Chemo-immunotherapy for Pediatric Brain Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Theodore S. Johnson, MD, PhD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Theodore S. Johnson

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: Autoimmune disease, Cardiovascular disease, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a new treatment combining two drugs, ibrutinib and indoximod, with chemotherapy for young patients whose brain cancer has not responded to other treatments. The goal is to boost the immune system's ability to fight the cancer by blocking proteins that help cancer cells survive.

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.

What data supports the effectiveness of the drugs used in the Chemo-immunotherapy for Pediatric Brain Cancer trial?

Research shows that cyclophosphamide and etoposide, which are part of the trial, have been used in combination with other drugs to treat pediatric brain tumors, such as medulloblastoma, with some success. Additionally, etoposide has been part of effective chemotherapy regimens for other types of brain tumors, indicating its potential usefulness in this trial. ^{1 2 3 4 5}

Is chemo-immunotherapy for pediatric brain cancer safe?

Etoposide, one of the drugs used in chemo-immunotherapy, has been studied in children with various types of tumors. Research shows that it has been used safely, but like all treatments, it can have side effects, and the maximum safe dose has been determined in some studies. ^{6 7 8 9 10}

How is the chemo-immunotherapy drug combination for pediatric brain cancer different from other treatments?

This treatment is unique because it combines chemo-immunotherapy, using drugs like cyclophosphamide and etoposide, with newer agents like ibrutinib and indoximod, which may enhance the immune system's ability to fight cancer, offering a novel approach compared to traditional chemotherapy and radiotherapy. ^{1 2 4 11 12}

Research Team

Theodore S. Johnson, MD, PhD

Principal Investigator

Augusta University

Eligibility Criteria

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.

Pregnant or breastfeeding women are ineligible for this study

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.

Trial Timeline

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

Treatment Details

Interventions

• Cyclophosphamide (Alkylating Agent)
• Etoposide (Topoisomerase Inhibitor)
• Ibrutinib (BTK Inhibitor)
• Indoximod (IDO Inhibitor)

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.

Participant Groups

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 Canada, Japan for the following indications:

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Augusta University, Georgia Cancer Center Augusta, GA

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+

Dr. David C. Hess

Augusta University

Chief Executive Officer since 2017

MD from Johns Hopkins University, Neurology residency and Vascular Neurology fellowship at Augusta University

Dr. David C. Hess

Augusta University

Chief Medical Officer since 2017

MD from University of Maryland School of Medicine

Findings from Research

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 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]

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]

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 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]

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]

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]

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]

References

1. United States 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. [2015]

2. Germany pubmed.ncbi.nlm.nih.gov

Irinotecan, vincristine, cisplatin, cyclophosphamide, and etoposide for refractory or relapsed medulloblastoma/PNET in pediatric patients. [2021]

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

Preirradiation ifosfamide, carboplatin, and etoposide for the treatment of anaplastic astrocytomas and glioblastoma multiforme: a phase II study. [2019]

4. United Arab Emirates pubmed.ncbi.nlm.nih.gov

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

5. Switzerland pubmed.ncbi.nlm.nih.gov

Improving the Brain Delivery of Chemotherapeutic Drugs in Childhood Brain Tumors. [2020]

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

Intra-arterial chemotherapy with osmotic blood-brain barrier disruption for aggressive oligodendroglial tumors: results of a phase I study. [2021]

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

Preirradiation chemotherapy with carboplatin and etoposide in newly diagnosed embryonal pediatric CNS tumors. [2017]

8. Netherlands 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. [2022]

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

Phase I study of oral etoposide in children with refractory solid tumors. [2017]

10. United States 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. [2018]

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

The chemotherapy of posterior fossa tumors in childhood. [2019]

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

A phase I and II trial of dose-intensified cyclophosphamide and GM-CSF in pediatric malignant brain tumors. [2020]