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

Study Purpose

Historically, medulloblastoma treatment has been determined by the amount of leftover disease present after surgery, also known as clinical risk (standard vs.#46; 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)

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 3 Years - 39 Years
Gender All
More Inclusion & Exclusion Criteria

INCLUSION CRITERIA.

  • - 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.
  • - Biological parent(s) of participant (child) enrolling on this protocol.
These parents will be assigned to cohort P. The exclusion criteria below do not apply to this cohort. EXCLUSION CRITERIA.
  • - 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.
  • - Alkaline Phosphatase ≤ 1.5X the institutional ULN.
  • - Serum albumin ≥ 2.5 g/dL.
Participants in the exercise intervention portion of the study must meet all criteria below:
  • - Must be ≥ 5 years and < 22 years at the time of enrollment.
  • - Must have no congenital heart disease.
  • - Must be capable of performing the exercise intervention at the time of baseline assessment as determined by the treating physician.
Participants in the cognitive remediation intervention portion of the study must meet all criteria below:
  • - Completed protocol-directed radiation therapy.
  • - ≥5 years at the time of remediation intervention consent or age is greater than or equal to 22 years and less than 40 years and patient has SHH medulloblastoma.
  • - English as primary language and training aide who speaks English available to participate in required sessions.
  • - No significant cognitive impairment operationalized as either an IQ < 70 for children with St. Jude SJMB12 study baseline testing or based on clinician judgment baseline IQ missing.
- No major sensory or motor impairment that would preclude valid cognitive testing (e.g., unresolved posterior fossa syndrome, blindness, poorly controlled seizures/photosensitive epilepsy, psychosis) or a major psychological condition that would preclude completion of the intervention (e.g., significant oppositionality, autism spectrum disorder, severe anxiety or depressive symptoms)

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT01878617
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

St. Jude Children's Research Hospital
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Amar Gajjar, MDGiles Robinson, MD
Principal Investigator Affiliation St. Jude Children's Research HospitalSt. Jude Children's Research Hospital
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other, Industry, NIH
Overall Status Active, not recruiting
Countries Australia, Canada, New Zealand, United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Medulloblastoma
Study Website: View Trial Website
Additional Details

Primary Objectives:

  • - To estimate the progression free survival distribution of WNT-medulloblastoma patients treated on Stratum W1 with reduced-dose craniospinal irradiation and reduced-dose cyclophosphamide.
  • - To estimate progression-free survival distribution of Non-WNT Non-SHH medulloblastoma patients treated on Stratum N1 with reduced dose cyclophosphamide.
  • - To estimate the progression free survival distribution of skeletally mature SHH medulloblastoma patients assigned to Stratum S1 and treated with oral maintenance therapy using a targeted SHH pathway inhibitor (vismodegib) after the adjuvant chemotherapy regimen is complete and to compare the outcome to molecularly and clinically matched historical controls from SJMB03 as well as outcome from other published cohorts.
  • - To evaluate the effect of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on cardiopulmonary fitness.
  • - To assess the impact of a computer-based working memory intervention (administered prophylactically at the end of chemotherapy), relative to standard of care, on a performance-based measure of working memory.
Secondary Objectives:
  • - To estimate overall survival distribution of WNT-medulloblastoma patients treated on Stratum W1 with reduced-dose craniospinal irradiation and reduced-dose cyclophosphamide and compare progression free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study.
  • - To estimate the progression free (in S1 skeletally immature and S2 both sub-strata) and overall survival distributions of SHH medulloblastoma patients enrolled on Strata S1 and S2 some of whom will be treated with oral maintenance therapy using a targeted SHH pathway inhibitor (vismodegib) after adjuvant chemotherapy regimen is complete and compare these outcomes to molecularly and clinically matched historical controls from SJMB03 as well as outcome from other published cohorts.
  • - To estimate the progression free and overall survival distributions of Non-WNT Non-SHH medulloblastoma patients treated on Strata N2 and N3 with 3 cycles of pemetrexed and gemcitabine in addition to 4 cycles of conventional adjuvant chemotherapy and compare the progression-free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study separately for each stratum.
  • - To estimate the overall survival distribution of Non-WNT Non-SHH medulloblastoma patients treated on Stratum N1 with reduced dose cyclophosphamide and compare progression free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study.
  • - To evaluate the feasibility and toxicity of adding pemetrexed and gemcitabine to adjuvant chemotherapy regimen of intermediate and high risk Non-WNT Non-SHH medulloblastoma patients (Strata N2 and N3).
  • - To evaluate the feasibility and toxicity of oral maintenance therapy with the targeted SHH inhibitor (vismodegib) after conventional adjuvant chemotherapy regimen is complete.
  • - To estimate the cumulative incidence of local disease failure at 2 and 5 years based on treatment regimen, strata, and clinical and treatment factors.
  • - To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on physical performance, fatigue, health related quality of life, memory, attention and executive function at the end of the intervention, at the end of adjuvant chemotherapy, and one, two and five years off adjuvant chemotherapy, among children treated for medulloblastoma.
  • - To evaluate the impact of an aerobic training intervention on sleep quality and quantity in children with medulloblastoma.
  • - To evaluate the relation between baseline cognitive performance and the variables of sleep quality and quantity, and fatigue in children with medulloblastoma.
  • - To estimate change in neurocognitive performance using a comprehensive assessment battery (e.g., measures of intellectual function, academic abilities, attention, memory, processing speed and executive functions) and investigate the relationship of change to relevant demographic factors (e.g., gender, age at treatment, time since treatment and socioeconomic status) and clinical factors (e.g., treatment intensity/risk group, posterior fossa syndrome).
  • - To assess the impact of a computer-based working memory intervention, relative to standard of care, on additional performance- and rater-based measures of attention, processing speed and executive functions.
  • - To compare the impact of a computer-based working memory intervention in conjunction with an aerobic training intervention, relative to either intervention in isolation, on measures of attention, processing speed and executive functions.
  • - To evaluate the maintenance of improvements on measures of attention, working memory, processing speed and executive functions six months following participation in the computer-based working memory intervention program.
Outline: This is a multicenter study. Patients are stratified according to molecular subgroup assignment (WNT, SHH, or Non-WNT Non- SHH) and then by clinical risk stratification (extent of resection, M stage, histologic subtype, and cytogenetic features). All patients will be treated with risk-adapted radiation therapy and adjuvant chemotherapy. Patients assigned to Stratum W1 will receive reduced dose radiation therapy. Patients assigned to Stratum W2, S1, N1, or N2 will receive standard dose radiation therapy. Patients assigned to Stratum W3, S2, or N3 will receive high dose radiation therapy. Radiation therapy will be followed by 4 cycles of adjuvant conventional chemotherapy with cyclophosphamide, cisplatin and vincristine for all patients. Patients assigned to Stratum N2 or N3 (Non-WNT Non-SHH with high risk factors) will receive 3 additional cycles of pemetrexed and gemcitabine chemotherapy intermixed into the conventional adjuvant chemotherapy cycles. Patients with SHH subtype (Stratum S1 or S2) who are skeletally mature will receive 12 months additional maintenance therapy with vismodegib. Patients may consent to provide tumor tissue, blood, and CSF samples for biological studies. Tumor tissues are analyzed for the activation of the WNT signaling pathway, activation of the SHH signaling pathway, validation of novel patterns of gene expression via immunohistochemical (IHC) analysis; validation of genetic abnormalities via interphase fluorescence in situ hybridization (iFISH); construction of gene expression profiles via microarray analysis; construction of DNA methylation profiling via microarrays; single nucleotide polymorphism (SNP) analysis for DNA copy number aberrations; potential oncogenes and tumor suppressor genes via DNA sequence analysis; expression of a number of cell signal proteins implicated in the biology of medulloblastoma via western blot; expression of additional proteins encoded by genes associated through SNP and gene expression array analysis with clinical disease behavior. Blood samples are analyzed from patients whose tumors contain gene mutations via sequence analysis of constitutional DNA. CSF and blood samples are analyzed for identification of potential tumor markers. Parents may consent to have blood samples analyzed for inheritable gene mutations associated with medulloblastoma. Patients may also consent to exploratory research that include additional functional MRI imaging to investigate damage to neural connections from therapy; additional psychological testing to identify neurocognitive effects of therapy; additional heart and lung testing to identify treatment effects; additional endocrine studies to identify treatment effect on growth and development. After completion of study treatment, patients are followed every 6 months for 5 years.

Arms & Interventions

Arms

Experimental: Stratum W1: Low Risk

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.

Experimental: Stratum W2: Atypical

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.

Experimental: Stratum W3: High Risk

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.

Experimental: Stratum S1: Standard Risk

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.

Experimental: Stratum S2: High Risk

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.

Experimental: Stratum N1: Standard Risk

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.

Experimental: Stratum N2: Intermediate Risk

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.

Experimental: Stratum N3: High Risk

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.

Interventions

Radiation: - Craniospinal Irradiation with boost to the primary tumor site

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.

Drug: - Cyclophosphamide

Route of Administration (ROA): Intravenously (IV)

Drug: - Cisplatin

ROA: IV

Drug: - Vincristine

ROA: IV

Drug: - Vismodegib

ROA: Orally (PO)

Drug: - Pemetrexed

ROA: IV

Drug: - Gemcitabine

ROA: IV

Other: - Aerobic Training

Other: - Neurocognitive Remediation

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Palo Alto, California

Status

Address

Lucille Packard Children's Hospital at Stanford University Medical Center

Palo Alto, California, 94304

Rady Children's Hospital, San Diego, California

Status

Address

Rady Children's Hospital

San Diego, California, 92123

Yale University, New Haven, Connecticut

Status

Address

Yale University

New Haven, Connecticut, 06520

Children's National Medical Center, Washington, District of Columbia

Status

Address

Children's National Medical Center

Washington, District of Columbia, 20010

University of Florida, Gainesville, Florida

Status

Address

University of Florida

Gainesville, Florida, 32611

Arnold Palmer Hospital for Children, Orlando, Florida

Status

Address

Arnold Palmer Hospital for Children

Orlando, Florida, 32806

Minneapolis, Minnesota

Status

Address

Children's Hospital and Clinics of Minnesota

Minneapolis, Minnesota, 55102

Durham, North Carolina

Status

Address

Duke Children's Hospital and Health Center

Durham, North Carolina, 27710

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Status

Address

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104

Medical University of South Carolina, Charleston, South Carolina

Status

Address

Medical University of South Carolina

Charleston, South Carolina, 29425

St. Jude Children's Research Hospital, Memphis, Tennessee

Status

Address

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105

Dallas, Texas

Status

Address

University of Texas Southwestern Medical Center

Dallas, Texas, 75390

Cook Children's Medical Center, Fort Worth, Texas

Status

Address

Cook Children's Medical Center

Fort Worth, Texas, 76104

Texas Children's Cancer Center, Houston, Texas

Status

Address

Texas Children's Cancer Center

Houston, Texas, 77030-2399

International Sites

Sydney Children's Hospital, Randwick, New South Wales, Australia

Status

Address

Sydney Children's Hospital

Randwick, New South Wales, 2031

Children's Hospital at Westmead, Westmead, New South Wales, Australia

Status

Address

Children's Hospital at Westmead

Westmead, New South Wales, 2145

Queensland Children's Hospital, Brisbane, Queensland, Australia

Status

Address

Queensland Children's Hospital

Brisbane, Queensland, 4029

Royal Children's Hospital, Melbourne, Melbourne, Victoria, Australia

Status

Address

Royal Children's Hospital, Melbourne

Melbourne, Victoria, 3052

Perth Children's Hospital, Perth, Western Australia, Australia

Status

Address

Perth Children's Hospital

Perth, Western Australia, 6008

Alberta Children's Hospital, Calgary, Alberta, Canada

Status

Address

Alberta Children's Hospital

Calgary, Alberta, T3B 6A8

The Hospital for Sick Children, Toronto, Ontario, Canada

Status

Address

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8

Montreal, Quebec, Canada

Status

Address

Centre Hospitalier Universitaire Sainte-Justine

Montreal, Quebec, H3T 1C5

Starship Children's Hospital, Auckland, New Zealand

Status

Address

Starship Children's Hospital

Auckland, , 1142