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

Glioblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04049669
• Other study ID #: GCC1949
• Secondary ID: R01CA229646
• Status: Recruiting
• Phase: Phase 2
• Start date: October 2, 2019
• Est. completion date: October 2, 2027

Study information

• Verified date: December 2023
• Source: Augusta University
• Contact: Theodore S Johnson, MD, PhD
• Phone: 706-721-4962
• Email: thjohnson[@]augusta.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 140
• Est. completion date: October 2, 2027
• Est. primary completion date: October 2, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 21 Years

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

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

Locations

Country	Name	City	State
United States	Augusta University, Georgia Cancer Center	Augusta	Georgia
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Emory University, Children's Heathcare of Atlanta	Druid Hills	Georgia

Sponsors (4)

Lead Sponsor	Collaborator
Theodore S. Johnson	Augusta University, Emory University, National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & 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 1 trial. Neuro Oncol. 2023 Sep 16:noad174. doi: 10.1093/neuonc/noad174. Online ahead of print. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	12-month Overall Survival (OS)	For patients with newly diagnosed DIPG (diffuse intrinsic pontine glioma).	Up to 5 years
Secondary	Median Overall Survival (OS)	For each disease cohort	Up to 5 years
Secondary	Median iRANO-PFS (Progression-Free Survival, defined by immune-adapted iRANO criteria)	For each disease cohort	Up to 5 years
Secondary	Median Time to Regimen Failure (TTRF)	For each disease cohort	Up to 5 years