Study of the IDO Pathway Inhibitor, Indoximod, and Temozolomide for Pediatric Patients With Progressive Primary Malignant Brain Tumors
- Conditions
- MedulloblastomaDiffuse Intrinsic Pontine GliomaGlioblastoma MultiformeMalignant Brain TumorEpendymomaGliosarcomaGliomaPrimary CNS Tumor
- Interventions
- Radiation: Conformal Radiation
- Registration Number
- NCT02502708
- Lead Sponsor
- NewLink Genetics Corporation
- Brief Summary
This is a first-in-children phase 1 trial using indoximod, an inhibitor of the immune "checkpoint" pathway indoleamine 2,3-dioxygenase (IDO), in combination with temozolomide-based therapy to treat pediatric brain tumors. Using a preclinical glioblastoma model, it was recently shown that adding IDO-blocking drugs to temozolomide plus radiation significantly enhanced survival by driving a vigorous, tumordirected inflammatory response. This data provided the rationale for the companion adult phase 1 trial using indoximod (IND#120813) plus temozolomide to treat adults with glioblastoma, which is currently open (NCT02052648). The goal of this pediatric study is to bring IDO-based immunotherapy into the clinic for children with brain tumors. This study will provide a foundation for future pediatric trials testing indoximod combined with radiation and temozolomide in the up-front setting for patients with newly diagnosed central nervous system tumors.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 81
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group 3b Indoximod Indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with newly diagnosed treatment-naive diffuse intrinsic pontine glioma (DIPG). Indoximod will be administered at the RP2D of 19.2 mg/kg/dose BID. Temozolomide to be given at 200 mg/m\^2 x 5 days Group 4 Indoximod Continued access to indoximod in combination with low-dose oral cyclophosphamide and etoposide for patients with progressive disease after treatment with indoximod plus temozolomide. Indoximod will be administered at 32 mg/kg/dose divided twice daily. Cyclophosphamide to be given at 2.5 mg/kg/dose daily Etoposide to be given at 50 mg/m2/dose daily Group 3 (CLOSED) Conformal Radiation Dose-escalation of indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with progressive brain tumors. Indoximod will be administered in escalating doses. Initial dosing will be 12.8 mg/kg/dose BID with escalation planned to 22.4 mg/kg/dose BID. Temozolomide to be given at 200 mg/m\^2 x 5 days Group 3b Conformal Radiation Indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with newly diagnosed treatment-naive diffuse intrinsic pontine glioma (DIPG). Indoximod will be administered at the RP2D of 19.2 mg/kg/dose BID. Temozolomide to be given at 200 mg/m\^2 x 5 days Group 1 (CLOSED) Indoximod Core Regimen: Dose-escalation of indoximod, in combination with temozolomide, for pediatric patients with progressive brain tumors. Indoximod will be administered in escalating doses. Initial dosing will be 12.8 mg/kg/dose BID with escalation planned to 22.4 mg/kg/dose BID. Temozolomide to be given at 200 mg/m\^2 x 5 days Group 3b Temozolomide Indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with newly diagnosed treatment-naive diffuse intrinsic pontine glioma (DIPG). Indoximod will be administered at the RP2D of 19.2 mg/kg/dose BID. Temozolomide to be given at 200 mg/m\^2 x 5 days Group 1 (CLOSED) Temozolomide Core Regimen: Dose-escalation of indoximod, in combination with temozolomide, for pediatric patients with progressive brain tumors. Indoximod will be administered in escalating doses. Initial dosing will be 12.8 mg/kg/dose BID with escalation planned to 22.4 mg/kg/dose BID. Temozolomide to be given at 200 mg/m\^2 x 5 days Group 2 (CLOSED) Temozolomide Expansion cohorts: Indoximod therapy at the pediatric recommended phase 2 dose (RP2D) determined by Group 1, in combination with temozolomide. Indoximod will be administered at the RP2D of 19.2 mg/kg/dose BID. Temozolomide to be given at 200 mg/m\^2 x 5 days Group 2 (CLOSED) Indoximod Expansion cohorts: Indoximod therapy at the pediatric recommended phase 2 dose (RP2D) determined by Group 1, in combination with temozolomide. Indoximod will be administered at the RP2D of 19.2 mg/kg/dose BID. Temozolomide to be given at 200 mg/m\^2 x 5 days Group 3 (CLOSED) Temozolomide Dose-escalation of indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with progressive brain tumors. Indoximod will be administered in escalating doses. Initial dosing will be 12.8 mg/kg/dose BID with escalation planned to 22.4 mg/kg/dose BID. Temozolomide to be given at 200 mg/m\^2 x 5 days Group 3 (CLOSED) Indoximod Dose-escalation of indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with progressive brain tumors. Indoximod will be administered in escalating doses. Initial dosing will be 12.8 mg/kg/dose BID with escalation planned to 22.4 mg/kg/dose BID. Temozolomide to be given at 200 mg/m\^2 x 5 days Group 4 Cyclophosphamide Continued access to indoximod in combination with low-dose oral cyclophosphamide and etoposide for patients with progressive disease after treatment with indoximod plus temozolomide. Indoximod will be administered at 32 mg/kg/dose divided twice daily. Cyclophosphamide to be given at 2.5 mg/kg/dose daily Etoposide to be given at 50 mg/m2/dose daily Group 4 Etoposide Continued access to indoximod in combination with low-dose oral cyclophosphamide and etoposide for patients with progressive disease after treatment with indoximod plus temozolomide. Indoximod will be administered at 32 mg/kg/dose divided twice daily. Cyclophosphamide to be given at 2.5 mg/kg/dose daily Etoposide to be given at 50 mg/m2/dose daily
- Primary Outcome Measures
Name Time Method Incidence of regimen limiting toxicities (RLTs) First 35 days of treatment To estimate the RP2D of indoximod combined with conformal radiation
Objective Response Rate Up to three years To assess preliminary evidence of efficacy of indoximod and temozolomide using COG brain tumor measurement criteria.
Safety and tolerability assessed by development of AEs and laboratory parameters of indoximod in combination with cyclophosphamide and etoposide. Up to three years In patients who initially achieve prolonged stable disease or better with Indoximod plus temozolomide but then develop progressive disease
- Secondary Outcome Measures
Name Time Method Progression Free Survival (PFS) Up to three years Group 2
Overall Survival Start of study until end of follow-up, up to five years Group 2
Pharmacokinetics: Serum concentrations (Cmax/Steady State) First 48 hours of treatment Group 1
Safety and Tolerability of Indoximod combined with Temozolomide as assessed by incidence and severity of adverse events, dose interruptions and dose reductions. Continuous during study until 30 days after study treatment is complete. Group 1 and 2
Time to Progression Start of study until disease progression follow-up, up to three years Group 2
Safety and Feasibility of Indoximod combined with conformal radiation as assessed by incidence and severity of adverse events, dose interruptions and dose reductions. Continuous during study until 30 days after study treatment is complete. Group 3
Trial Locations
- Locations (5)
Children's Heathcare of Atlanta
🇺🇸Atlanta, Georgia, United States
Augusta University
🇺🇸Augusta, Georgia, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Arnold Palmer Hospital for Children
🇺🇸Orlando, Florida, United States
Children's Hospitals and Clinics of Minnesota
🇺🇸Minneapolis, Minnesota, United States