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

• ClinicalTrials.gov Identifier: NCT04049669
• Recruitment Status: Recruiting
• First Posted: August 8, 2019
• Last Update Posted: April 12, 2023
• Sponsor: Theodore S. Johnson
• Collaborators: National Cancer Institute (NCI); Augusta University; Emory University
• Information provided by (Responsible Party): Theodore S. Johnson, Augusta University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Glioblastoma; Medulloblastoma; Ependymoma; Diffuse Intrinsic Pontine Glioma	Drug: Indoximod; Radiation: Partial Radiation; Radiation: Full-dose Radiation; Drug: Temozolomide; Drug: Cyclophosphamide; Drug: Etoposide; Drug: Lomustine	Phase 2

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)

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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)

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 140 participants
• Allocation: Non-Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Trial of Indoximod With Chemotherapy and Radiation for Children With Progressive Brain Tumors or Newly Diagnosed DIPG
• Actual Study Start Date: October 2, 2019
• Estimated Primary Completion Date: October 2, 2025
• Estimated Study Completion Date: October 2, 2027

Arms and Interventions

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.; Radiation: Partial Radiation; Palliative low-dose or partial-field radiation plan (low-dose radiation or not all disease sites included).; 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 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.; Radiation: Full-dose Radiation; Palliative full-dose radiation plan to all known sites of disease (>50 Gy to brain, >45 Gy to spine).; Drug: Temozolomide; Temozolomide will be taken by mouth once daily, on days 1-5 of each chemo-immunotherapy treatment cycle.
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.

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 12-month Overall Survival (OS) [ Time Frame: Up to 5 years ]
   For patients with newly diagnosed DIPG (diffuse intrinsic pontine glioma).

Secondary Outcome Measures :

1. Median Overall Survival (OS) [ Time Frame: Up to 5 years ]
   For each disease cohort
2. Median iRANO-PFS (Progression-Free Survival, defined by immune-adapted iRANO criteria) [ Time Frame: Up to 5 years ]
   For each disease cohort
3. Median Time to Regimen Failure (TTRF) [ Time Frame: Up to 5 years ]
   For each disease cohort

Eligibility Criteria

• Ages Eligible for Study: 3 Years to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

.

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

Contacts and Locations

Contacts

Contact: Theodore S Johnson, MD, PhD; 706-721-4962; thjohnson@augusta.edu

Contact: Taylor King, RN; 706-721-2949; TAYKING@AUGUSTA.EDU

Locations

United States, Georgia

Augusta University, Georgia Cancer Center; Recruiting

Augusta, Georgia, United States, 30912

Contact: Theodore S Johnson, MD, PhD 706-721-4962 thjohnson@augusta.edu

Contact: Taylor King, RN 706-721-2949 TAYKING@AUGUSTA.EDU

Principal Investigator: Theodore S Johnson, MD, PhD

Emory University, Children's Heathcare of Atlanta; Recruiting

Druid Hills, Georgia, United States, 30322

Contact: Olivia Floyd, RN, CCRP 404-785-0232 olivia.floyd@choa.org

Principal Investigator: Tobey J MacDonald, MD

United States, Massachusetts

Dana-Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Seo Won Kim 857-215-2297 seowon_kim@dfci.harvard.edu

Principal Investigator: Kee Kiat Yeo, MD

United States, Ohio

Cincinnati Children's Hospital Medical Center; Recruiting

Cincinnati, Ohio, United States, 45229

Contact: Trent Hummel, MD 513-636-2799 cancer@cchmc.org

Principal Investigator: Trent Hummel, MD

Sponsors and Collaborators

Theodore S. Johnson

National Cancer Institute (NCI)

Augusta University

Emory University

Investigators

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

More Information

• Responsible Party: Theodore S. Johnson, Associate Professor, Augusta University
• ClinicalTrials.gov Identifier: NCT04049669
• Other Study ID Numbers: GCC1949; R01CA229646 ( U.S. NIH Grant/Contract )
• First Posted: August 8, 2019
• Last Update Posted: April 12, 2023
• Last Verified: April 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Theodore S. Johnson, Augusta University:

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

Additional relevant MeSH terms:

Glioblastoma; Brain Neoplasms; Ependymoma; Medulloblastoma; Diffuse Intrinsic Pontine Glioma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuroectodermal Tumors, Primitive; Brain Stem Neoplasms; Infratentorial Neoplasms; Cyclophosphamide; Temozolomide; Lomustine; Etoposide; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs