A phase I clinical trial on combined (neo-)adjuvant intravenous plus intracranial administration of ipilimumab and nivolumab in recurrent glioblastoma (NEO-GLITIPNI).

2049 Background: Intravenous (IV) administration of ipilimumab (IPI) and nivolumab (NIVO) has shown limited activity in recurrent glioblastoma (rGBM). Intracerebral (iCer; within the brain tissue lining the resection cavity) and intracavitary (iCav; through an Ommaya reservoir) administration (admin) of IPI and NIVO was proven to be safe and resulted in promising survival outcomes (Duerinck et al. Neuro-Oncol 2024). Adding a neoadjuvant (NEOADJ) treatment phase to iCer/iCav IPI/NIVO may further improve outcome. Methods: In the Neo-Glitipni trial (NCT06097975), a single center, phase I clinical trial, patients (pts) with resectable rGBM (WHO grade 4, IDH wild type) who progressed after radiotherapy and temozolomide, with a baseline ECOG performance status of 0-2 and ≤8 mg methylprednisolone daily, received 2 NEOADJ cycles of IV IPI 1 mg/kg + NIVO 3 mg/kg followed by maximal safe resection (MSR) in week 5 with iCer admin of IPI 5 mg + NIVO 10 mg and iCav admin of IPI 1 mg + NIVO 10 mg. The adjuvant phase consists of biweekly postoperative iCav admin of IPI 1 mg + NIVO 10 mg and IV NIVO 240 mg for 12 cycles, followed by monthly NIVO 480 mg IV maintenance for up to two years. Results: 5 pts (4 male, median age 57 years (44-65); 1st recurrence in 3 pts) were enrolled. All pts received the 1 st and 4 pts also the 2 nd NEOADJ dose of IV IPI/NIVO. Out of the 5 pts, 3 were not amenable to MSR with iCer/iCav IPI/NIVO admin according to the protocol because of disease progression during the NEOADJ treatment phase and required corticosteroids (1 pt in week 2, 2 pts in week 4). Two pts successfully underwent MSR with iCer/iCav admin of IPI/NIVO per protocol. One pt initiated adjuvant treatment with iCav IPI/NIVO and IV NIVO. There were no unexpected adverse events (AE). Two pts experienced an immune-related AE that required corticosteroids and interruption of study treatment (grade 4 hepatitis in 1 pt, onset 8 days after MSR and grade 2 colitis in 1 pt, onset 28 days after MSR). One pt developed a thyroiditis during the NEOADJ treatment phase and 2 pts experienced a grade 3 treatment related AE that was not immune-related (seizure and Ommaya reservoir infection). None of the rGBM were characterized by a high tumor mutational burden on next generation sequencing. Gene expression profiling, and pharmacokinetic analysis of NIVO and IPI in the cerebrospinal fluid and blood are ongoing. After a median follow-up of 15 weeks (9-35w) all pts are alive, one pt remains free of progression (median progression free survival: 4.3 weeks). Conclusions: Four weeks of NEOADJ IV IPI/NIVO (comprising 2 admin) is safe, but symptomatic disease progression was observed in 3 out of 5 rGBM pts prior to the planned MSR with iCer/iCav IPI/NIVO admin in week 5. Therefore, the trial is being amended by shortening the NEOADJ treatment phase to 2 weeks (1 admin) and planned MSR with iCer/iCav IPI/NIVO admin in week 3. Clinical trial information: NCT06097975 .