Risk-Directed Therapy for Medulloblastoma

Recruiting at 9 trial locations

Overseen By Jean Laboe, MSN, RN

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Must not be taking: Radiotherapy, Chemotherapy, Immunotherapy, others

Disqualifiers: Other CNS tumors, Significant organ dysfunction, 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: 4

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatment options for children with newly diagnosed medulloblastoma, a type of brain cancer. The study examines how different combinations of surgery, chemotherapy (including drugs like Carboplatin, Cisplatin, Cyclophosphamide, Etoposide, Methotrexate, Topotecan, and Vincristine), and potentially radiation can be tailored based on the tumor's specific molecular characteristics. Children under five years old who have recently been diagnosed with medulloblastoma and have not yet received other treatments may be eligible. The goal is to find more effective ways to treat medulloblastoma in young children by customizing therapy to the tumor's specific traits. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to advancements in pediatric cancer care.

Do I need to stop my current medications to join the trial?

The trial requires that any chemotherapy, immunotherapy, or targeted agents for non-cancer conditions be stopped at least 14 days before starting the trial treatment. Corticosteroid therapy is allowed.

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

Research has shown that the treatments in this trial have been studied before. For example, Methotrexate has shown promise in young children with brain tumors and is used during chemotherapy to better manage high-risk cases. Cisplatin has a history of use in cancer treatments, with studies supporting its safety and effectiveness in similar conditions.

Vincristine, another chemotherapy drug, was shown to be safe in previous studies, especially for certain types of medulloblastoma. Cyclophosphamide, carboplatin, and topotecan are also commonly used in cancer treatments and have been studied for their safety in young patients. While these drugs are generally well-tolerated, they can have side effects, which are closely monitored during clinical trials.

Etoposide and radiation therapy are also part of the treatment plan. Radiation therapy, although effective, can have side effects, but has been used safely in children with average-risk medulloblastoma. Overall, these treatments have been used in various forms for cancer treatment and have shown a safety profile that supports further research.

This trial is in its second phase, indicating some evidence that these treatments are safe in humans, but more data is needed to confirm this. While the trial aims to find new ways to treat medulloblastoma, the treatments being tested are based on drugs that have been used and studied before, providing a foundation of safety data. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments being explored for medulloblastoma because they offer a tailored, risk-directed approach that could improve outcomes for young patients. Unlike traditional treatments, which typically involve a standard chemotherapy regimen and radiation, these investigational treatments use high-dose methotrexate either systemically or intraventricularly, depending on the specific medulloblastoma subgroup. This targeted use of methotrexate, along with conventional chemotherapy, aims to delay radiation in very young children, potentially reducing long-term side effects. Additionally, the inclusion of personalized cognitive interventions, like educational videos and games, represents a novel strategy to support cognitive development during treatment. This holistic approach to treatment and care is what sets these trials apart and fuels researchers' optimism.

What evidence suggests that this trial's treatments could be effective for medulloblastoma?

Research has shown that adding methotrexate to chemotherapy can improve survival chances for young children with certain types of medulloblastoma, particularly those in the Sonic Hedgehog (SHH) group. Some studies report five-year survival rates reaching 100% for these patients. In this trial, participants in Stratum S-1 and Stratum S-2 will receive methotrexate as part of their treatment regimen. Cisplatin proves effective, especially for patients in the SHH and Group 4 categories, which generally have better outcomes than other groups. All trial participants will receive Cisplatin. Vincristine, a component of standard chemotherapy, extends the time without disease progression in SHH and Group 4 tumors but is less effective alone for Group 3 cases. Cyclophosphamide contributes to a high cure rate in average-risk tumors, though it is less effective for high-risk Group 3 tumors. Adding carboplatin to radiotherapy significantly improves survival rates in high-risk Group 3 medulloblastoma. Topotecan effectively treats pediatric medulloblastoma, especially for those who have only had surgery. Radiation therapy is crucial, with many studies showing excellent outcomes for Group 4 patients. Participants in Stratum N will receive radiation therapy as part of their treatment. ^{3 4 6 7 8}

Who Is on the Research Team?

Giles Robinson, MD

Principal Investigator

St. Jude Children's Research Hospital

Aditi Bagchi

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

This trial is for children under 5 years with newly diagnosed medulloblastoma. They must have a certain level of organ function, no prior brain tumor treatments except surgery, and a performance score over 30. Parents can consent and participate in educational interventions.

Inclusion Criteria

My disease was confirmed with brain and spine MRI and CSF test.

My medulloblastoma diagnosis has been confirmed by a central review.

My medulloblastoma belongs to a specific molecular subgroup.

Exclusion Criteria

I have received treatment for medulloblastoma before.

Participant who is actively receiving any other investigational agents

Participants with other clinically significant medical disorders that could compromise their ability to tolerate protocol therapy or would interfere with the study procedure

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgery

Surgical resection of the tumor prior to chemotherapy

1 week

Chemotherapy

Participants receive systemic high-dose methotrexate (HD-MTX) and conventional chemotherapy, with variations based on stratum assignment

8-12 months

Courses repeat every 4 weeks

Radiation

Risk-stratified craniospinal irradiation (CSI) for Stratum N participants at 36 months of age

4-6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

84 months

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Cisplatin
• Cyclophosphamide
• Etoposide
• Filgrastim
• Irradiation
• Methotrexate
• Ommaya/VPS
• Pegfilgrastim
• Surgical resection
• Topotecan
• Vincristine

Trial Overview The study tests molecular and clinical risk-directed therapies including chemotherapy drugs like Carboplatin, Topotecan, Etoposide; surgical procedures; Methotrexate; irradiation; and supportive care with Pegfilgrastim or Filgrastim to boost white blood cells.

How Is the Trial Designed?

Group I: Stratum S-2 Experimental Treatment 9 Interventions

Patients with Sonic Hedgehog subgroup 2 (SHH-2), 0-2.99 years, or M0 and 3-4.99 years, will receive systemic high-dose methotrexate (HD-MTX) and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim

Group II: Stratum S-1 Experimental Treatment 10 Interventions

Patients with SHH-1, SHH-3, SHH-4, or SHH-Not otherwise specified (NOS), 0-2.99 years, will receive intraventricular methotrexate (IVT-MTX) in parallel with systemic HD-MTX and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim

Group III: Stratum N Experimental Treatment 11 Interventions

Patients with Medulloblastoma (MB) group 3 or group 4 (G3/G4) or MB \[including Non-WNT non-SHH medulloblastoma (NWNS) NOS or otherwise indeterminate cases\] (0-2.99 years) will receive systemic HD-MTX and conventional chemotherapy only for radiation delaying purposes. At 3 years of age, these patients will receive risk-stratified craniospinal irradiation (CSI). Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Etoposide, Pegfilgrastim, Filgrastim, Radiation

Group IV: Cognitive Study Group I (educational video and games) Experimental Treatment 1 Intervention

Educational video and games

Group V: Cognitive Study Group II (standard-of-care control) Active Control 1 Intervention

Standard-of-care (SOC) followed by educational video and games

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 69 patients undergoing cisplatin chemotherapy for testicular cancer, aprepitant significantly improved the complete response rate to 42% compared to only 13% with placebo, indicating its efficacy in preventing nausea and vomiting.

Patients overwhelmingly preferred the aprepitant treatment cycle, with no reported toxicity, suggesting that aprepitant is a safe and effective addition to standard antiemetic therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, double-blind, placebo-controlled, phase III cross-over study evaluating the oral neurokinin-1 antagonist aprepitant in combination with a 5HT3 receptor antagonist and dexamethasone in patients with germ cell tumors receiving 5-day cisplatin combination chemotherapy regimens: a hoosier oncology group study. Albany, C., Brames, MJ., Fausel, C., et al.[2022]

In a study of 17 children with high-risk medulloblastoma, the treatment combining weekly vincristine during radiation and adjuvant carboplatin and vincristine resulted in a 3-year overall survival rate of 70.6% and a progression-free survival (PFS) rate of 58.8%.

The treatment was generally well tolerated, with only 17.6% of patients experiencing severe neutropenia during radiation, although complications increased during adjuvant chemotherapy, indicating that while the approach is effective, patients with metastatic disease may need more aggressive treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concomitant weekly vincristine and radiation followed by adjuvant vincristine and carboplatin in the treatment of high risk medulloblastoma: Ain Shams University Hospital and Sohag Cancer Center study. Salama, MM., Ghorab, EM., Al-Abyad, AG., et al.[2020]

Current pediatric guidelines for preventing chemotherapy-induced nausea and vomiting (CINV) in children primarily recommend a serotonin 5-HT(3) receptor antagonist combined with a corticosteroid, but lack robust evidence and do not include many effective agents used in adults.

The review highlights the need for alternative antiemetic options for children who cannot tolerate or do not respond to standard treatments, discussing both established and emerging therapies like metopimazine, nabilone, and acupuncture, which may offer additional relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing emetic control in children receiving antineoplastic therapy: beyond the guidelines. Dupuis, LL., Nathan, PC.[2021]

In a study of 23 children with high-risk medulloblastoma, replacing cisplatinum with carboplatin in the chemotherapy protocol resulted in a 5-year overall survival rate of 60% and a 5-year progression-free survival rate of 41.8%.

The revised protocol showed a significant reduction in ototoxicity, with 11 out of 12 patients tested having normal hearing (grade 0) after treatment, indicating a safer option for managing this common complication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of newly diagnosed high risk medulloblastoma treated with carboplatin, vincristine, cyclophosphamide and etoposide. Sirachainan, N., Pakakasama, S., Anurathapan, U., et al.[2018]

In a study of 24 medulloblastoma patients treated with carboplatin instead of cisplatin, 23 patients were alive at the time of assessment, indicating a favorable overall survival rate.

Only 10.5% of patients experienced significant hearing loss, suggesting that carboplatin has a lower risk of ototoxicity compared to traditional cisplatin treatments, especially in younger patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and ototoxicity: hearing loss rates among survivors of childhood medulloblastoma. Musial-Bright, L., Fengler, R., Henze, G., et al.[2021]

In a study of 79 pediatric patients undergoing chemotherapy, the combination of fosaprepitant and ondansetron significantly reduced the frequency and severity of chemotherapy-induced nausea and vomiting (CINV) compared to ondansetron alone.

Fosaprepitant was found to be safe and well-tolerated, with no significant difference in adverse events between the two groups, making it a promising alternative for CINV prophylaxis in pediatric patients who cannot use dexamethasone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, safety and feasibility of fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in pediatric patients receiving moderately and highly emetogenic chemotherapy - results of a non-interventional observation study. Willier, S., Cabanillas Stanchi, KM., von Have, M., et al.[2020]

A survey of pediatric oncologists revealed that antiemetics are used 17%, 79%, and 98% of the time for chemotherapy agents associated with mild, moderate, and severe nausea and vomiting, respectively, indicating a strong reliance on antiemetic therapy based on the severity of symptoms.

The choice of antiemetics is primarily influenced by oncologists' personal experiences rather than current literature, which suggests that existing practices may not always align with the best available evidence for managing chemotherapy-induced nausea and vomiting in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A survey of antiemetic use in children with cancer. van Hoff, J., Hockenberry-Eaton, MJ., Patterson, K., et al.[2015]

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]

In a study involving 113 patients undergoing cisplatin chemotherapy for testicular cancer, ondansetron plus dexamethasone was found to be significantly more effective than metoclopramide plus dexamethasone in controlling nausea and vomiting, with 71% of patients on ondansetron experiencing 2 or fewer emetic episodes compared to only 26% on metoclopramide.

Ondansetron was well tolerated with no reported extrapyramidal reactions, while metoclopramide required a dose reduction due to such side effects in some patients, highlighting ondansetron's safety profile as a preferred treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of ondansetron plus dexamethasone in fractionated chemotherapy. Räth, U., Upadhyaya, BK., Arechavala, E., et al.[2018]

In a study of 26 pediatric patients with high-risk medulloblastoma, a treatment regimen of carboplatin, etoposide, and radiotherapy resulted in a 69% global survival rate and a 64% disease-free survival rate after 60 months.

The treatment was found to be safe, with no significant renal or auditory toxicity, and any hematological toxicity experienced was temporary and reversible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival of patients with medulloblastoma treated with carboplatin and etoposide before and after radiotherapy. Lopez-Aguilar, E., Sepulveda-Vildosola, AC., Rivera-Marquez, H., et al.[2018]

In a study of 89 ovarian cancer patients receiving paclitaxel and carboplatin, the combination of aprepitant, ramosetron, and dexamethasone effectively prevented chemotherapy-induced nausea and vomiting (CINV), achieving a complete response rate of 98.8% in the acute phase after the first cycle.

The treatment was well-tolerated, with only 38.9% of cycles experiencing adverse events, and none of the patients discontinued due to these events, indicating a favorable safety profile for this antiemetic regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of aprepitant, ramosetron, and dexamethasone for chemotherapy-induced nausea and vomiting in patients with ovarian cancer treated with paclitaxel/carboplatin. Choi, CH., Kim, MK., Park, JY., et al.[2021]

In a study of 30 patients with testicular germ cell tumors undergoing 5-day cisplatin chemotherapy, the combination of palonosetron, aprepitant, and dexamethasone achieved a high complete response rate of 90% for preventing vomiting during the first chemotherapy course.

The antiemetic regimen was well-tolerated, with only mild adverse effects reported, such as hiccups and anorexia, indicating a favorable safety profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiemetic efficacy and safety of a combination of palonosetron, aprepitant, and dexamethasone in patients with testicular germ cell tumor receiving 5-day cisplatin-based combination chemotherapy. Hamada, S., Hinotsu, S., Kawai, K., et al.[2021]

Citations

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Consensus treatment recommendations from SIOP-Europe ... Group 3 and Group 4 medulloblastomas represent overlapping disease groups [1], [2], and together comprise the WHO-defined 'non-WNT/non-SHH medulloblastoma' ...