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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

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

Accepts Healthy Volunteers
No

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.

Study Type
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 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 - 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

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.

Trial ID:
NCT01878617

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
Phase 2

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

Lead Sponsor
St. Jude Children's Research Hospital

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

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

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

Agency Class
OtherIndustryNIH
Overall Status Recruiting
Countries Australia, Canada, New Zealand, United States

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

Conditions
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 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 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 the progression-free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study 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.

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

Recruiting

Address

Lucille Packard Children's Hospital at Stanford University Medical Center

Palo Alto, California, 94304

Site Contact

Sonia Partap, MD

spartap@stanford.edu

650-723-0993

Rady Children's Hospital, San Diego, California

Status

Recruiting

Address

Rady Children's Hospital

San Diego, California, 92123

Site Contact

John Crawford, MD, MS

858-576-1700

Yale University, New Haven, Connecticut

Status

Recruiting

Address

Yale University

New Haven, Connecticut, 06520

Site Contact

Nina Kadan-Lottick, MD,SM

nina.kadan-lottick@yale.edu

203-785-5702

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

Status

Recruiting

Address

Children's National Medical Center

Washington, District of Columbia, 20010

Site Contact

Eugene I. Hwang, MD

ehwang@cnmc.org

202-476-4481

University of Florida, Gainesville, Florida

Status

Recruiting

Address

University of Florida

Gainesville, Florida, 32611

Site Contact

Sridharan Gururangan, MD

sridharan.gururangan@neurosurgery.ufl.edu

901-595-2544

Arnold Palmer Hospital for Children, Orlando, Florida

Status

Recruiting

Address

Arnold Palmer Hospital for Children

Orlando, Florida, 32806

Site Contact

Amy Smith, MD

321-841-8588

Minneapolis, Minnesota

Status

Recruiting

Address

Children's Hospital and Clinics of Minnesota

Minneapolis, Minnesota, 55102

Site Contact

Anne Bendel, MD

anne.bendel@childrensmn.org

651-220-6732

Durham, North Carolina

Status

Recruiting

Address

Duke Children's Hospital and Health Center

Durham, North Carolina, 27710

Site Contact

David Ashley, MBBS, FRAP, PhD

david.ashley@duke.edu

919-681-4047

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Status

Recruiting

Address

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104

Site Contact

Michael Fisher, MD

FISHERM@email.chop.edu

215-590-3025

Medical University of South Carolina, Charleston, South Carolina

Status

Completed

Address

Medical University of South Carolina

Charleston, South Carolina, 29425

Site Contact

901-595-2544

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

Status

Recruiting

Address

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105

Site Contact

Tabatha E. Doyle, RN

tabatha.doyle@stjude.org

901-595-2544

Dallas, Texas

Status

Recruiting

Address

University of Texas Southwestern Medical Center

Dallas, Texas, 75390

Site Contact

Daniel Bowers, MD

Daniel.Bowers@UTSouthwestern.edu

214-648-3150

Cook Children's Medical Center, Fort Worth, Texas

Status

Recruiting

Address

Cook Children's Medical Center

Fort Worth, Texas, 76104

Site Contact

Jeffrey Murray, MD

jeffrey.murray@cookchildrens.org

682-885-4007

Texas Children's Cancer Center, Houston, Texas

Status

Recruiting

Address

Texas Children's Cancer Center

Houston, Texas, 77030-2399

Site Contact

Murali Chintagumpala, MD

mxchinta@texaschildrenshospital.org

713-798-1354

International Sites

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

Status

Recruiting

Address

Sydney Children's Hospital

Randwick, New South Wales, 2031

Site Contact

Richard Cohn, FRACP

r.cohn@unsw.edu.au

61-2-9382-1730

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

Status

Recruiting

Address

Children's Hospital at Westmead

Westmead, New South Wales, 2145

Site Contact

Geoffrey B. McCowage, MD

geoffm@chw.edu.au

61-2-9845-1400

Brisbane, Queensland, Australia

Status

Recruiting

Address

Lady Cilento Children's Hospital, Brisbane

Brisbane, Queensland, 4029

Site Contact

Tim Hassall, MBBS, FRACP

tim_hassall@health.qld.gov.au

61-7-3636-9115

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

Status

Recruiting

Address

Royal Children's Hospital, Melbourne

Melbourne, Victoria, 3052

Site Contact

Michael Sullivan, MB, ChB, PhD

michael.sullivan@rch.org.au

+61 3 9345 5522

Princess Margaret Hospital for Children, Perth, Western Australia, Australia

Status

Recruiting

Address

Princess Margaret Hospital for Children

Perth, Western Australia, 6008

Site Contact

Nicholas J. Gottardo, MD

admin@childcancerresearch.com.au

08-9340-8330

Alberta Children's Hospital, Calgary, Alberta, Canada

Status

Recruiting

Address

Alberta Children's Hospital

Calgary, Alberta, T3B 6A8

Site Contact

Doug Strother, MD

901-595-2544

Montreal, Quebec, Canada

Status

Recruiting

Address

Centre Hospitalier Universitaire Sainte-Justine

Montreal, Quebec, H3T 1C5

Site Contact

Sebastien Perrault, MD

901-595-2544

Starship Children's Hospital, Auckland, New Zealand

Status

Recruiting

Address

Starship Children's Hospital

Auckland, , 1142

Site Contact

Stephen Laughton, MBChB

stephenl@adhb.govt.nz

64 9 3074949 #22416

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