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

December 16, 2023 updated by: Theodore S. Johnson

Phase 2 Trial of Indoximod With Chemotherapy and Radiation for Children With Progressive Brain Tumors or Newly Diagnosed DIPG

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Disease-specific Cohorts :

Cohort 1A, 1B: progressive glioblastoma (relapsed or refractory)

Cohort 2A, 2B: progressive medulloblastoma (relapsed or refractory)

Cohort 3A, 3B, 3C: progressive ependymoma (relapsed or refractory)

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

.

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)

Study Type

Interventional

Enrollment (Estimated)

140

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Georgia
      • Augusta, Georgia, United States, 30912
        • Recruiting
        • Augusta University, Georgia Cancer Center
        • Contact:
        • Contact:
        • Principal Investigator:
          • Theodore S Johnson, MD, PhD
      • Druid Hills, Georgia, United States, 30322
        • Recruiting
        • Emory University, Children's Heathcare of Atlanta
        • Contact:
        • Principal Investigator:
          • Tobey J MacDonald, MD
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Recruiting
        • Dana-Farber Cancer Institute
        • Contact:
        • Principal Investigator:
          • Kee Kiat Yeo, MD
    • Ohio
      • Cincinnati, Ohio, United States, 45229
        • Recruiting
        • Cincinnati Children's Hospital Medical Center
        • Contact:
        • Principal Investigator:
          • Trent Hummel, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 years to 21 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

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.

.

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Core Regimen, sub-cohort A
For patients not eligible for re-irradiation; Start with Core Regimen chemo-immunotherapy (indoximod with oral temozolomide).
Drug: Indoximod
Indoximod will be taken by mouth twice daily during radiation and throughout each chemo-immunotherapy treatment cycle.
Drug: Temozolomide
Temozolomide will be taken by mouth once daily, on days 1-5 of each chemo-immunotherapy treatment cycle.
Experimental: 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).
Drug: Indoximod
Indoximod will be taken by mouth twice daily during radiation and throughout each chemo-immunotherapy treatment cycle.
Drug: Temozolomide
Temozolomide will be taken by mouth once daily, on days 1-5 of each chemo-immunotherapy treatment cycle.
Radiation: Partial Radiation
Palliative low-dose or partial-field radiation plan (low-dose radiation or not all disease sites included).
Experimental: 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).
Drug: Indoximod
Indoximod will be taken by mouth twice daily during radiation and throughout each chemo-immunotherapy treatment cycle.
Drug: Temozolomide
Temozolomide will be taken by mouth once daily, on days 1-5 of each chemo-immunotherapy treatment cycle.
Radiation: Full-dose Radiation
Palliative full-dose radiation plan to all known sites of disease (>50 Gy to brain, >45 Gy to spine).
Experimental: 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).
Drug: Indoximod
Indoximod will be taken by mouth twice daily during radiation and throughout each chemo-immunotherapy treatment cycle.
Drug: Cyclophosphamide
Cyclophosphamide will be taken by mouth once daily, on days 1-21 of each chemo-immunotherapy treatment cycle.
Drug: Etoposide
Etoposide will be taken by mouth once daily, on days 1-21 of each chemo-immunotherapy treatment cycle.
Experimental: 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).
Drug: Indoximod
Indoximod will be taken by mouth twice daily during radiation and throughout each chemo-immunotherapy treatment cycle.
Drug: Temozolomide
Temozolomide will be taken by mouth once daily, on days 1-5 of each chemo-immunotherapy treatment cycle.
Drug: Lomustine
Lomustine will be taken by mouth once daily, on day 1 of each chemo-immunotherapy treatment cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
8-month iRANO-PFS (Progression-Free Survival, defined by immune-adapted iRANO criteria)
Time Frame: Up to 5 years
For patients with relapsed glioblastoma, medulloblastoma, or ependymoma.
Up to 5 years
12-month Overall Survival (OS)
Time Frame: Up to 5 years
For patients with newly diagnosed DIPG (diffuse intrinsic pontine glioma).
Up to 5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Median Overall Survival (OS)
Time Frame: Up to 5 years
For each disease cohort
Up to 5 years
Median iRANO-PFS (Progression-Free Survival, defined by immune-adapted iRANO criteria)
Time Frame: Up to 5 years
For each disease cohort
Up to 5 years
Median Time to Regimen Failure (TTRF)
Time Frame: Up to 5 years
For each disease cohort
Up to 5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Theodore S. Johnson

Collaborators

National Cancer Institute (NCI)
Emory University
Augusta University

Investigators

  • Principal Investigator: Theodore S Johnson, MD, PhD, Augusta University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 2, 2019

Primary Completion (Estimated)

October 2, 2025

Study Completion (Estimated)

October 2, 2027

Study Registration Dates

First Submitted

August 2, 2019

First Submitted That Met QC Criteria

August 5, 2019

First Posted (Actual)

August 8, 2019

Study Record Updates

Last Update Posted (Actual)

December 19, 2023

Last Update Submitted That Met QC Criteria

December 16, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GCC1949
  • R01CA229646 (U.S. NIH Grant/Contract)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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