irAEs were infrequent and mild. Median PFS and OS were 5w(95% CI 1-8) and 23w(95% CI 0-53) in A and 13w(95% CI 7-19) and 42w(95% CI 30-54) in B, respectively. >90% of CSF samples had elevated protein levels and lymphocytic pleocytosis. There was no evidence for accumulation of NIVO/IPI in the CSF. CONCLUSION Repeated intracavitary or intrathecal administration of NIVO +/- IPI in rGB is feasible and safe. Favourable survival outcome is seen in patients amenable to surgical resection.