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

NCT04049669 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: GCC1949R01CA229646
• Study Type: interventional
• Target: 130
• Locations: 1 country
• Sites: 5

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.

Conditions

Glioblastoma; Medulloblastoma; Ependymoma; Diffuse Intrinsic Pontine Glioma

Keywords

IDO; indoleamine 2,3-dioxygenase; indoximod; pediatric; childhood; brain tumor; glioblastoma; medulloblastoma; ependymoma; diffuse intrinsic pontine glioma; DIPG; radiation; temozolomide; cyclophosphamide; etoposide; lomustine; immunotherapy; immune; central nervous system; CNS

Outcome Measures

Primary Outcomes (2)

• 8-month iRANO-PFS (Progression-Free Survival, defined by immune-adapted iRANO criteria)

  For patients with relapsed glioblastoma, medulloblastoma, or ependymoma.

  Up to 5 years

• 12-month Overall Survival (OS)

  For patients with newly diagnosed DIPG (diffuse intrinsic pontine glioma).

  Up to 5 years

Secondary Outcomes (3)

• Median Overall Survival (OS)

  Up to 5 years

• Median iRANO-PFS (Progression-Free Survival, defined by immune-adapted iRANO criteria)

  Up to 5 years

• Median Time to Regimen Failure (TTRF)

  Up to 5 years

Study Arms (5)

Core Regimen, sub-cohort A

EXPERIMENTAL

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

Drug: Indoximod; Drug: Temozolomide

Core Regimen, sub-cohort B

EXPERIMENTAL

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).

Drug: Indoximod; Radiation: Partial Radiation; Drug: Temozolomide

Core Regimen, sub-cohort C

EXPERIMENTAL

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).

Drug: Indoximod; Radiation: Full-dose Radiation; Drug: Temozolomide

Salvage Regimen 1

EXPERIMENTAL

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).

Drug: Indoximod; Drug: Cyclophosphamide; Drug: Etoposide

Salvage Regimen 2

EXPERIMENTAL

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

Drug: Indoximod; Drug: Temozolomide; Drug: Lomustine

Interventions

Indoximod DRUG

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

Core Regimen, sub-cohort A; Core Regimen, sub-cohort B; Core Regimen, sub-cohort C; Salvage Regimen 1; Salvage Regimen 2

Partial Radiation RADIATION

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

Core Regimen, sub-cohort B

Full-dose Radiation RADIATION

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

Core Regimen, sub-cohort C

Temozolomide DRUG

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

Core Regimen, sub-cohort A; Core Regimen, sub-cohort B; Core Regimen, sub-cohort C; Salvage Regimen 2

Cyclophosphamide DRUG

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

Salvage Regimen 1

Etoposide DRUG

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

Salvage Regimen 1

Lomustine DRUG

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

Salvage Regimen 2

Eligibility Criteria

• Age: 3 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Theodore S. Johnson: lead
• National Cancer Institute (NCI): collaborator
• Augusta University: collaborator
• Emory University: collaborator

Study Sites (5)

Augusta University, Georgia Cancer Center

Augusta, Georgia, 30912, United States

Location

Emory University, Children's Heathcare of Atlanta

Druid Hills, Georgia, 30322, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (2)

• 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.

  PMID: 37715730 BACKGROUND

• 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.

  PMID: 34614413 BACKGROUND

MeSH Terms

Conditions

Glioblastoma; Medulloblastoma; Ependymoma; Diffuse Intrinsic Pontine Glioma; Brain Neoplasms

Interventions

1-methyltryptophan; Temozolomide; Cyclophosphamide; Etoposide; Lomustine

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Brain Stem Neoplasms; Infratentorial Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Nitrosourea Compounds; Urea; Amides; Nitroso Compounds

Study Officials

• Theodore S Johnson, MD, PhD

  Augusta University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: August 2, 2019
• First Posted: August 8, 2019
• Study Start: October 2, 2019
• Primary Completion (Estimated): August 2, 2026
• Study Completion (Estimated): October 2, 2027
• Last Updated: January 8, 2026

Record last verified: 2026-01

Locations

US (5)