Study of the IDO Pathway Inhibitor, Indoximod, and Temozolomide for Pediatric Patients With Progressive Primary Malignant Brain Tumors

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I Trial of Indoximod and Temozolomide-Based Therapy for Children With Progressive Primary Brain Tumors

Conditions
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Gliosarcoma, Glioblastoma Multiforme, Glioma, Malignant Brain Tumor, Ependymoma, Medulloblastoma, Diffuse Intrinsic Pontine Glioma, Primary CNS Tumor

Intervention / Treatment
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* Drug: Indoximod
* Drug: Temozolomide
* Radiation: Conformal Radiation
* Drug: Cyclophosphamide
* Drug: Etoposide


Participation Criteria
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Eligibility Criteria
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Eligibility Criteria Age: 3-21 years. Group 1 or Group 3: histologically proven initial diagnosis of primary malignant brain tumor, with no known curative treatment options. Group 2: histologically proven initial diagnosis of high-grade glioma (WHO grade III and IV), ependymoma, medulloblastoma, or other primary central nervous system tumor. Group 3b: Patients with a radiographic diagnosis or histologically proven diagnosis of diffuse intrinsic pontine glioma (DIPG). MRI confirmation of tumor progression or regrowth. Patients must be able to swallow whole capsules. Patients with metastatic disease are eligible for enrollment. Lansky or Karnofsky performance status score must be > 50%. Seizure disorders must be well controlled on antiepileptic medication. DIPG patients enrolled to Group 3b must not have been previously treated with radiation or any medical therapy. Patients previously treated with temozolomide, cyclophosphamide, and/or etoposide are eligible for enrollment. Exclusion Criteria Prior invasive malignancy, other than the primary central nervous system tumor, unless the patient has been disease free and off therapy for that disease for a minimum of 3 years Patients with baseline QTc interval of more than 470 msec at study entry, and patients with congenital long QTc syndrome. Active autoimmune disease

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (CLOSED)<br>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 | Drug: Indoximod<br>* Indoximod will be administered orally twice daily.<br>* Other names: D-1MT;Drug: Temozolomide<br>* Temozolomide will be administered on days 1-5 of every 28 day cycle.<br>* Other names: Methazolastone;|
| Experimental: Group 2 (CLOSED)<br>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 | Drug: Indoximod<br>* Indoximod will be administered orally twice daily.<br>* Other names: D-1MT;Drug: Temozolomide<br>* Temozolomide will be administered on days 1-5 of every 28 day cycle.<br>* Other names: Methazolastone;|
| Experimental: Group 3 (CLOSED)<br>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 | Drug: Indoximod<br>* Indoximod will be administered orally twice daily.<br>* Other names: D-1MT;Drug: Temozolomide<br>* Temozolomide will be administered on days 1-5 of every 28 day cycle.<br>* Other names: Methazolastone;Radiation: Conformal Radiation<br>* Conformal radiation will be administered on days 3-7 of induction cycle.<br>|
| Experimental: Group 3b<br>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 | Drug: Indoximod<br>* Indoximod will be administered orally twice daily.<br>* Other names: D-1MT;Drug: Temozolomide<br>* Temozolomide will be administered on days 1-5 of every 28 day cycle.<br>* Other names: Methazolastone;Radiation: Conformal Radiation<br>* Conformal radiation will be administered on days 3-7 of induction cycle.<br>|
| Experimental: Group 4<br>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 | Drug: Indoximod<br>* Indoximod will be administered orally twice daily.<br>* Other names: D-1MT;Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered orally daily.<br>Drug: Etoposide<br>* Etoposide will be administered orally daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of regimen limiting toxicities (RLTs) | To estimate the RP2D of indoximod combined with temozolomide | First 28 days of treatment | 
| Objective Response Rate | To assess preliminary evidence of efficacy of indoximod and temozolomide using COG brain tumor measurement criteria. | Up to three years | 
| Incidence of regimen limiting toxicities (RLTs) | To estimate the RP2D of indoximod combined with conformal radiation | First 35 days of treatment | 
| Safety and tolerability assessed by development of AEs and laboratory parameters of indoximod in combination with cyclophosphamide and etoposide. | In patients who initially achieve prolonged stable disease or better with Indoximod plus temozolomide but then develop progressive disease | Up to three years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics: Serum concentrations (Cmax/Steady State) | Group 1 | First 48 hours of treatment | 
| Safety and Tolerability of Indoximod combined with Temozolomide as assessed by incidence and severity of adverse events, dose interruptions and dose reductions. | Group 1 and 2 | Continuous during study until 30 days after study treatment is complete. | 
| Progression Free Survival (PFS) | Group 2 | Up to three years | 
| Time to Progression | Group 2 | Start of study until disease progression follow-up, up to three years | 
| Overall Survival | Group 2 | Start of study until end of follow-up, up to five years | 
| Safety and Feasibility of Indoximod combined with conformal radiation as assessed by incidence and severity of adverse events, dose interruptions and dose reductions. | Group 3 | Continuous during study until 30 days after study treatment is complete. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glioblastoma multiforme, glioma, gliosarcoma, malignant brain tumor, ependymoma, medulloblastoma