SJMB12: A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma/PNET

Clinical and Molecular Risk-Directed Craniospinal Irradiation and Combination Chemotherapy in Treating Younger Patients With Newly Diagnosed Medulloblastoma

Category:

Brain Tumor

Diseases Treated:

Medulloblastoma (includes all variants of medulloblastoma and posterior fossa PNET)

Eligibility Overview:

  • Diagnosis of newly medulloblastoma
  • Must be least 3 but not more than 22 years of age
  • Has not received previous treatment with radiation therapy or chemotherapy
  • Must start treatment within 36 days of surgery to remove the tumor
  1. Brief Summary

    Treatment for medulloblastoma has historically 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 that respond differently to treatment. This suggests that clinical risk alone is not adequate to identify actual risk of recurrence. To address this, we will stratify medulloblastoma treatment in this phase 2 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 compared to cure rates in participants from the previous St. Jude study.

    All participants in 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. Each participant will be assigned to one of 3 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 [e.g., 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)

    Primary Objectives

    • To estimate the progression-free survival (PFS) distribution of WNT-medulloblastoma participants treated on Stratum W1 with reduced-dose craniospinal irradiation and reduced-dose cyclophosphamide
    • To estimate PFS distribution of non-WNT/non-SHH medulloblastoma participants 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

    Trial Outline

    This is a multicenter study. Participants 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 participants will be treated with risk-adapted radiation therapy and adjuvant chemotherapy.

    Interventions

    For Strata W1: Low Risk, W2: Atypical, W3: High Risk, Stratum N1: Standard Risk

    Radiation: craniospinal irradiation with boost to the primary tumor site
    Drugs: Cyclophosphamide, cisplatin, vincristine
    Other: Aerobic training; 
neurocognitive remediation

    For Strata S1: Standard Risk and Stratum S2: High Risk

    Radiation: craniospinal irradiation with boost to the primary tumor site
    Drugs: Cyclophosphamide, cisplatin, vincristine, vismodegib
    Other: Aerobic training; neurocognitive remediation

    For Strata N2: Intermediate Risk and N3: High Risk

    Radiation: craniospinal irradiation with boost to the primary tumor site
    Drugs: Cyclophosphamide, cisplatin, vincristine, pemetrexed, gemcitabine
    Other: Aerobic training; neurocognitive remediation

    Study Arms

    Experimental: Stratum W1: Low Risk

    Participants undergo reduced-dose craniospinal irradiation with boost to the primary tumor site once daily, five days a week for six weeks. Six weeks after completion of radiotherapy, participants receive one cycle of chemotherapy (cisplatin, vincristine, and cyclophosphamide) once every four weeks for four cycles in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.

    Experimental: Stratum W2: Atypical

    Participants 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, participants receive 1 cycle of chemotherapy (cisplatin, vincristine, and 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 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, participants receive 1 cycle of chemotherapy (cisplatin, vincristine, and 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 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, participants receive 1 cycle of chemotherapy (cisplatin, vincristine, and cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. After completion of four cycles of chemotherapy, participants will receive maintenance chemotherapy with vismodegib. Some participants will complete aerobic training and/or neurocognitive remediation.

    Experimental: Stratum S2: High Risk

    Participants 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, participants receive 1 cycle of chemotherapy (cisplatin, vincristine, and cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. After completion of 4 cycles of chemotherapy, participants will receive maintenance chemotherapy with vismodegib. Some participants will complete aerobic training and/or neurocognitive remediation.

    Experimental: Stratum N1: Standard Risk

    Participants 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, participants receive 1 cycle of chemotherapy (cisplatin, vincristine, and 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 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, participants receive standard chemotherapy (cisplatin, vincristine, and 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 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, participants receive standard chemotherapy (cisplatin, vincristine, and 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.

    Eligibility Criteria

    Inclusion Criteria:

    • Medulloblastoma or medulloblastoma variants including posterior fossa primitive neuroectodermal tumor (PNET) as documented by an institutional pathologist.
    • ≥ 3 years old and < 22 years of age when diagnosed.
    • No previous radiotherapy, chemotherapy or other brain tumor directed therapy other than corticosteroid therapy and surgery.
    • 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 breastfeeding. Female participants > 10 years of age or post-menarche must have a negative serum or urine pregnancy test prior to enrollment.

    Exclusion Criteria:

    • Central nervous system (CNS) embryonal tumor other than medulloblastoma or PNET in the posterior fossa, such as patients with diagnosis of atypical teratoid/rhabdoid tumor (ATRT), supratentorial PNET, pineoblastoma, ependymoblastoma, or embryonal tumor with abundant neuropil and true rosettes (ETANTR).
    • 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 exercise intervention portion of the study must meet all criteria below:
      • > 5 years at the time of enrollment.
      • No congenital heart disease or posterior fossa syndrome
    • 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)

    Study Design

    • Allocation: Non-Randomized
    • Endpoint Classification: Efficacy Study
    • Intervention Model: Parallel Assignment
    • Masking: Open Label
    • Primary Purpose: Treatment
  2. About this clinical trial 

    Medulloblastoma is a cancerous tumor, which is also called cerebellar primitive neuroectodermal tumor (PNET). It is the most common cancerous brain tumor in children.

    Medulloblastomas start in the region of the brain at the base of the skull, called the posterior fossa. They can spread to other parts of the brain and to the spinal cord. In the past medulloblastoma treatment was only based on the amount of tumor leftover after surgery and whether the tumor had spread to areas outside the brain. This is known as clinical risk. However, recent studies show that there are different types of medulloblastoma based on the molecular make-up of the tumor and each responds differently to treatment. This suggests that clinical risk alone is not enough to reduce the chances of your child’s cancer returning after treatment.

    For this reason, St. Jude is offering this Phase II study. It is the only such clinical trial for medulloblastoma that focuses on both your child’s clinical risk AND the type of medulloblastoma your child has (molecular risk).

    Purpose of this clinical trial

    The main goal of this clinical trial is to lower radiation and chemotherapy doses to participants who have tumors that do not seem to need such high doses to cure them. St. Jude researchers want to find out if there will be fewer side effects while still achieving the same survival rate as the past St. Jude study. Also, St. Jude researchers want to find out if adding new chemotherapy drugs to the standard chemotherapy will improve the survival.

    Treatment

    There are three parts to this study:

    • Screening – Tests and procedures will be done to find out if this study is a good option for your child. 
    • Treatment –The amount of radiation therapy and the type of chemotherapy your child receives will depend on the tumor type (molecular risk) and clinical risk.
    • Follow-up – After treatment ends, your child will undergo a series of tests to find out how well treatment worked to kill the cancer.

    Eligibility overview

    • Diagnosis of newly medulloblastoma
    • Must be least 3 but not more than 22 years of age
    • Has not received previous treatment with radiation therapy or chemotherapy
    • Must start treatment within 36 days of surgery to remove the tumor
  3. SJMB12  Quick View
    Sponsor St. Jude Children’s Research Hospital
    Collaborator Genentech
    ClinicalTrials.gov identifier
     
    NCT01878617
    Trial start date June 2013
    Estimated enrollment 350
    Study type Interventional
    Study phase Phase 2
    Condition Medulloblastoma
    Ages
     
    3 years to 21 years
    Principal investigator Amar Gajjar, MD
    Study sites St. Jude Children's Research Hospital and collaborating sites in the U.S., Australia and New Zealand
    For a consultation or to discuss SJMB12 St. Jude Brain Tumor Program
    Phone: 901-595-2544 or 901-595-4599
    Fax: 901-595-6211

Contact

Amar Gajjar, MD

St. Jude Children’s Research Hospital
262 Danny Thomas Place
Memphis, TN 38105  USA
Phone: 901-595-2544 or 901-595-4599
Fax: 901-595-6211

OR

Tabatha E. Doyle, RN
Coordinator, Brain Tumor Program
MS 260
262 Danny Thomas Place
Memphis, TN 38105
Phone: (901) 595-2544
FAX: (901) 595-6211

The above information is intended to provide only a basic description about a research protocol that may be currently active at St. Jude. The details made available here may not be the most up-to-date information on protocols used by St. Jude. To receive full details about a protocol and its status and or use at St. Jude, a physician must contact St. Jude directly.