Pediatric Trial of Indoximod With Chemotherapy and Radiation for Relapsed Brain Tumors or Newly Diagnosed DIPG
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| ClinicalTrials.gov Identifier: NCT04049669 |
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Recruitment Status :
Recruiting
First Posted : August 8, 2019
Last Update Posted : December 19, 2023
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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 |
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 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 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Core Regimen, sub-cohort A
For patients not eligible for re-irradiation; Start with Core Regimen chemo-immunotherapy (indoximod with oral temozolomide).
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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. |
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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).
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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. |
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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).
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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. |
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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).
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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. |
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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).
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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. |
- 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.
- 12-month Overall Survival (OS) [ Time Frame: Up to 5 years ]For patients with newly diagnosed DIPG (diffuse intrinsic pontine glioma).
- Median Overall Survival (OS) [ Time Frame: Up to 5 years ]For each disease cohort
- Median iRANO-PFS (Progression-Free Survival, defined by immune-adapted iRANO criteria) [ Time Frame: Up to 5 years ]For each disease cohort
- Median Time to Regimen Failure (TTRF) [ Time Frame: Up to 5 years ]For each disease cohort
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| Ages Eligible for Study: | 3 Years to 21 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04049669
| Contact: Theodore S Johnson, MD, PhD | 706-721-4962 | thjohnson@augusta.edu | |
| Contact: Taylor King, RN | 706-721-2949 | tayking@augusta.edu |
| 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: Kee Kiat Yeo, MD 617-632-4210 keek_yeo@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 | |
| Principal Investigator: | Theodore S Johnson, MD, PhD | Augusta University |
| 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 Key Record Dates |
| Last Update Posted: | December 19, 2023 |
| Last Verified: | December 2023 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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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 |
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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 |