Risk-Directed Therapy for Medulloblastoma

Not currently recruiting at 23 trial locations

Overseen By Tabatha E. Doyle, RN

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Disqualifiers: Other CNS tumors, Medical disorders, 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: 11

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new ways to treat medulloblastoma, a type of brain cancer, by examining both clinical risk and the tumor's specific molecular traits. The researchers aim to determine if adjusting treatment based on these factors can improve outcomes and reduce side effects. Participants will be grouped according to their tumor's molecular subtype and risk level to test different combinations of radiation and chemotherapy, including drugs like Cisplatin, Cyclophosphamide, and Vincristine. Suitable candidates have undergone surgery to remove a medulloblastoma and have not yet received other cancer treatments. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, since participants must not have had previous radiotherapy, chemotherapy, or other brain tumor-directed therapy (except corticosteroids and surgery), it's best to discuss your current medications with the trial team.

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

Research shows that the treatments in this trial have varying safety levels based on previous studies.

For cisplatin, studies indicate it can improve survival rates in children with medulloblastoma. However, it may cause hearing loss and other side effects, such as ear and nerve damage. Some research suggests that replacing part of cisplatin with cyclophosphamide can reduce these side effects.

Cyclophosphamide is generally well-tolerated. Data shows it does not usually cause severe issues like a significant drop in white blood cells or damage to the kidneys or liver. Its safety is carefully monitored during treatment.

Craniospinal irradiation, which involves radiation to the brain and spine, is a common treatment for medulloblastoma. Research indicates it has acceptable short-term side effects, but long-term effects require further study.

Vincristine, another chemotherapy drug used in this trial, has been shown to help with survival rates. Like other chemotherapy drugs, it can have side effects, such as nerve problems, which are usually monitored and managed during treatment.

Lastly, vismodegib, used for some patients, has been well-tolerated in trials. It is mainly used for specific tumor types and helps slow tumor growth with few serious side effects.

Overall, while each treatment has potential risks, they have been studied extensively and are generally considered safe with manageable side effects. Participants in clinical trials will be closely monitored to ensure their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the risk-directed therapy for medulloblastoma because it tailors treatment intensity based on the patient's risk level, which is not typically done in standard care. Unlike traditional one-size-fits-all approaches, this trial uses a combination of craniospinal irradiation, chemotherapy, and for some, maintenance therapy with vismodegib, which is a hedgehog pathway inhibitor. Additionally, the trial includes aerobic training and neurocognitive remediation, aiming to improve both physical and cognitive recovery. This personalized strategy has the potential to maximize treatment effectiveness while minimizing side effects, offering a more comprehensive approach to fighting medulloblastoma.

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

This trial will evaluate different treatment strategies for medulloblastoma, assigning participants to various treatment arms based on risk levels. Research has shown that a combination of cisplatin, craniospinal irradiation, cyclophosphamide, and vincristine effectively improves survival rates. Participants in this trial may receive these treatments in different combinations and dosages depending on their assigned stratum. Studies indicate that cisplatin, when combined with other treatments, has increased survival rates in children. Craniospinal irradiation plays a crucial role, raising 5-year survival rates to over 70%. Cyclophosphamide, commonly used, improves outcomes when added to standard care. Vincristine extends the time patients live without disease progression in both average and high-risk patients. For SHH-positive tumors, vismodegib has shown promise in slowing tumor growth, particularly in the SHH subgroup. These treatments, when matched to the tumor's specific type, offer a targeted approach that could enhance effectiveness. ^{1 5 6 7 8}

Who Is on the Research Team?

Amar Gajjar, MD

Principal Investigator

St. Jude Children's Research Hospital

Giles Robinson, MD

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

This trial is for individuals aged 3-22 with newly diagnosed medulloblastoma, or those up to age 40 with SHH subtype. They must have had surgery within the last 36 days and not received prior brain tumor treatments. Good performance status is required, and women of childbearing potential must not be pregnant.

Inclusion Criteria

Biological parent(s) of participant enrolling on this protocol

My health status meets the required level for my age.

My age fits the trial's requirements for my specific diagnosis and treatment plan.

Exclusion Criteria

Other clinically significant medical disorders that could compromise ability to tolerate protocol therapy

My brain tumor is not a medulloblastoma or PNET located in the back of my brain.

I am eligible for the Stratum S maintenance chemotherapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgery

Participants undergo surgery to remove as much of the primary tumor as safely possible

1 week

Radiation Therapy

Participants receive craniospinal irradiation with a boost to the primary tumor site, 5 days a week for 6 weeks

6 weeks

5 visits per week (in-person)

Chemotherapy

Participants receive adjuvant chemotherapy with cisplatin, vincristine, and cyclophosphamide for 4 cycles, with additional cycles for certain strata

16-40 weeks

Maintenance Therapy

Participants in certain strata receive maintenance therapy with vismodegib for 12 months

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• Craniospinal Irradiation with boost to the primary tumor site
• Cyclophosphamide
• Vincristine
• Vismodegib

Trial Overview The study tests a tailored treatment approach based on both clinical risk (low to high) and molecular subtype (WNT, SHH, Non-WNT/Non-SHH) of medulloblastoma. It involves varying doses of radiation and chemotherapy including cyclophosphamide, cisplatin, vincristine; targeted drugs like vismodegib; new agents pemetrexed, gemcitabine; plus supportive therapies such as aerobic training and neurocognitive remediation.

How Is the Trial Designed?

Group I: Stratum W3: High Risk Experimental Treatment 6 Interventions

Participants in stratum W3 will undergo high dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.

Group II: Stratum W2: Atypical Experimental Treatment 6 Interventions

Participants in stratum W2 will undergo standard dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.

Group III: Stratum W1: Low Risk Experimental Treatment 6 Interventions

Participants in stratum W1 will undergo reduced dose Craniospinal Irradiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.

Group IV: Stratum S2: High Risk Experimental Treatment 7 Interventions

Participants in stratum S2 will undergo high dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. After completion of 4 cycles of chemotherapy, participants who are skeletally mature will receive maintenance chemotherapy with vismodegib. Some participants will complete aerobic training and/or neurocognitive remediation.

Group V: Stratum S1: Standard Risk Experimental Treatment 7 Interventions

Participants in stratum S1 will undergo standard dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. After completion of 4 cycles of chemotherapy, participants who are skeletally mature will receive maintenance chemotherapy with vismodegib. Some participants will complete aerobic training and/or neurocognitive remediation.

Group VI: Stratum N3: High Risk Experimental Treatment 8 Interventions

Participants in stratum N3 will undergo high dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive standard chemotherapy (cisplatin, vincristine, cyclophosphamide) for 4 cycles intermixed with an additional 3 cycles of chemotherapy with pemetrexed and gemcitabine in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.

Group VII: Stratum N2: Intermediate Risk Experimental Treatment 8 Interventions

Participants in stratum N2 will undergo standard dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive standard chemotherapy (cisplatin, vincristine, cyclophosphamide) for 4 cycles intermixed with an additional 3 cycles of chemotherapy with pemetrexed and gemcitabine in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.

Group VIII: Stratum N1: Standard Risk Experimental Treatment 6 Interventions

Participants in stratum N1 will undergo standard dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.

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

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4591537/

Cumulative Cisplatin Dose Is Not Associated With Event-Free ... Survival rates for children with medulloblastoma have risen over the past decade, in part due to the addition of cisplatin-containing adjuvant chemotherapy.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12263714/

Impact of partial substitution of cisplatin with ... No significant differences were found in grade ≥ 3 leukopenia, nephrotoxicity or hepatotoxicity. The 2-year overall survival was 96.4% (95% CI: ...

3. medicine.yale.edu medicine.yale.edu/ycci/clinicaltrials/trial/a-study-of-treatment-for-medulloblastoma-using-sodium-thiosulfate-to-reduce-hearing-loss/

A Phase 3 Study of Sodium Thiosulfate for Reduction of ... Previous studies with STS have shown that it may help reduce or prevent hearing loss caused by cisplatin. In the low-risk medulloblastoma ...

4. cancerblog.mayoclinic.org cancerblog.mayoclinic.org/2024/05/29/advances-in-medulloblastoma-treatment-for-children/

Advances in medulloblastoma treatment for children Cisplatin, a chemotherapy drug effective in treating medulloblastoma, is associated with hearing loss. Research has shown this may be due to the ...

5. nature.com nature.com/articles/s41598-019-42001-7

The effect of locally delivered cisplatin is dependent on an ... Our results demonstrate that intratumoral cisplatin treatment was effective with a narrow therapeutic window and may be an efficient approach for glioma or ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/23956184/

Cumulative cisplatin dose is not associated with event-free or ... Results: Eight-year event-free survival (EFS) and overall survival (OS) estimates were 78.2 ± 2.6% and 83.9 ± 2.4%, respectively. Only 73 patients received the ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S1878747923001307

Medulloblastoma in the Modern Era: Review of ... Outcomes remain inferior for patients with high-risk disease (60–70% 5-year EFS and OS), motivating investigation of treatment intensification strategies [5, 6, ...

8. link.springer.com link.springer.com/article/10.1007/s11060-025-05098-7

Impact of partial substitution of cisplatin with ... Partial substitution of cisplatin with cyclophosphamide showed a better toxicity profile, particularly for ototoxicity and neurotoxicity, with no significant ...