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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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

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 st

Detailed Summary:

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.
  • To estimate the pro
    Sponsor: St. Jude Children's Research Hospital

    Current Primary Outcome:

    • Progression-free survival distribution (Stratum W1) [ Time Frame: 2 years after last patient enrollment ]
      Progression-free survival 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.)
    • Progression free survival distribution (Stratum N1) [ Time Frame: 2 years after last patient enrollment ]
      Progression-free survival 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.)
    • Change in VO2 peak values [ Time Frame: baseline and 12 weeks post-randomization ]
      To evaluate the effect of an aerobic training intervention on cardiopulmonary fitness.
    • Change in spatial span backward standard score [ Time Frame: baseline and 10-12 weeks post baseline ]
      To assess the impact of a computer-based working memory intervention, relative to standard of care, on a performance-based measure of working memory.


    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • Compare progression-free survival by strata with prior St. Jude SJMB03 study participants [ Time Frame: 2 years after last patient enrollment ]
      To estimate progression-free survival distribution and compare by strata to molecularly and clinically matched historical controls from St. Jude SJMB03 study.
    • Compare overall survival by strata with prior St. Jude SJMB03 study participants [ Time Frame: 2 years after last patient enrollment ]
      To estimate overall survival distribution by strata and compare to molecularly and clinically matched historical controls from St. Jude SJMB03 study.
    • Proportion of patients able to complete protocol therapy [ Time Frame: 10 months after the last patient enrollment ]
      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).
    • Number of patients who go off treatment for reasons other than progressive disease [ Time Frame: 20 months after the last patient enrollment ]
      To evaluate the feasibility and toxicity of oral maintenance therapy with the targeted SHH inhibitor (vismodegib) after conventional adjuvant chemotherapy regimen is complete.
    • Number of local failures [ Time Frame: 2 and 5 years after the last patient enrollment ]
      To estimate the cumulative incidence of local disease failure at 2 and 5 years based on treatment regimen, strata, and clinical and treatment factors.
    • Change in hand grip strength [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
      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 hand grip strength as measured using a hand-held dynamometer among children treated for medulloblastoma. Participants will be seated with the shoulder at 0-10 degrees and the elbow in 90 degrees of flexion. The forearm will be positioned in neutral. Each participant will complete three trials, the average used for analysis.
    • Change in range of motion [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
      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 range of motion as measured with a goniometer among children treated for medulloblastoma. The goniometer is a reliable and valid measure of active and passive range of motion with standard procedures.
    • Change in overall flexibility [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
      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 overall flexibility among children treated for medulloblastoma. Flexibility will be measured by having participants perform a "sit and reach test." A yardstick is placed on a firm flat surface and tape is placed across it at a right angle to the 15 inch mark. The participant sits with the yardstick between the legs, with legs extended at right angles to the taped line on the floor. The heels of the feet touch the edge of the taped line and are 10-12 inches apart. The participant reaches forward with both hands as far as possible, and the best value for three trials, in centimeters, at the fingertips is recorded.
    • Change in motor proficiency [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
      Measured by the Bruininks-Oseretsky Test of Motor Proficiency, Version 2 (BOT-2). 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 motor proficiency among children treated for medulloblastoma.
    • Change in quality of life (QOL) score [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
      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 health related quality of life (QoL) among children treated for medulloblastoma. QoL will be assessed using the 23-item PedsQL(TM) 4.0 Generic Core Scales whic

      Original Secondary Outcome:

      • Compare progression-free survival by strata with prior St. Jude SJMB03 study participants [ Time Frame: 2 years after last patient enrollment ]
        To estimate progression-free survival distribution and compare by strata to molecularly and clinically matched historical controls from St. Jude SJMB03 study.
      • Compare overall survival by strata with prior St. Jude SJMB03 study participants [ Time Frame: 2 years after last patient enrollment ]
        To estimate overall survival distribution by strata and compare to molecularly and clinically matched historical controls from St. Jude SJMB03 study.
      • Proportion of patients able to complete protocol therapy [ Time Frame: 10 months after the last patient enrollment ]
        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).
      • Number of patients who go off treatment for reasons other than progressive disease [ Time Frame: 20 months after the last patient enrollment ]
        To evaluate the feasibility and toxicity of oral maintenance therapy with the targeted SHH inhibitor (vismodegib) after conventional adjuvant chemotherapy regimen is complete.
      • Number of local failures [ Time Frame: 2 and 5 years after the last patient enrollment ]
        To estimate the cumulative incidence of local disease failure at 2 and 5 years based on treatment regimen, strata, and clinical and treatment factors.
      • Change in hand grip strength [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
        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 hand grip strength among children treated for medulloblastoma.
      • Change in range of motion [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
        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 range of motion among children treated for medulloblastoma.
      • Change in overall flexibility [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
        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 overall flexibility among children treated for medulloblastoma.
      • Change in motor proficiency [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
        Measured by the Bruininks-Oseretsky Test of Motor Proficiency, Version 2. 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 motor proficiency among children treated for medulloblastoma.
      • Change in quality of life (QOL) score [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
        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 health related quality of life among children treated for medulloblastoma.
      • Change in fatigue score [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
        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 fatigue among children treated for medulloblastoma.
      • Change in measure of memory function [ Time Frame: Baseline (at enrollment), 12 weeks, and at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3). ]
        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 memory function at the end of the intervention and at

        Information By: St. Jude Children's Research Hospital

        Dates:
        Date Received: June 10, 2013
        Date Started: June 23, 2013
        Date Completion: December 31, 2026
        Last Updated: March 30, 2017
        Last Verified: February 2017