Randomized Phase IIIII Clinical and Translational Trial of

Randomized Phase II/III Clinical and Translational Trial of Combination Checkpoint and IDO 1 Inhibition with Chemoradiotherapy/Radiotherapy for Newly Diagnosed Glioblastoma Rimas Lukas, MD Associate Chief, Neuro-Oncology Division Lou & Jean Malnati Brain Tumor Institute at the Lurie Comprehensive Cancer Center Northwestern University

IDO 1 is an IFNinducible enzyme that converts tryptophan into kynurenine

Background • ↑IDO expression w/ ↑glioma grade • ↑ GBM IDO 1 expression is associated with ↓ patient survival and ↓time to recurrence Zhai, et al. CCR. 2017; 23(21): 6650 -60.

Hypothesis CD 8+ T cells increase GBM cell IDO 1 levels, which in -turn, enhances intratumoral Treg accumulation Zhai et al. , 2017; Clin. Can. Res. 23(21): 6650 -6660.

Background 0 Injection 17 20 23 21 14 35 28 Days Post ic. injection 42 Wild-type mice ic. unmodified GL 261 Percent Survival Concurrent radiotherapy, IDO 1 enzyme inhibition + PD 1 blockade synergizes to increase survival in an advanced, immunocompetent mouse GBM model WBRT PD-1 m. Ab IDO 1 i (BID) T cell Analysis **** Days Post-Intracranial (ic. ) Injection Ladomersky, et al. ; CCR. 2018; 24(11): 2559 -73

Phase I Trial of BMS-986205 + Nivolumab + (Chemo)radiotherapy for Newly Diagnosed GBM Basic Eligibility: Newly diagnosed GBM, ≥ 18 yo, KPS≥ 70 RT Newly Dx GBM MGMT Methylated MGMT Unmethylated TMZ BMS-986205 nivo BMS-986205 TMZ nivo +/-TTF RT BMS-986205 nivo RT BMS-986205 Nivolumab TTF BMS-986205 nivo +/-TTF 60 Gy 100 mg po QDay 240 mg IV Q 2 wks (480 mg IV Q 4 wks) 200 k. Hz

Randomized Phase II/III Trial of Radiotherapy+BMS-986205 + Nivolumab vs (Chemo)radiotherapy for Newly Diagnosed IDHwt GBM RT Newly Dx GBM BMS-986205 IDHwt nivo MGMT unmethylated RT TMZ BMS-986205 nivo TMZ Inclusion/Exclusion Criteria: • Stable or decreasing steroids for 7 days at time of consent • No steroids at initiation of study Tx • Low dose bevacizumab allowed for up to 3 doses for cerebral edema

Study Design Randomized Phase 2 Primary endpoint • OS 12 Secondary endpoints • PFS • RR Exploratory endpoints • Immunocorrelatives Phase 3 Primary endpoint • OS Secondary endpoints • PFS • RR • OS 24 Exploratory endpoints • Immunocorrelatives

Points of Consideration • Incidence of pseudoprogression in newly Dx GBM Tx w/ immuno. Tx unreported • Use of non-radiographic endpoint allows for low-dose bev for cerebral edema (as opposed to steroids)

ACKNOWLEDGEMENTS NRG ONCOLOGY Minesh Mehta, MD & NRG Brain Committee Biostatistics Mei Polley, Ph. D WAYNE STATE Csaba Juhasz, MD Ph. D FUNDING SOURCES P 50 CA 221747 SPORE NORTHWESTERN UNIVERSITY Radiation Oncology Sean Sachdev, MD Vinai Gondi, MD Timothy Kruser, MD Neuro-Oncology Roger Stupp, MD Priya Kumthekar, MD Jeff Raizer, MD Karan Dixit, MD Sean Grimm, MD Neurosurgery Derek Wainwright, Ph. D Maciej Lesniak, MD C. David James, Ph. D Christina Amidei, Ph. D, APN Neuropathology Daniel Brat, MD Craig Horbinski, MD