A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma

NCT01878617 | Active Not Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: SJMB12NCI-2013-01125R01CA187079
• Study Type: interventional
• Target: 660
• Locations: 4 countries
• Sites: 23

Brief Summary

Historically, medulloblastoma treatment has been determined by the amount of leftover disease present after surgery, also known as clinical risk (standard vs. high risk). Recent studies have shown that medulloblastoma is made up of distinct molecular subgroups which respond differently to treatment. This suggests that clinical risk alone is not adequate to identify actual risk of recurrence. In order to address this, we will stratify medulloblastoma treatment in this phase II clinical trial based on both clinical risk (low, standard, intermediate, or high risk) and molecular subtype (WNT, SHH, or Non-WNT Non-SHH). This stratified clinical and molecular treatment approach will be used to evaluate the following:

• To find out if participants with low-risk WNT tumors can be treated with a lower dose of radiation to the brain and spine, and a lower dose of the chemotherapy drug cyclophosphamide while still achieving the same survival rate as past St. Jude studies with fewer side effects.
• To find out if adding targeted chemotherapy after standard chemotherapy will benefit participants with SHH positive tumors.
• To find out if adding new chemotherapy agents to the standard chemotherapy will improve the outcome for intermediate and high risk Non-WNT Non-SHH tumors.
• To define the cure rate for standard risk Non-WNT Non-SHH tumors treated with reduced dose cyclophosphamide and compare this to participants from the past St. Jude study. All participants on this study will have surgery to remove as much of the primary tumor as safely possible, radiation therapy, and chemotherapy. The amount of radiation therapy and type of chemotherapy received will be determined by the participant's treatment stratum. Treatment stratum assignment will be based on the tumor's molecular subgroup assignment and clinical risk. The participant will be assigned to one of three medulloblastoma subgroups determined by analysis of the tumor tissue for tumor biomarkers:
• WNT (Strata W): positive for WNT biomarkers
• SHH (Strata S): positive for SHH biomarkers
• Non-WNT Non-SHH, Failed, or Indeterminate (Strata N): negative for WNT and SHH biomarkers or results are indeterminable Participants will then be assigned to a clinical risk group (low, standard, intermediate, or high) based on assessment of:
• How much tumor is left after surgery
• If the cancer has spread to other sites outside the brain \[i.e., to the spinal cord or within the fluid surrounding the spinal cord, called cerebrospinal fluid (CSF)\]
• The appearance of the tumor cells under the microscope
• Whether or not there are chromosomal abnormalities in the tumor, and if present, what type (also called cytogenetics analysis)

Conditions

Medulloblastoma

Keywords

SJMB12; Brain Cancer; Brain Tumors in Children; Cisplatin; Cyclophosphamide; Embryonal Tumors of CNS; GDC-0449; Gemcitabine; Hedgehog Pathway Inhibitor; Infratentorial; Mass in Brain; Medulloblastoma; Medulloblastoma Brain Tumor; Medulloblastoma Tumor; Molecular; Neuroectodermal Tumor, Primitive; Newly Diagnosed Childhood Medulloblastoma; Non-SHH Non-WNT; Pediatric Brain Tumor; Pemetrexed; Posterior Fossa Tumor; Proton Beam Therapy; Radiation Therapy; Rare Brain Tumor; Risk; SHH; Sonic Hedgehog Pathway; St Jude Medullo; St. Jude Brain Tumor Studies; St. Jude Medullo; St. Jude Studies; St. Jude Treatment; Treatment for Brain Tumors in Children; Untreated Childhood Medulloblastoma; Vincristine; Vismodegib; WNT

Outcome Measures

Primary Outcomes (5)

• Progression-free Survival in Stratum W1

  Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact.

  2 years after diagnosis

• Progression-free Survival in Stratum N1

  Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact.

  2 years after diagnosis

• Progression-free Survival in Stratum S1 Skeletally Mature Cohort

  Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact. PFS in SJMB12 stratum S1 skeletally mature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.

  2 years after diagnosis

• Change in VO2 Peak Value

  To evaluate the effect of an aerobic training intervention on cardiopulmonary fitness.

  baseline and 12 weeks post-randomization

• Change in Spatial Span Backward Standard Score

  To assess the impact of a computer-based working memory intervention, relative to standard of care, on a performance-based measure of working memory.

  baseline and 10-12 weeks post baseline

Secondary Outcomes (53)

• Progression-free Survival in Stratum W1 Compared to Historical Controls

  2 years after diagnosis

• Overall Survival in Stratum W1

  2 years after diagnosis

• Progression-free Survival in Stratum S1 Skeletally Immature Cohort

  2 years after diagnosis

• Progression-free Survival in Stratum S2 Skeletally Mature Cohort

  2 years after diagnosis

• Progression-free Survival in Stratum S2 Skeletally Immature Cohort

  2 years after diagnosis

Study Arms (8)

Stratum W1: Low Risk

EXPERIMENTAL

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.

Radiation: Craniospinal Irradiation with boost to the primary tumor site; Drug: Cyclophosphamide; Drug: Cisplatin; Drug: Vincristine; Other: Aerobic Training; Other: Neurocognitive Remediation

Stratum W2: Atypical

EXPERIMENTAL

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.

Radiation: Craniospinal Irradiation with boost to the primary tumor site; Drug: Cyclophosphamide; Drug: Cisplatin; Drug: Vincristine; Other: Aerobic Training; Other: Neurocognitive Remediation

Stratum W3: High Risk

EXPERIMENTAL

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.

Radiation: Craniospinal Irradiation with boost to the primary tumor site; Drug: Cyclophosphamide; Drug: Cisplatin; Drug: Vincristine; Other: Aerobic Training; Other: Neurocognitive Remediation

Stratum S1: Standard Risk

EXPERIMENTAL

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.

Radiation: Craniospinal Irradiation with boost to the primary tumor site; Drug: Cyclophosphamide; Drug: Cisplatin; Drug: Vincristine; Drug: Vismodegib; Other: Aerobic Training; Other: Neurocognitive Remediation

Stratum S2: High Risk

EXPERIMENTAL

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.

Radiation: Craniospinal Irradiation with boost to the primary tumor site; Drug: Cyclophosphamide; Drug: Cisplatin; Drug: Vincristine; Drug: Vismodegib; Other: Aerobic Training; Other: Neurocognitive Remediation

Stratum N1: Standard Risk

EXPERIMENTAL

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.

Radiation: Craniospinal Irradiation with boost to the primary tumor site; Drug: Cyclophosphamide; Drug: Cisplatin; Drug: Vincristine; Other: Aerobic Training; Other: Neurocognitive Remediation

Stratum N2: Intermediate Risk

EXPERIMENTAL

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.

Radiation: Craniospinal Irradiation with boost to the primary tumor site; Drug: Cyclophosphamide; Drug: Cisplatin; Drug: Vincristine; Drug: Pemetrexed; Drug: Gemcitabine; Other: Aerobic Training; Other: Neurocognitive Remediation

Stratum N3: High Risk

EXPERIMENTAL

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.

Radiation: Craniospinal Irradiation with boost to the primary tumor site; Drug: Cyclophosphamide; Drug: Cisplatin; Drug: Vincristine; Drug: Pemetrexed; Drug: Gemcitabine; Other: Aerobic Training; Other: Neurocognitive Remediation

Interventions

Craniospinal Irradiation with boost to the primary tumor site RADIATION

All participants will undergo craniospinal irradiation (CSI) with boost to the primary tumor site. The dose given is based on the molecular and risk group as noted in the arm descriptions. The type of radiation used includes conformal radiation therapy (photons) or intensity modulated radiation therapy (IMRT) or proton beam therapy.

Also known as: CSI, Radiation treatments

Stratum N1: Standard Risk; Stratum N2: Intermediate Risk; Stratum N3: High Risk; Stratum S1: Standard Risk; Stratum S2: High Risk; Stratum W1: Low Risk; Stratum W2: Atypical; Stratum W3: High Risk

Cyclophosphamide DRUG

Route of Administration (ROA): Intravenously (IV)

Also known as: Cytoxan(R)

Stratum N1: Standard Risk; Stratum N2: Intermediate Risk; Stratum N3: High Risk; Stratum S1: Standard Risk; Stratum S2: High Risk; Stratum W1: Low Risk; Stratum W2: Atypical; Stratum W3: High Risk

Cisplatin DRUG

ROA: IV

Also known as: Platinol-AQ(R)

Stratum N1: Standard Risk; Stratum N2: Intermediate Risk; Stratum N3: High Risk; Stratum S1: Standard Risk; Stratum S2: High Risk; Stratum W1: Low Risk; Stratum W2: Atypical; Stratum W3: High Risk

Vincristine DRUG

ROA: IV

Also known as: Oncovin(R)

Stratum N1: Standard Risk; Stratum N2: Intermediate Risk; Stratum N3: High Risk; Stratum S1: Standard Risk; Stratum S2: High Risk; Stratum W1: Low Risk; Stratum W2: Atypical; Stratum W3: High Risk

Vismodegib DRUG

ROA: Orally (PO)

Also known as: Erivedge(TM), GDC-0449

Stratum S1: Standard Risk; Stratum S2: High Risk

Pemetrexed DRUG

ROA: IV

Also known as: Almita(R)

Stratum N2: Intermediate Risk; Stratum N3: High Risk

Gemcitabine DRUG

ROA: IV

Also known as: Gemzar

Stratum N2: Intermediate Risk; Stratum N3: High Risk

Aerobic Training OTHER

Also known as: Exercise

Stratum N1: Standard Risk; Stratum N2: Intermediate Risk; Stratum N3: High Risk; Stratum S1: Standard Risk; Stratum S2: High Risk; Stratum W1: Low Risk; Stratum W2: Atypical; Stratum W3: High Risk

Neurocognitive Remediation OTHER

Also known as: Computer-based working memory intervention, Cogmed

Stratum N1: Standard Risk; Stratum N2: Intermediate Risk; Stratum N3: High Risk; Stratum S1: Standard Risk; Stratum S2: High Risk; Stratum W1: Low Risk; Stratum W2: Atypical; Stratum W3: High Risk

Eligibility Criteria

• Age: 3 Years - 39 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Medulloblastoma or medulloblastoma variants including posterior fossa PNET as documented by an institutional pathologist.
• Participant's age meets one of the following: (1) Age greater than or equal to 3 years and less than 22 years of age at the time of diagnosis (may enroll on Strata W, S or N), OR (2) age is greater than or equal to 22 years and less than 40 years AND patient has SHH medulloblastoma (must enroll on Stratum S).
• No previous radiotherapy, chemotherapy or other brain tumor directed therapy other than corticosteroid therapy and surgery.
• Patients must begin treatment as outlined in the protocol within 36 days of definitive surgery (day of surgery is day 0; definitive surgery includes second surgeries to resect residual tumor).
• Adequate performance status: children \< 10-Lansky Score ≥ 30; children ≥ 10-Karnofsky ≥ 30 (except for posterior fossa syndrome).
• Females of child-bearing potential cannot be pregnant or breast-feeding. Female participants \> 10 years of age or post-menarche must have a negative serum or urine pregnancy test prior to enrollment.

You may not qualify if:

• CNS embryonal tumor other than medulloblastoma or PNET in the posterior fossa, for example, patients with diagnosis of Atypical Teratoid / Rhabdoid Tumor (ATRT), supratentorial PNET, pineoblastoma, ependymoblastoma, ETANTR are excluded.
• Research participants with other clinically significant medical disorders that could compromise their ability to tolerate protocol therapy or would interfere with the study procedures or results history.
• Participants in the Stratum S maintenance chemotherapy portion of the study must meet the criteria below prior to start of vismodegib therapy:
• Participants must be Stratum S (SHH)
• Participants must be skeletally mature defined as females with a bone age ≥ 15 years and males with a bone age ≥ 17 years.
• Must be able to swallow pills
• BSA must be \>0.67 and \<2.5 m2
• Male and female participants of reproductive potential must agree to effective contraception during and after study treatment. See Appendices I and II for further guidance for participants receiving vismodegib
• ANC ≥ 1000/mm\^3 (after G-CSF discontinued)
• Platelets ≥ 50,000/mm\^3 (without support)
• Hgb ≥ 8 g/dL (with or without transfusion support)
• Serum creatinine ≤ 1.5 mg/dL
• Total bilirubin ≤ 1.5X the institutional ULN
• SGPT (ALT) ≤ 2.5X the institutional ULN
• SGOT (AST) ≤ 2.5X the institutional ULN

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• Genentech, Inc.: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (23)

Lucille Packard Children's Hospital at Stanford University Medical Center

Palo Alto, California, 94304, United States

Location

Rady Children's Hospital

San Diego, California, 92123, United States

Location

Yale University

New Haven, Connecticut, 06520, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

University of Florida

Gainesville, Florida, 32611, United States

Location

Arnold Palmer Hospital for Children

Orlando, Florida, 32806, United States

Location

Children's Hospital and Clinics of Minnesota

Minneapolis, Minnesota, 55102, United States

Location

Duke Children's Hospital and Health Center

Durham, North Carolina, 27710, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Cook Children's Medical Center

Fort Worth, Texas, 76104, United States

Location

Texas Children's Cancer Center

Houston, Texas, 77030-2399, United States

Location

Sydney Children's Hospital

Randwick, New South Wales, 2031, Australia

Location

Children's Hospital at Westmead

Westmead, New South Wales, 2145, Australia

Location

Queensland Children's Hospital

Brisbane, Queensland, 4029, Australia

Location

Royal Children's Hospital, Melbourne

Melbourne, Victoria, 3052, Australia

Location

Perth Children's Hospital

Perth, Western Australia, 6008, Australia

Location

Alberta Children's Hospital

Calgary, Alberta, T3B 6A8, Canada

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Centre Hospitalier Universitaire Sainte-Justine

Montreal, Quebec, H3T 1C5, Canada

Location

Starship Children's Hospital

Auckland, 1142, New Zealand

Location

Related Publications (1)

• Khan RB, Patay Z, Klimo P, Huang J, Kumar R, Boop FA, Raches D, Conklin HM, Sharma R, Simmons A, Sadighi ZS, Onar-Thomas A, Gajjar A, Robinson GW. Clinical features, neurologic recovery, and risk factors of postoperative posterior fossa syndrome and delayed recovery: a prospective study. Neuro Oncol. 2021 Sep 1;23(9):1586-1596. doi: 10.1093/neuonc/noab030.

  PMID: 33823018 DERIVED

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Medulloblastoma; Brain Neoplasms; Neuroectodermal Tumors, Primitive; Infratentorial Neoplasms

Interventions

Craniospinal Irradiation; Radiotherapy; Cyclophosphamide; Cisplatin; Vincristine; HhAntag691; Pemetrexed; Gemcitabine; Exercise

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Guanine; Hypoxanthines; Purinones; Purines; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• Amar Gajjar, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

• Giles Robinson, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 10, 2013
• First Posted: June 17, 2013
• Study Start: June 23, 2013
• Primary Completion (Estimated): October 13, 2028
• Study Completion (Estimated): October 13, 2031
• Last Updated: November 13, 2025

Record last verified: 2025-11

Locations

NZ (1); US (14); AU (5); CA (3)