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

Trial Summary

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.

What data supports the effectiveness of the drugs used in the Risk-Directed Therapy for Medulloblastoma?

The research articles provided focus on managing chemotherapy-induced nausea and vomiting (CINV) in patients receiving treatments like cisplatin and carboplatin, which are part of the medulloblastoma therapy. These studies suggest that antiemetic combinations, such as ondansetron with dexamethasone, are effective in reducing CINV, which can improve the overall treatment experience for patients undergoing similar chemotherapy regimens. ^{1 2 3 4 5}

Is the treatment for medulloblastoma generally safe in humans?

The treatment for medulloblastoma using carboplatin, etoposide, and other drugs has been studied for safety. Some patients experienced hearing loss and blood-related side effects, but these treatments are generally considered safe with manageable side effects. ^{6 7 8 9 10}

What makes the Risk-Directed Therapy for Medulloblastoma treatment unique?

This treatment is unique because it combines multiple chemotherapy drugs, radiation, and surgery to target medulloblastoma, a type of brain cancer, based on the patient's specific risk factors. This personalized approach aims to maximize effectiveness while minimizing side effects, unlike standard treatments that may not be tailored to individual risk levels. ^{2 4 5 11 12}

What is the purpose of this trial?

This is a multi-center, multinational phase 2 trial that aims to explore the use of molecular and clinical risk-directed therapy in treatment of children 0-4.99 years of age with newly diagnosed medulloblastoma.

Research Team

Giles Robinson, MD

Principal Investigator

St. Jude Children's Research Hospital

Aditi Bagchi

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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 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]

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 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 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]

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 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]

References

1. Germany 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. [2021]

2. England 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. [2020]

3. Germany 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. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Role of ondansetron plus dexamethasone in fractionated chemotherapy. [2018]

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

Optimizing emetic control in children receiving antineoplastic therapy: beyond the guidelines. [2021]

6. Scotland pubmed.ncbi.nlm.nih.gov

Outcome of newly diagnosed high risk medulloblastoma treated with carboplatin, vincristine, cyclophosphamide and etoposide. [2018]

7. England 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. [2020]

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

Survival of patients with medulloblastoma treated with carboplatin and etoposide before and after radiotherapy. [2018]

9. Germany pubmed.ncbi.nlm.nih.gov

Carboplatin and ototoxicity: hearing loss rates among survivors of childhood medulloblastoma. [2021]

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]

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

A survey of antiemetic use in children with cancer. [2015]

12. United States 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. [2022]