Chemo-immunotherapy for Pediatric Brain Cancer

Overseen By Robin Dobbins, RN

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Theodore S. Johnson

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: Autoimmune disease, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 18 months

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for children and young adults with brain cancer unresponsive to standard treatments. The study aims to determine the safest dose of a new drug, ibrutinib (a type of chemo-immunotherapy), when combined with three other drugs to enhance the body's immune response against cancer. It seeks participants aged 6 to 25 with recurrent or treatment-resistant brain cancer who can swallow pills. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot take any other investigational or commercial agents to treat your cancer while in the study. If you are on medications like warfarin or strong CYP3A inhibitors, you may need to stop those.

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

A previous study found cyclophosphamide effective in treating brain tumors in children. However, it may cause side effects such as a decrease in blood cells and a very low risk of developing other cancers. It can also harm the kidneys and bladder, so drinking plenty of water is important.

Research has shown that etoposide, another cancer drug, is still under study for safety in children. It stops cancer cells from growing but can lower blood cell counts and increase the risk of infection.

Ibrutinib, often used for other conditions, might increase the risk of infections, including a rare brain infection. Its safety in children with brain cancer remains under evaluation.

Indoximod has been tested in children with brain cancer and is generally well-tolerated. It aims to boost the body's immune response against tumors.

This trial combines these drugs to determine a safe dose and assess their effectiveness together. Early trials focus on safety, so side effects are carefully monitored. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this chemo-immunotherapy treatment for pediatric brain cancer because it combines traditional chemotherapy drugs with novel immune-targeting agents. Unlike the standard treatments, which typically use chemotherapy alone, this regimen includes Ibrutinib and Indoximod, which are designed to bolster the body's immune response against cancer cells. Ibrutinib works by inhibiting a specific enzyme involved in cancer cell survival, while Indoximod boosts the immune system's ability to fight tumors. This unique combination aims to enhance the effectiveness of treatment and potentially improve outcomes for young patients.

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

Research has shown that combining ibrutinib (a drug that blocks a protein) with indoximod (a drug that blocks an enzyme) in chemo-immunotherapy might help treat brain cancer in children and young adults. This trial will evaluate the effectiveness of this combination, which targets a specific process in cancer cells and potentially enhances the immune system's ability to fight the cancer. Early results suggest that these drugs, when used with chemotherapy, could work together to improve treatment. Previous studies have shown promise with similar methods, but the exact results for this specific combination are still under investigation. The aim is to increase treatment success while keeping side effects manageable. ^{6 7 8 9 10}

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 young people aged 12-25 with relapsed or refractory primary brain cancer, such as glioblastoma or medulloblastoma. They must be able to swallow pills, have no curative treatment options left, and not be pregnant. Participants need proper kidney and liver function, controlled seizures if present, and a certain level of physical ability.

Inclusion Criteria

I am not receiving any cancer treatments other than what this study offers.

My kidney function is within the required range for the trial.

My brain cancer has worsened or not responded to treatment, and there are no standard cures left for me.

Exclusion Criteria

I have been diagnosed with lymphoma in my brain or spinal cord.

I need blood thinners like warfarin.

I do not have HIV, active Hepatitis B or C, or any uncontrolled infections.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Escalation

A dose-escalation cohort will determine the best safe dose of ibrutinib for the 4-drug combination

90 days

Treatment

Participants receive the 4-drug chemo-immunotherapy regimen, with cycles of a minimum of 28 days

Up to 18 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Etoposide
• Ibrutinib
• Indoximod

Trial Overview The study tests the combination of Ibrutinib (BTK-inhibitor) with Indoximod (IDO-inhibitor) alongside chemotherapy drugs Cyclophosphamide and Etoposide in pediatric brain cancer patients. It aims to find the safest dose that enhances immune response against tumors without severe overlapping toxicity.

How Is the Trial Designed?

Group I: Treatment Regimen Experimental Treatment 4 Interventions

Patients will be treated with the 4-drug chemo-immunotherapy regimen. Cycles are a minimum of 28 days.

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+

Rally Foundation for Childhood Cancer Research

Collaborator

Trials

6

Recruited

500+

CureSearch for Children's Cancer

Collaborator

Trials

2

Recruited

40+

Rally Foundation for Childhood Cancer Research

Collaborator

Trials

6

Recruited

500+

Augusta University

Collaborator

Trials

219

Recruited

85,900+

Published Research Related to This Trial

In a study involving 13 pediatric patients with refractory or relapsed brain tumors, a combination chemotherapy regimen showed an objective tumor response rate of 38.5%, with some patients achieving complete and long-term responses.

The treatment was generally well-tolerated, with no severe grade III or IV toxicities reported, although some patients experienced mild side effects like thrombocytopenia and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan, vincristine, cisplatin, cyclophosphamide, and etoposide for refractory or relapsed medulloblastoma/PNET in pediatric patients. Kim, H., Kang, HJ., Lee, JW., et al.[2021]

Conventional treatments for childhood brain tumors, including surgery and radiotherapy, have not been as effective as treatments for other childhood cancers, highlighting a need for improved strategies.

Chemotherapy has shown some effectiveness in causing regressions of recurrent brain tumors, particularly with agents like cisplatinum, cyclophosphamide, and methotrexate, but has not yet led to cures, indicating the necessity for more targeted drug selection and larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The chemotherapy of posterior fossa tumors in childhood. Friedman, HS., Oakes, WJ.[2019]

In the phase 3 BEACON trial involving 852 women with heavily pretreated breast cancer, etirinotecan pegol (EP) significantly improved overall survival in patients with brain metastases, showing a median survival of 10.0 months compared to 4.8 months for the treatment of physician's choice (TPC).

Patients receiving EP experienced fewer severe side effects (grade ≥3 toxicity) compared to those on TPC (50% vs. 70%), indicating that EP may be a safer option for this challenging patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial. Cortés, J., Rugo, HS., Awada, A., et al.[2022]

A high-dose intensity regimen of cyclophosphamide combined with GM-CSF was tested in 23 children with brain tumors, showing partial responses in 5 out of 6 patients with primitive neuroectodermal tumors (PNET), but no effectiveness against malignant glioma.

The treatment resulted in a manageable safety profile, with a short duration of severe neutropenia, although fever during neutropenia was common, occurring in 54 out of 83 treatment cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I and II trial of dose-intensified cyclophosphamide and GM-CSF in pediatric malignant brain tumors. Abrahamsen, TG., Lange, BJ., Packer, RJ., et al.[2020]

In a Phase II study involving 11 pediatric patients with anaplastic astrocytoma (AA) or glioblastoma multiforme (GM), postoperative chemotherapy using ifosfamide, carboplatin, and etoposide (ICE) resulted in a 60% complete response rate after four treatment courses, significantly reducing tumor size.

The overall survival rate at 53 months was 70%, indicating that ICE chemotherapy can effectively increase survival in children with malignant astrocytomas, although brainstem tumors showed a poor response to this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preirradiation ifosfamide, carboplatin, and etoposide for the treatment of anaplastic astrocytomas and glioblastoma multiforme: a phase II study. López-Aguilar, E., Sepúlveda-Vildósola, AC., Rivera-Márquez, H., et al.[2019]

Recent clinical trials highlight the importance of combining new drugs with radiotherapy in treating pediatric brain tumors, focusing on both survival rates and quality of life.

Specific studies, such as the SIOP/UKCCSG PNET-3 trial, have shown that pre-irradiation chemotherapy can be more effective than radiotherapy alone for medulloblastoma, while the French M-SFOP 98 protocol suggests that hyper-fractionated radiotherapy may reduce early relapses and preserve intellectual function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A literature review of the recent radiotherapy clinical trials in pediatric brain tumors. Skowrońska-Gardas, A.[2019]

The BCNU, cisplatin, and vincristine (BCV) regimen showed a low response rate of only 20% in treating newly diagnosed children with high-grade glioma, indicating limited efficacy.

The treatment was associated with significant pulmonary toxicity, including interstitial pneumonitis in seven patients, which resulted in six deaths, making it an unsafe option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of children treated with preradiation chemotherapy for a high-grade glioma: results of a French Society of Pediatric Oncology (SFOP) Pilot Study. Chastagner, P., Kalifa, C., Doz, F., et al.[2015]

In a trial involving 13 patients with temozolomide-refractory anaplastic oligodendroglioma or oligoastrocytoma, the maximum tolerated dose of intra-arterial melphalan was determined to be 4 mg/m²/d, with acceptable toxicity levels including some cases of grade 4 thrombocytopenia.

The treatment regimen, which included blood-brain barrier disruption, showed promising efficacy with 2 complete responses and 3 partial responses, particularly in patients with deletions of chromosomes 1p and 19q, and a median progression-free survival of 11 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intra-arterial chemotherapy with osmotic blood-brain barrier disruption for aggressive oligodendroglial tumors: results of a phase I study. Guillaume, DJ., Doolittle, ND., Gahramanov, S., et al.[2021]

In a study of 25 patients with newly diagnosed embryonal CNS tumors, preirradiation treatment with carboplatin and etoposide resulted in a 48% overall response rate, with 53% response in patients with high-risk medulloblastoma.

The treatment was associated with significant hematologic toxicity, particularly grade IV neutropenia, but had lower rates of ototoxicity compared to cisplatin, suggesting a potential benefit in terms of safety despite a higher progression rate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preirradiation chemotherapy with carboplatin and etoposide in newly diagnosed embryonal pediatric CNS tumors. Heideman, RL., Kovnar, EH., Kellie, SJ., et al.[2017]

In a phase I study involving 20 children with refractory solid tumors, the maximum-tolerated dose (MTD) of orally administered etoposide (VP-16) was determined to be 60 mg/m2 per day, with diarrhea identified as the dose-limiting toxicity at 75 mg/m2.

The treatment was generally well tolerated, with responses observed in 7 out of 14 patients who received additional courses of etoposide, indicating potential efficacy in this heavily pretreated pediatric population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of oral etoposide in children with refractory solid tumors. Mathew, P., Ribeiro, RC., Sonnichsen, D., et al.[2017]

In a Phase II study involving 53 children with high-risk medulloblastoma, oral etoposide was found to be tolerable and effective when administered during radiotherapy, leading to a high response rate with 40.4% achieving complete response and 51.1% partial response.

The study reported promising survival rates, with 2-year progression-free survival (PFS) at 76.6% and overall survival (OS) at 80.9%, indicating that this treatment regimen could improve outcomes for children with this aggressive form of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II feasibility study of oral etoposide given concurrently with radiotherapy followed by dose intensive adjuvant chemotherapy for children with newly diagnosed high-risk medulloblastoma (protocol POG 9631): A report from the Children's Oncology Group. Esbenshade, AJ., Kocak, M., Hershon, L., et al.[2018]

Intrathecal (IT) chemotherapy is a safe and effective method for delivering antineoplastic agents directly into the central nervous system, particularly in pediatric patients with primary and metastatic tumors, and has replaced neurotoxic cranial irradiation for certain conditions.

While methods like blood-brain barrier disruption and intra-arterial chemotherapy show promise for improving drug delivery to the brain, they are not commonly used due to their invasiveness and potential for serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving the Brain Delivery of Chemotherapeutic Drugs in Childhood Brain Tumors. Triarico, S., Maurizi, P., Mastrangelo, S., et al.[2020]

Citations

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NCT05106296 | Chemo-immunotherapy Using Ibrutinib ... ... Ibrutinib With Indoximod Plus Metronomic Cyclophosphamide and Etoposide for Pediatric Patients With Brain Cancer ... outcomes at undue risk. Ages Eligible ...

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Immunotherapy for Pediatric Brain and Spine Tumors In this review, we summarize the current immunotherapy landscape for various pediatric brain tumor types including choroid plexus tumors, embryonal tumors.

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Chemo-immunotherapy for Pediatric Brain Cancer This trial tests a new treatment combining two drugs, ibrutinib and indoximod, with chemotherapy for young patients whose brain cancer has not responded to ...

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Cyclophosphamide Oral Formulation (Cytoxan®, Neosar ... Secondary Malignancies: There is a very low risk of developing leukemia or another type of cancer due to treatment with this medication, which ...

7. go.drugbank.com go.drugbank.com/drugs/DB00531

Cyclophosphamide: Uses, Interactions, Mechanism of Action Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. Modality: Small Molecule; Groups: Approved, Investigational; Structure. 3D.

8. aacrjournals.org aacrjournals.org/clincancerres/article-abstract/26/7/1563/83198

Exposure–Toxicity Association of Cyclophosphamide and Its ... Young infants (<6 months) exhibited higher mean 4OH-CTX exposure than did young children (138.4 vs. 107.2 μmol/L·h, P < 0.0001).

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Exposure-Toxicity Association of Cyclophosphamide and Its ... Cyclophosphamide, a well-known chemotherapeutic agent with demonstrated pediatric brain tumor efficacy (5–7), is associated with myelosuppression as a primary ...

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Cyclophosphamide for Childhood Cancer Patients Cyclophosphamide can harm the kidneys and bladder. Patients receiving cyclophosphamide should drink plenty of fluids. They may receive IV fluids and a medicine ...