Pediatric Trial of Indoximod With Chemotherapy and Radiation for Relapsed Brain Tumors or Newly Diagnosed DIPG

NCT ID: NCT04049669

Last Updated: 2026-01-08

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 130 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-02
• Study Completion Date: 2027-10-02

Brief Summary

Indoximod was developed to inhibit the IDO (indoleamine 2,3-dioxygenase) enzymatic pathway, which is important in the natural regulation of immune responses. This potent immune suppressive mechanism has been implicated in regulating immune responses in settings as diverse as infection, tissue/organ transplant, autoimmunity, and cancer. By inhibiting the IDO pathway, we hypothesize that indoximod will improve antitumor immune responses and thereby slow the growth of tumors.

The central clinical hypothesis for the GCC1949 study is that inhibiting the pivotal IDO pathway by adding indoximod immunotherapy during chemotherapy and/or radiation is a potent approach for breaking immune tolerance to pediatric tumors that will improve outcomes, relative to standard therapy alone.

This is an NCI-funded (R01 CA229646, MPI: Johnson and Munn) open-label phase 2 trial using indoximod-based combination chemo-radio-immunotherapy for treatment of patients age 3 to 21 years who have progressive brain cancer (glioblastoma, medulloblastoma, or ependymoma), or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). Statistical analysis will stratify patients based on whether their treatment plan includes up-front radiation (or proton) therapy in combination with indoximod. Central review of tissue diagnosis from prior surgery is required, except non-biopsied DIPG. This study will use the "immune-adapted Response Assessment for Neuro-Oncology" (iRANO) criteria for measurement of outcomes. Planned enrollment is up to 140 patients.

Detailed Description

Disease-specific Cohorts :

Cohort 1A, 1B (closed to enrollment): relapsed or refractory glioblastoma

Cohort 2A, 2B: relapsed or refractory medulloblastoma

Cohort 3A, 3B, 3C: relapsed or refractory ependymoma

Cohort 4C (closed to enrollment): newly-diagnosed DIPG (must have no prior radiation or other therapy)

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Radiation (or proton) plan sub-cohorts:

Sub-cohort A: for patients not eligible for re-irradiation

Sub-cohort B: for patients who are eligible for partial re-irradiation

Sub-cohort C: for patients who are eligible for full-dose radiation (All newly diagnosed DIPG patients and some relapsed ependymoma patients)

Conditions

Glioblastoma; Medulloblastoma; Ependymoma; Diffuse Intrinsic Pontine Glioma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Core Regimen, sub-cohort A

For patients not eligible for re-irradiation; Start with Core Regimen chemo-immunotherapy (indoximod with oral temozolomide).

Group Type: EXPERIMENTAL

Indoximod

Intervention Type: DRUG

Indoximod will be taken by mouth twice daily during radiation and throughout each chemo-immunotherapy treatment cycle.

Temozolomide

Intervention Type: DRUG

Temozolomide will be taken by mouth once daily, on days 1-5 of each chemo-immunotherapy treatment cycle.

Core Regimen, sub-cohort B

For patients who are eligible for partial re-irradiation; Start with indoximod plus up-front re-irradiation, using a palliative low-dose or partial-field radiation plan (low-dose radiation or not all disease sites included); Followed by Core Regimen chemo-immunotherapy (indoximod with oral temozolomide).

Group Type: EXPERIMENTAL

Indoximod

Intervention Type: DRUG

Indoximod will be taken by mouth twice daily during radiation and throughout each chemo-immunotherapy treatment cycle.

Partial Radiation

Intervention Type: RADIATION

Palliative low-dose or partial-field radiation plan (low-dose radiation or not all disease sites included).

Temozolomide

Intervention Type: DRUG

Temozolomide will be taken by mouth once daily, on days 1-5 of each chemo-immunotherapy treatment cycle.

Core Regimen, sub-cohort C

For patients who are eligible for full-dose radiation; (All newly diagnosed DIPG patients and some relapsed ependymoma patients); Start with indoximod plus up-front radiation, using a palliative full-dose radiation plan to all known sites of disease (\>50 Gy to brain, \>45 Gy to spine); Followed by Core Regimen chemo-immunotherapy (indoximod with oral temozolomide).

Group Type: EXPERIMENTAL

Indoximod

Intervention Type: DRUG

Indoximod will be taken by mouth twice daily during radiation and throughout each chemo-immunotherapy treatment cycle.

Full-dose Radiation

Intervention Type: RADIATION

Palliative full-dose radiation plan to all known sites of disease (\>50 Gy to brain, \>45 Gy to spine).

Temozolomide

Intervention Type: DRUG

Temozolomide will be taken by mouth once daily, on days 1-5 of each chemo-immunotherapy treatment cycle.

Salvage Regimen 1

For patients who wish to continue access to indoximod after progression on the Core Regimen; Cross-over to indoximod with oral metronomic cyclophosphamide and etoposide).

Group Type: EXPERIMENTAL

Indoximod

Intervention Type: DRUG

Indoximod will be taken by mouth twice daily during radiation and throughout each chemo-immunotherapy treatment cycle.

Cyclophosphamide

Intervention Type: DRUG

Cyclophosphamide will be taken by mouth once daily, on days 1-21 of each chemo-immunotherapy treatment cycle.

Etoposide

Intervention Type: DRUG

Etoposide will be taken by mouth once daily, on days 1-21 of each chemo-immunotherapy treatment cycle.

Salvage Regimen 2

For patients who wish to continue access to indoximod after progression on the Core Regimen; Cross-over to indoximod with oral lomustine and temozolomide).

Group Type: EXPERIMENTAL

Indoximod

Intervention Type: DRUG

Indoximod will be taken by mouth twice daily during radiation and throughout each chemo-immunotherapy treatment cycle.

Temozolomide

Intervention Type: DRUG

Temozolomide will be taken by mouth once daily, on days 1-5 of each chemo-immunotherapy treatment cycle.

Lomustine

Intervention Type: DRUG

Lomustine will be taken by mouth once daily, on day 1 of each chemo-immunotherapy treatment cycle.

Interventions

Indoximod

Indoximod will be taken by mouth twice daily during radiation and throughout each chemo-immunotherapy treatment cycle.

Intervention Type: DRUG

Partial Radiation

Palliative low-dose or partial-field radiation plan (low-dose radiation or not all disease sites included).

Intervention Type: RADIATION

Full-dose Radiation

Palliative full-dose radiation plan to all known sites of disease (\>50 Gy to brain, \>45 Gy to spine).

Intervention Type: RADIATION

Temozolomide

Temozolomide will be taken by mouth once daily, on days 1-5 of each chemo-immunotherapy treatment cycle.

Intervention Type: DRUG

Cyclophosphamide

Cyclophosphamide will be taken by mouth once daily, on days 1-21 of each chemo-immunotherapy treatment cycle.

Intervention Type: DRUG

Etoposide

Etoposide will be taken by mouth once daily, on days 1-21 of each chemo-immunotherapy treatment cycle.

Intervention Type: DRUG

Lomustine

Lomustine will be taken by mouth once daily, on day 1 of each chemo-immunotherapy treatment cycle.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Diagnosis:

• Progressive disease with histologically proven initial diagnosis of glioblastoma, medulloblastoma, or ependymoma; With confirmation of progression by either MRI or CSF analysis; Measureable disease is not required for study entry; Patients with progressive disease must have been previously treated with therapeutic radiation as part of treatment for the initial brain cancer diagnosis or for a prior relapse.
• Newly diagnosed DIPG (diffuse intrinsic pontine glioma) with no prior therapy (including no prior radiation); Biopsy is not required for DIPG.
• Central review of tissue diagnosis is required, except non-biopsied DIPG; Archival tumor tissue must be located and available prior to study entry.
• Patients with metastatic disease are eligible.

Lansky or Karnofsky performance status score must be ≥ 50%.

Adequate renal function: creatinine ≤ 1.5-times upper limit of age-adjusted normal.

Adequate liver function:

• ALT ≤ 5-times upper limit of normal.
• Total bilirubin ≤ 1.5-times upper limit of normal.

Adequate Bone marrow function:

• Absolute neutrophil count (ANC) ≥ 750/mcL.
• Platelets ≥ 75,000/mcL (transfusion independent).
• Hemoglobin ≥ 8 g/dL (transfusion independent).

Central nervous system: seizure disorders must be well controlled on antiepileptic medication.

Prior therapy

• DIPG patients must not have been treated with any prior radiation or medical therapy.
• Patients previously treated with indoximod are excluded.
• Patients previously treated with any other immunotherapy agent, including other IDO-targeted drugs, are eligible for enrollment.
• Patients previously treated with chemotherapy drugs included in this protocol are eligible for enrollment.

Patients must be 14 days from the administration of any investigational agent or prior cytotoxic therapy with the following exceptions:

• Temozolomide dosed at or above 150 mg/m2 (allowed, but must be at least 21 days from the last dose of temozolomide).
• Must be 28 days from administration of antibody-based therapies (e.g., bevacizumab), tumor-directed vaccines, or cellular immune therapies (e.g., T cells, NK cells, etc).
• Must be 56 days from administration of tumor-directed therapies using infectious agents (e.g., viruses, bacteria, etc).

Pregnant women are excluded from this study, where pregnancy is confirmed by a positive urine or serum hCG laboratory test.

Patients must be able to swallow pills.

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Exclusion Criteria

Patients who cannot swallow indoximod pills are excluded.

Patients previously treated with indoximod are excluded.

Patients with DIPG who have been treated with any prior radiation or medical therapy are excluded.

Midline glioma that does not include significant brain stem involvement is not considered DIPG for enrollment purposes, and is excluded.

Patients with active systemic infection requiring treatment, including any HIV infection or toxoplasmosis, are excluded.

Patients with active autoimmune disease that requires systemic therapy are excluded.

Pregnant women are excluded

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Augusta University

OTHER

Sponsor Role: collaborator

Emory University

OTHER

Sponsor Role: collaborator

Theodore S. Johnson

OTHER

Sponsor Role: lead

Responsible Party

Theodore S. Johnson

Associate Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Theodore S Johnson, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Augusta University

Locations

Augusta University, Georgia Cancer Center

Augusta, Georgia, United States

Emory University, Children's Heathcare of Atlanta

Druid Hills, Georgia, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

MD Anderson Cancer Center

Houston, Texas, United States

Countries

United States

References

Johnson TS, MacDonald TJ, Pacholczyk R, Aguilera D, Al-Basheer A, Bajaj M, Bandopadhayay P, Berrong Z, Bouffet E, Castellino RC, Dorris K, Eaton BR, Esiashvili N, Fangusaro JR, Foreman N, Fridlyand D, Giller C, Heger IM, Huang C, Kadom N, Kennedy EP, Manoharan N, Martin W, McDonough C, Parker RS, Ramaswamy V, Ring E, Rojiani A, Sadek RF, Satpathy S, Schniederjan M, Smith A, Smith C, Thomas BE, Vaizer R, Yeo KK, Bhasin MK, Munn DH. Indoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trial. Neuro Oncol. 2024 Feb 2;26(2):348-361. doi: 10.1093/neuonc/noad174.

Reference Type: BACKGROUND

PMID: 37715730 (View on PubMed)

Sharma MD, Pacholczyk R, Shi H, Berrong ZJ, Zakharia Y, Greco A, Chang CS, Eathiraj S, Kennedy E, Cash T, Bollag RJ, Kolhe R, Sadek R, McGaha TL, Rodriguez P, Mandula J, Blazar BR, Johnson TS, Munn DH. Inhibition of the BTK-IDO-mTOR axis promotes differentiation of monocyte-lineage dendritic cells and enhances anti-tumor T cell immunity. Immunity. 2021 Oct 12;54(10):2354-2371.e8. doi: 10.1016/j.immuni.2021.09.005. Epub 2021 Oct 5.

Reference Type: BACKGROUND

PMID: 34614413 (View on PubMed)

Other Identifiers

R01CA229646

Identifier Type: NIH

Identifier Source: secondary_id

View Link

GCC1949

Identifier Type: -

Identifier Source: org_study_id