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

NewLink Genetics

Status and phase: Completed; Phase 1

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

Treatments: Drug: Etoposide; Drug: Temozolomide; Drug: Cyclophosphamide; Radiation: Conformal Radiation; Drug: Indoximod

Study type: Interventional

Funder types: Industry

Identifiers

NCT02502708

NLG2105

Details and patient eligibility

About

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.

Enrollment: 81 patients

Sex: All

Ages: 3 to 21 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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81 participants in 5 patient groups

Group 1 (CLOSED)

Experimental group

Description:

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

Treatment:

Drug: Indoximod

Drug: Temozolomide

Group 2 (CLOSED)

Experimental group

Description:

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

Treatment:

Drug: Indoximod

Drug: Temozolomide

Group 3 (CLOSED)

Experimental group

Description:

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

Treatment:

Drug: Indoximod

Radiation: Conformal Radiation

Drug: Temozolomide

Group 3b

Experimental group

Description:

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

Treatment:

Drug: Indoximod

Radiation: Conformal Radiation

Drug: Temozolomide

Group 4

Experimental group

Description:

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

Treatment:

Drug: Indoximod

Drug: Etoposide

Drug: Cyclophosphamide