Intravenous (IV) administration of IPI and NIVO has low activity in patients (pts) with recurrent glioblastoma (rGB). IT administration of IPI and NIVO was safe in cohort C1 and C2 of the GlITIpNi phase I clinical trial (Schwarze et al. ASCO 2020, abstract #2534). In C3 and C4, IT administration of IPI and NIVO was followed by repeated IC and IV administrations of NIVO.
Pts with resectable rGB were recruited in C4; pts with non-resectable rGB in C3 (biopsy only). IT administration (in the brain tissue lining the resection cavity) of IPI (5 mg) plus NIVO (10 mg), was followed by IC-NIVO (through an Ommaya reservoir) at a dose of 1, 5 or 10 mg Q2w plus IV-NIVO (10mg) Q2w (max 12x). Cerebrospinal fluid (CSF) was collected prior to each drug administration for biochemical/cytological analysis, and concentration measurements of IPI and NIVO. NGS (RNA/DNA) was performed on resected tissue.
32 pts (23 male; med age 55y [38-77]; IDH1 R132H mutation [n=2], 1p/19q LOH [n=1]) diagnosed with rGB were enrolled (C3 [n=17], C4 [n=15]). After a median FU of 37w (1-82w), study treatment is ongoing in 2 pts. All pts received the predefined IT dose of IPI and NIVO. Median number of IC/IV NIVO administrations in C3 and C4 were respectively 5 [1-12] and 4 [1-12]. Most frequent AEs were fatigue (n=27), headache (n=17), fever (n=9), and seizures (n=5). Bacterial colonization of the Ommaya reservoir requiring removal and antibiotic therapy occurred in 4 pts. There were no G5 AEs. In C3, 1 pt has an ongoing PR after 83w (best response was PD in all other 15 evaluable pts); 11 pts have died (due to PD; median OS is 38w [95% CI 9-61]). In C4, 3 pts remain relapse-free after 30, 31 and 32w; 5 pts have died (all due to PD; median OS not reached). In 5 (C3) and 6 (C4) pts, elevated protein levels as well as lymphocytic pleocytosis were documented. There was no evidence for accumulation of NIVO in the CSF during therapy. Cytokine, cfDNA analysis of CSF and NGS on tumor tissue are ongoing.
IT administration of NIVO and IPI followed by IC/IV administration of NIVO was feasible and sufficiently safe to warrant further investigation in pts with rGB.
Clinical trial identification
Legal entity responsible for the study
Department of Medical Oncology, Universitair Ziekenhuis Brussel.
Stichting Tegen Kanker.
J.K. Schwarze: Travel/Accommodation/Expenses: Merck Sharp & Dohme; Travel/Accommodation/Expenses: Amgen. G. Awada: Research grant/Funding (institution): Pfizer; Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Astellas. B. Neyns: Research grant/Funding (institution): Roche; Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: EtheRNA; Advisory/Consultancy: CryoStorage; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Merck-Serono. All other authors have declared no conflicts of interest.