IMCT-21UPDATES ON PHASE 1B/2 COMBINATION STUDY OF THE IDO PATHWAY IHIBITOR INDOXIMOD WITH TEMOZOLOMIDE FOR ADULT PATIENTS WITH TEMOZOLOMIDE-REFRACTORY PRIMARY MALIGNANT BRAIN TUMORS

Abstract

BACKGROUND: Indoleamine 2, 3-dioxygenase (IDO) is a key immune-modulatory enzyme within the IDO Pathway that inhibits CD8+ T cells and enhances the suppressor activity of Tregs. IDO is expressed in 50 to 90% of glioblastoma (GBM), and this high expression correlates with poor prognosis. IDO pathway inhibitors such as indoximod can improve anti-tumor T cell response slowing the tumor growth in vivo. We have demonstrated a synergistic effect of indoximod when combined with temozolomide (TMZ) and radiation in a syngeneic orthotopic brain tumor model. The purpose of this study is to determine the safety and preliminary efficacy of indoximod in combination with TMZ in recurrent refractory malignant brain tumors. METHODS: After progression on TMZ, patients are treated with indoximod (1200 mg BID orally) combined with a standard fixed dose of TMZ (150mg/m2x5 days). In the phase 2 expansion, patients are enrolled into 3 cohorts: 2a: indoximod with TMZ, 2b: indoximod with TMZ and bevacizumab (after progression on bevacizumab), 2c: indoximod with TMZ in conjunction with stereotactic radiosurgery in selected patients. Indoximod is administered for 28 days of each treatment cycle. RESULTS: 30 patients of a planned 105 are enrolled of which 12 patients completed the phase 1b cohort with no DLTs. The ready for phase 2 dose was 1200mg BID. 4 patients in phase 1b remain on study, the longest for 15 months. Best responses to date in the phase 1b component include one patient demonstrating an ongoing PR at 15 months per RANO criteria and SD in 4 patients lasting between 4 and 11 months. No severe AEs or change in TMZ dosing due to indoximod addition were documented. CONCLUSIONS: The phase 1b part has been successfully concluded with encouraging preliminary observations. Enrollment into the phase 2 portion is ongoing. Updates will be presented at the meeting. NCT02052648.