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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT04049669
Other study ID # GCC1949
Secondary ID R01CA229646
Status Recruiting
Phase Phase 2
First received
Last updated
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
Health authority
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) . 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. . 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 Design


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
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