Abstract
BACKGROUND
The indoleamine 2,3-dioxygenase (IDO) pathway is a natural immune-checkpoint mechanism often exploited by tumors to escape anti-tumor immunity. Small-molecule IDO pathway inhibitor drugs, such as indoximod, are in multiple trials for adults. Combining indoximod immunotherapy with re-irradiation is a highly innovative approach for treating children with progressive brain cancer.
DESIGN/METHODS
The goal of this first-in-children trial is to assess the feasibility, safety, and preliminary evidence of efficacy of combining indoximod either with temozolomide, or with radiation followed by maintenance therapy with indoximod/temozolomide, for children age 3 to 21 with progressive malignant brain tumors. The study includes two dose-escalation cohorts using a standard 3 + 3 design to determine a recommended phase-2 dose (RP2D) for indoximod in combination with either temozolomide (planned n=12) or radiation (planned n=12). Indoximod dose-levels are 80%, 100%, and 120% of the adult RP2D.
RESULTS
We present up-to-date toxicity/side-effect data and follow-up results for all patients treated with indoximod plus radiation. Currently, 26 children have enrolled, and 15 of these have been treated with indoximod plus radiation, including children with ependymoma (n=9), medulloblastoma (n=3), glioblastoma (n=1), bithalamic glioma (n=1), PNET (n=1). Some children received more than one radiation plan over time. All patients were heavily pre-treated, and many patients required target volume and dose adaptation to reduce toxicity risks. Among patients treated to date, median total radiation dose was 30 Gy (range 14-54 Gy), median number of radiation fraction was 20 (range 1-30), and median follow-up duration was 8 months (range 2-15 months). Overall, indoximod combined with re-irradiation has been well tolerated with manageable adverse events. To date, all patients have been able to complete their planned radiation and start maintenance therapy with indoximod/temozolomide without delay.
CONCLUSIONS
The combination of indoximod and radiation has been well tolerated in this patient population with good overall quality-of-life.