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

Primary Purpose

Glioblastoma, Medulloblastoma, Ependymoma

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Indoximod
Partial Radiation
Full-dose Radiation
Temozolomide
Cyclophosphamide
Etoposide
Lomustine
Sponsored by
Theodore S. Johnson
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring 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

Eligibility Criteria

3 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Augusta University, Georgia Cancer CenterRecruiting
  • Emory University, Children's Heathcare of AtlantaRecruiting
  • Dana-Farber Cancer InstituteRecruiting
  • Cincinnati Children's Hospital Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Core Regimen, sub-cohort A

Core Regimen, sub-cohort B

Core Regimen, sub-cohort C

Salvage Regimen 1

Salvage Regimen 2

Arm Description

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

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).

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).

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).

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

Outcomes

Primary Outcome Measures

8-month iRANO-PFS (Progression-Free Survival, defined by immune-adapted iRANO criteria)
For patients with relapsed glioblastoma, medulloblastoma, or ependymoma.
12-month Overall Survival (OS)
For patients with newly diagnosed DIPG (diffuse intrinsic pontine glioma).

Secondary Outcome Measures

Median Overall Survival (OS)
For each disease cohort
Median iRANO-PFS (Progression-Free Survival, defined by immune-adapted iRANO criteria)
For each disease cohort
Median Time to Regimen Failure (TTRF)
For each disease cohort

Full Information

First Posted
August 2, 2019
Last Updated
October 4, 2023
Sponsor
Theodore S. Johnson
Collaborators
National Cancer Institute (NCI), Augusta University, Emory University
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1. Study Identification

Unique Protocol Identification Number
NCT04049669
Brief Title
Pediatric Trial of Indoximod With Chemotherapy and Radiation for Relapsed Brain Tumors or Newly Diagnosed DIPG
Official Title
Phase 2 Trial of Indoximod With Chemotherapy and Radiation for Children With Progressive Brain Tumors or Newly Diagnosed DIPG
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 2, 2019 (Actual)
Primary Completion Date
October 2, 2025 (Anticipated)
Study Completion Date
October 2, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Theodore S. Johnson
Collaborators
National Cancer Institute (NCI), Augusta University, Emory University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
140 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Core Regimen, sub-cohort A
Arm Type
Experimental
Arm Description
For patients not eligible for re-irradiation; Start with Core Regimen chemo-immunotherapy (indoximod with oral temozolomide).
Arm Title
Core Regimen, sub-cohort B
Arm Type
Experimental
Arm Description
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).
Arm Title
Core Regimen, sub-cohort C
Arm Type
Experimental
Arm Description
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).
Arm Title
Salvage Regimen 1
Arm Type
Experimental
Arm Description
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).
Arm Title
Salvage Regimen 2
Arm Type
Experimental
Arm Description
For patients who wish to continue access to indoximod after progression on the Core Regimen; Cross-over to indoximod with oral lomustine and temozolomide).
Intervention Type
Drug
Intervention Name(s)
Indoximod
Intervention Description
Indoximod will be taken by mouth twice daily during radiation and throughout each chemo-immunotherapy treatment cycle.
Intervention Type
Radiation
Intervention Name(s)
Partial Radiation
Intervention Description
Palliative low-dose or partial-field radiation plan (low-dose radiation or not all disease sites included).
Intervention Type
Radiation
Intervention Name(s)
Full-dose Radiation
Intervention Description
Palliative full-dose radiation plan to all known sites of disease (>50 Gy to brain, >45 Gy to spine).
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Intervention Description
Temozolomide will be taken by mouth once daily, on days 1-5 of each chemo-immunotherapy treatment cycle.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
Cyclophosphamide will be taken by mouth once daily, on days 1-21 of each chemo-immunotherapy treatment cycle.
Intervention Type
Drug
Intervention Name(s)
Etoposide
Intervention Description
Etoposide will be taken by mouth once daily, on days 1-21 of each chemo-immunotherapy treatment cycle.
Intervention Type
Drug
Intervention Name(s)
Lomustine
Intervention Description
Lomustine will be taken by mouth once daily, on day 1 of each chemo-immunotherapy treatment cycle.
Primary Outcome Measure Information:
Title
8-month iRANO-PFS (Progression-Free Survival, defined by immune-adapted iRANO criteria)
Description
For patients with relapsed glioblastoma, medulloblastoma, or ependymoma.
Time Frame
Up to 5 years
Title
12-month Overall Survival (OS)
Description
For patients with newly diagnosed DIPG (diffuse intrinsic pontine glioma).
Time Frame
Up to 5 years
Secondary Outcome Measure Information:
Title
Median Overall Survival (OS)
Description
For each disease cohort
Time Frame
Up to 5 years
Title
Median iRANO-PFS (Progression-Free Survival, defined by immune-adapted iRANO criteria)
Description
For each disease cohort
Time Frame
Up to 5 years
Title
Median Time to Regimen Failure (TTRF)
Description
For each disease cohort
Time Frame
Up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
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. . 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Theodore S Johnson, MD, PhD
Phone
706-721-4962
Email
thjohnson@augusta.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Taylor King, RN
Phone
706-721-2949
Email
TAYKING@AUGUSTA.EDU
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Theodore S Johnson, MD, PhD
Organizational Affiliation
Augusta University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Augusta University, Georgia Cancer Center
City
Augusta
State/Province
Georgia
ZIP/Postal Code
30912
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Theodore S Johnson, MD, PhD
Phone
706-721-4962
Email
thjohnson@augusta.edu
First Name & Middle Initial & Last Name & Degree
Taylor King, RN
Phone
706-721-2949
Email
TAYKING@AUGUSTA.EDU
First Name & Middle Initial & Last Name & Degree
Theodore S Johnson, MD, PhD
Facility Name
Emory University, Children's Heathcare of Atlanta
City
Druid Hills
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Olivia Floyd, RN, CCRP
Phone
404-785-0232
Email
olivia.floyd@choa.org
First Name & Middle Initial & Last Name & Degree
Tobey J MacDonald, MD
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kee Kiat Yeo, MD
Phone
617-632-4210
Email
keek_yeo@dfci.harvard.edu
First Name & Middle Initial & Last Name & Degree
Kee Kiat Yeo, MD
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Trent Hummel, MD
Phone
513-636-2799
Email
cancer@cchmc.org
First Name & Middle Initial & Last Name & Degree
Trent Hummel, MD

12. IPD Sharing Statement

Citations:
PubMed Identifier
37715730
Citation
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.
Results Reference
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PubMed Identifier
34614413
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.
Results Reference
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Pediatric Trial of Indoximod With Chemotherapy and Radiation for Relapsed Brain Tumors or Newly Diagnosed DIPG

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