Indoximod + Chemotherapy/Radiation for Pediatric Brain Cancer

Recruiting at 6 trial locations

Overseen By Robin Dobbins, RN

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Theodore S. Johnson

Disqualifiers: Pregnancy, Active infection, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

140 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you must be 14 days from any investigational agent or prior cytotoxic therapy, with specific longer periods for certain treatments. Seizure disorders must be well controlled on antiepileptic medication.

What data supports the idea that Indoximod + Chemotherapy/Radiation for Pediatric Brain Cancer is an effective treatment?

The available research shows that temozolomide, a drug used in combination with other treatments for pediatric brain cancer, has shown some effectiveness. In a study, patients with high-grade gliomas who received temozolomide and lomustine had a median survival of 17.6 months, with 60% surviving one year and 40% surviving two years. However, there were significant side effects, including myelosuppression and myelodysplasia, which are serious blood-related conditions. While temozolomide has shown promise, the data also highlights the challenges and risks associated with its use. There is no specific data on Indoximod in the provided information, so its effectiveness in combination with chemotherapy and radiation for pediatric brain cancer cannot be directly assessed from the available research. ^{1 2 3 4 5}

What safety data is available for Indoximod and chemotherapy/radiation in pediatric brain cancer treatment?

The safety data for the treatment involving temozolomide (TMZ) and lomustine (CCNU) in pediatric brain cancer includes findings from several studies. A phase I trial determined the maximum tolerated dose (MTD) of TMZ with lomustine, noting dose-limiting myelosuppression and thrombocytopenia at higher doses. The MTD was established at 160 mg/m²/day for TMZ with 90 mg/m² lomustine. Radiographic changes post-radiation therapy (RT) complicated early tumor progression assessment, and metastatic disease was common before death. Another study highlighted high-grade hematotoxicity as a frequent side effect in TMZ/lomustine therapy. Overall, TMZ is noted for a lower toxicity profile compared to traditional chemotherapy agents, making it a candidate for combined radio-chemotherapy treatments. ^{1 5 6 7 8}

Is the drug combination of Cyclophosphamide, Etoposide, Full-dose Radiation, Lomustine, and Temozolomide promising for treating pediatric brain cancer?

Yes, the drug combination, especially Temozolomide and Lomustine, shows promise in treating pediatric brain cancer by improving survival rates and achieving positive responses in some patients. ^{1 2 3 9 10}

What is the purpose of this trial?

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.

Research Team

Theodore S Johnson, MD, PhD

Principal Investigator

Augusta University

Eligibility Criteria

This trial is for children and young adults aged 3 to 21 with progressive brain cancers like glioblastoma, medulloblastoma, ependymoma, or newly diagnosed DIPG. They must be able to swallow pills, have a certain level of physical function (Lansky/Karnofsky score ≥50%), controlled seizures if present, and not have had recent treatments or other specific conditions.

Inclusion Criteria

My seizures are under control with medication.

I can do most activities but need help with some.

It has been at least 14 days since I last received experimental treatment or chemotherapy.

Exclusion Criteria

I have been treated with indoximod before.

I cannot swallow pills.

Pregnant women

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive up-front radiation therapy in combination with indoximod

6-8 weeks

Weekly visits for radiation sessions

Chemo-immunotherapy

Participants receive indoximod with oral temozolomide as part of the Core Regimen

8-12 weeks

Bi-weekly visits for chemotherapy administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Quarterly visits for follow-up assessments

Salvage Regimen

Participants may opt to continue access to indoximod with alternative chemotherapy after progression

Variable

Treatment Details

Interventions

• Cyclophosphamide
• Etoposide
• Full-dose Radiation
• Indoximod
• Lomustine
• Partial Radiation
• Temozolomide

Trial Overview The trial tests whether adding indoximod immunotherapy to chemotherapy and radiation can improve outcomes in pediatric brain tumors by inhibiting the IDO pathway. It's an open-label phase 2 study comparing standard therapy alone versus the combination including indoximod.

Participant Groups

Group I: Salvage Regimen 2 Experimental Treatment 3 Interventions

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

Group II: Salvage Regimen 1 Experimental Treatment 3 Interventions

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).

Group III: Core Regimen, sub-cohort C Experimental Treatment 3 Interventions

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).

Group IV: Core Regimen, sub-cohort B Experimental Treatment 3 Interventions

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).

Group V: Core Regimen, sub-cohort A Experimental Treatment 2 Interventions

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

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Theodore S. Johnson

Lead Sponsor

Trials

2

Recruited

180+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Emory University

Collaborator

Trials

1,735

Recruited

2,605,000+

Augusta University

Collaborator

Trials

219

Recruited

85,900+

Findings from Research

The maximum tolerated dose (MTD) of temozolomide in combination with lomustine for pediatric patients with high-grade gliomas was determined to be 160 mg/m²/day for 5 days, with dose-limiting myelosuppression observed at higher doses.

After two courses of treatment at the MTD, 60% of patients had a median overall survival of 1 year, and 40% at 2 years, indicating potential efficacy, although many patients developed metastatic disease before death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of temozolomide and lomustine in newly diagnosed high-grade gliomas of childhood. Jakacki, RI., Yates, A., Blaney, SM., et al.[2021]

Temozolomide is an effective treatment for pediatric brain tumors, but it has been linked to serious side effects.

This study reports the first case of myelodysplasia, a life-threatening condition, occurring in a child as a result of temozolomide treatment, highlighting the need for careful monitoring of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-related myelodysplastic syndrome after temozolomide use in a child: first report. Dufour, C., Da Costa, L., Auger, N., et al.[2018]

Temozolomide, an oral chemotherapy drug, showed an initial partial response in an adult patient with relapsing medulloblastoma, indicating potential efficacy in this challenging condition.

The findings suggest that temozolomide could be beneficial either as a standalone treatment or in combination with radiotherapy for patients with relapsing medulloblastoma, which typically has a poor prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide treatment of an adult with a relapsing medulloblastoma. Durando, X., Thivat, E., Gilliot, O., et al.[2022]

The combination of temozolomide (TMZ) and BCNU before radiotherapy showed a modest response rate in newly diagnosed anaplastic glioma, with 27% of patients achieving a partial response and 54% maintaining stable disease.

However, this treatment regimen was associated with significant toxicity, particularly hematologic issues, as 46% of patients experienced severe thrombocytopenia and 20% had severe granulocytopenia, leading to a high rate of treatment discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of neoadjuvant 1, 3-bis (2-chloroethyl)-1-nitrosourea and temozolomide for newly diagnosed anaplastic glioma: a North American Brain Tumor Consortium Trial. Chang, SM., Prados, MD., Yung, WK., et al.[2018]

In a study involving 97 patients with malignant gliomas, temozolomide (TMZ) demonstrated a significantly higher response rate (35.71%) compared to lomustine (CCNU) (9.09%), indicating its greater efficacy in treating these aggressive brain tumors.

TMZ was found to have an acceptable safety profile, with common side effects being mild nausea and vomiting, suggesting it could be a preferred chemotherapy option for patients with refractory malignant brain gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A multicenter randomized controlled study of temozolomide in 97 patients with malignant brain glioma]. Qian, ZZ., Wang, HQ., Liu, XM., et al.[2018]

In a pilot study involving 29 patients with newly diagnosed anaplastic astrocytoma, the combination of carmustine and temozolomide with radiotherapy showed significant hematologic and pulmonary toxicities, leading to dose reductions in over 70% of patients in one treatment arm.

Due to the poor tolerance of the combination therapy, future studies will focus on comparing single-agent carmustine versus single-agent temozolomide, indicating a shift towards safer treatment options for brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study pilot arms of radiotherapy and carmustine with temozolomide for anaplastic astrocytoma (Radiation Therapy Oncology Group 9813): implications for studies testing initial treatment of brain tumors. Chang, SM., Seiferheld, W., Curran, W., et al.[2018]

In a phase III trial, the combination therapy of temozolomide (TMZ) and lomustine (CCNU) resulted in higher rates of high-grade hematotoxicity (36.4%) compared to TMZ alone (28.6%), indicating a trade-off between efficacy and safety in treating newly diagnosed glioblastoma.

Despite the increased hematotoxicity with CCNU/TMZ, this adverse effect did not correlate with shorter survival rates, suggesting that while monitoring for hematotoxicity is important, it may not impact overall patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial. Weller, J., Schäfer, N., Schaub, C., et al.[2023]

In a phase II clinical trial involving 21 patients with newly diagnosed glioblastoma multiforme (GBM), the combination of temozolomide (TMZ) with radiotherapy resulted in a one-year survival rate of 58% and a median survival time of 15.7 months, indicating its efficacy in extending survival.

The treatment regimen was well-tolerated, with only mild to moderate non-hematological side effects and minimal severe hematological toxicity, suggesting that TMZ has a favorable safety profile compared to traditional chemotherapy agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. Lanzetta, G., Campanella, C., Rozzi, A., et al.[2018]

Intrathecal methotrexate (MTX) has shown a high response rate (about 75%) in treating recurrent medulloblastoma, although it can be dangerous if used in cases with ventricular obstruction.

BCNU and CCNU have been effective in treating ependymoma, medulloblastoma, and brain stem glioma, while vincristine has primarily benefited medulloblastoma patients, highlighting the need for cooperative efforts to improve treatment outcomes for these rare tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy of primary malignant brain tumors in children. Shapiro, WR.[2019]

In a study of 28 children with newly diagnosed CNS embryonal tumors, the combination of carboplatin, etoposide, and high-dose methotrexate showed a high overall response rate of 79%, with 74% of medulloblastoma patients achieving either a complete or partial response.

The treatment was generally well tolerated, although side effects like myelosuppression and thrombocytopenia were common, indicating that while effective, careful monitoring of blood cell counts is necessary during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of postoperative carboplatin, etoposide, and high-dose methotrexate in pediatric CNS embryonal tumors: results of a phase II study in newly diagnosed children. Kellie, SJ., Wong, CK., Pozza, LD., et al.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

A phase I trial of temozolomide and lomustine in newly diagnosed high-grade gliomas of childhood. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Treatment-related myelodysplastic syndrome after temozolomide use in a child: first report. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Temozolomide treatment of an adult with a relapsing medulloblastoma. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Phase II study of neoadjuvant 1, 3-bis (2-chloroethyl)-1-nitrosourea and temozolomide for newly diagnosed anaplastic glioma: a North American Brain Tumor Consortium Trial. [2018]

5. China pubmed.ncbi.nlm.nih.gov

[A multicenter randomized controlled study of temozolomide in 97 patients with malignant brain glioma]. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Phase I study pilot arms of radiotherapy and carmustine with temozolomide for anaplastic astrocytoma (Radiation Therapy Oncology Group 9813): implications for studies testing initial treatment of brain tumors. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial. [2023]

8. Greece pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Chemotherapy of primary malignant brain tumors in children. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Activity of postoperative carboplatin, etoposide, and high-dose methotrexate in pediatric CNS embryonal tumors: results of a phase II study in newly diagnosed children. [2013]