First-In-Children Phase 1b Study Using The Ido Pathway Inhibitor Indoximod In Combination With Radiation And Chemotherapy For Children With Newly Diagnosed Dipg (Nct02502708, Nlg2105)

Abstract Background Diffuse intrinsic pontine glioma (DIPG) is a uniformly fatal brain tumor with no available cure. Indoximod blocks the IDO (indoleamine 2,3-dioxygenase) pathway, thereby reversing IDO-mediated immune suppression in the tumor microenvironment. Methods Patients aged 3 to 21 years with treatment-naive DIPG were eligible for this phase 1b dose-confirmation study of indoximod. The treatment regimen comprised continuous oral indoximod (38.4 mg/kg/day divided twice daily) with conformal photon radiation (54 Gy in 30 fractions), followed by cycles of indoximod with temozolomide (200 mg/m2/day, days 1–5 in 28-day cycles). Results Thirteen patients (median age 9 years, range 5 to 20 years) with DIPG were treated. Median OS was 14.5 months (follow-up ranged 4.8 to 29.3 months), 12-month OS was 61.5% (8/13), and 18-month OS was 30.8% (4/13), with 1 patient remaining in follow-up at the data cutoff. This compared favorably to expected median OS of approximately 10.8 months, 12-month OS of 45.3%, and 18-month OS of 16.2% taken from published historical data from the Pediatric Brain Tumor Consortium. Two patients showed near-complete responses lasting until relapsing after 7.6 months and 13.3 months of study therapy, respectively. Many patients had increased circulating non-classical monocytes (nc-Monos, CD16+, CD14neg, CD33+, HLA-DR+) within the first 3 treatment cycles, and elevation of this early pharmacodynamic marker was predictive of subsequent OS. Patients with nc-Monos >10% (n=7) had median OS of 19 months, whereas patients with nc-Monos below 10% (n=5) had median OS of 7 months (p=0.0047). No patients stopped therapy for toxicity. The most common indoximod-attributed adverse events were thrombocytopenia, neutropenia, nausea, vomiting, dizziness, and fatigue. Conclusions Adding indoximod immunotherapy to conventional radiation and chemotherapy for front-line treatment of pediatric patients with DIPG was well-tolerated. Improved outcomes were observed in patients having evidence of pharmacodynamic response. A follow-on phase 2 study is in progress (NCT04049669).