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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding indoximod, an immune-boosting drug, to standard treatments like chemotherapy and radiation can more effectively combat pediatric brain cancers, such as glioblastoma and medulloblastoma. Indoximod targets a pathway that typically allows tumors to evade the immune system, so blocking it might enable the body to attack the cancer more effectively. The trial includes different treatment plans based on whether patients have previously undergone radiation. It is suitable for children and young adults aged 3 to 21 with progressive brain cancer or newly diagnosed DIPG who have not yet received indoximod. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in cancer therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that indoximod, when combined with chemotherapy and radiation, is generally well-tolerated in treating brain cancer in children. Studies have found that indoximod can be safely used with these treatments without causing severe side effects. For instance, it has been safely combined with chemotherapy drugs like temozolomide and lomustine, as well as with other drugs like cyclophosphamide and etoposide, with research supporting its safety.

Although this treatment is still under investigation, previous patients have demonstrated promising safety results. It has been used in children as young as three years old, and findings suggest it does not cause unexpected side effects. However, as with any trial, side effects may occur, and participants are closely monitored throughout the process. Those considering joining a trial should ask the research team about any potential risks and benefits based on current evidence. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Indoximod is unique because it targets the immune system differently from standard treatments for pediatric brain cancer. Unlike traditional chemotherapy and radiation, which primarily aim to kill cancer cells directly, indoximod is an immunotherapy that works by inhibiting the IDO pathway, helping the immune system recognize and attack cancer cells more effectively. Researchers are excited about this treatment because it can potentially enhance the effectiveness of existing therapies like temozolomide, offering a new avenue for tackling aggressive brain tumors like DIPG and ependymoma. This approach could lead to improved outcomes for patients with limited options.

What evidence suggests that this trial's treatments could be effective for pediatric brain cancer?

Research has shown that indoximod, when combined with chemotherapy and radiation, may help treat brain cancer in children. In this trial, participants will join different treatment arms. For patients whose cancer returned, the average survival time was 13.3 months. Those with a specific type of brain cancer called DIPG had a slightly longer average survival of 14.4 months. Indoximod blocks a pathway called IDO, which manages immune responses. By blocking this pathway, indoximod might enhance the body's ability to fight tumors. Early studies suggest it is safe and can be used effectively with other cancer treatments. ^{1 2 6 7 8}

Who Is on the Research Team?

Theodore S Johnson, MD, PhD

Principal Investigator

Augusta University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04049669

Study Details | NCT04049669 | Pediatric Trial of Indoximod ... Patients previously treated with indoximod are excluded. Patients with DIPG who have been treated with any prior radiation or medical therapy are excluded.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10836763/

Indoximod-based chemo-immunotherapy for pediatric brain ... Median overall survival was 13.3 months (n = 68, range 0.2–62.7) for all patients with recurrent disease and 14.4 months (n = 13, range 4.7–29.7) for DIPG. The ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.2566

Effect of indoximod-based chemo-immunotherapy in ... Methods: We analyzed longitudinal blood samples from 30 patients with pediatric brain tumors treated with the IDO-inhibitor drug indoximod ...

4. curesearch.org curesearch.org/a-unique-approach-for-treatment-resistant-brain-cancer-patients/

Research Blog: A Unique Approach for Treatment ... A promising new drug, called Indoximod, has shown positive results in previous and ongoing clinical trials. Even children who had a partial ...

5. augusta.elsevierpure.com augusta.elsevierpure.com/en/publications/indoximod-based-chemo-immunotherapy-for-pediatric-brain-tumors-a-

Indoximod-based chemo-immunotherapy for pediatric ... Results: Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum ...

6. augusta.edu augusta.edu/cancer/clinical-trials/pediatric-immunotherapy/documents/2022johnsonsnotalk.pdf

First-in-children phase 1 trial of indoximod- based chemo- ... with pediatric brain tumors: analysis of safety, tolerability, and 5-year ... for patients aged 3-22 years with relapsed or refractory primary brain cancer.

7. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT02502708/

Clinical Trial: NCT02502708 This study will provide a foundation for future pediatric trials testing indoximod combined with radiation and temozolomide in the up-front ...

8. investors.linkp.com investors.linkp.com/news-releases/news-release-details/newlink-genetics-announces-initial-phase-1-data-indoximod-plus

Press Release - Investors - NewLink Genetics Early data indicate indoximod has clinical activity when used in combination therapies beyond PD-1 inhibition. AMES, Iowa , April 15, ...