Clinical Trials /

Reduced Craniospinal Radiation Therapy and Chemotherapy in Treating Younger Patients With Newly Diagnosed WNT-Driven Medulloblastoma

NCT02724579

Description:

This phase II trial studies how well reduced doses of radiation therapy to the brain and spine (craniospinal) and chemotherapy work in treating patients with newly diagnosed type of brain tumor called WNT)/Wingless (WNT)-driven medulloblastoma. Recent studies using chemotherapy and radiation therapy have been shown to be effective in treating patients with WNT-driven medulloblastoma. However, there is a concern about the late side effects of treatment, such as learning difficulties, lower amounts of hormones, or other problems in performing daily activities. Radiotherapy uses high-energy radiation from x-rays to kill cancer cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, vincristine sulfate, cyclophosphamide and lomustine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving reduced craniospinal radiation therapy and chemotherapy may kill tumor cells and may also reduce the late side effects of treatment.

Related Conditions:
  • Medulloblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Reduced Craniospinal Radiation Therapy and <span class="go-doc-concept go-doc-intervention">Chemotherapy</span> in Treating Younger Patients With Newly Diagnosed WNT-Driven <span class="go-doc-concept go-doc-disease">Medulloblastoma</span>

Title

  • Brief Title: Reduced Craniospinal Radiation Therapy and Chemotherapy in Treating Younger Patients With Newly Diagnosed WNT-Driven Medulloblastoma
  • Official Title: A Phase 2 Study of Reduced Therapy for Newly Diagnosed Average-Risk WNT-Driven Medulloblastoma Patients
  • Clinical Trial IDs

    NCT ID: NCT02724579

    ORG ID: ACNS1422

    NCI ID: NCI-2016-00150

    Trial Conditions

    Untreated Childhood Medulloblastoma

    Trial Interventions

    Drug Synonyms Arms
    Cisplatin Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, Platosin Treatment (reduced radiation therapy and chemotherapy)
    Cyclophosphamide (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719 Treatment (reduced radiation therapy and chemotherapy)
    Lomustine 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea, 1-Nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-, Belustin, Belustine, CCNU, Cecenu, CeeNU, Chloroethylcyclohexylnitrosourea, Citostal, Lomeblastin, Lomustinum, Lucostin, Lucostine, N-(2-Chloroethyl)-N'-cyclohexyl-N-nitrosourea, Prava, RB-1509, WR-139017 Treatment (reduced radiation therapy and chemotherapy)
    Vincristine Sulfate Kyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfate Treatment (reduced radiation therapy and chemotherapy)

    Trial Purpose

    This phase II trial studies how well reduced doses of radiation therapy to the brain and
    spine (craniospinal) and chemotherapy work in treating patients with newly diagnosed type of
    brain tumor called WNT)/Wingless (WNT)-driven medulloblastoma. Recent studies using
    chemotherapy and radiation therapy have been shown to be effective in treating patients with
    WNT-driven medulloblastoma. However, there is a concern about the late side effects of
    treatment, such as learning difficulties, lower amounts of hormones, or other problems in
    performing daily activities. Radiotherapy uses high-energy radiation from x-rays to kill
    cancer cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, vincristine
    sulfate, cyclophosphamide and lomustine, work in different ways to stop the growth of tumor
    cells, either by killing the cells, by stopping them from dividing, or by stopping them from
    spreading. Giving reduced craniospinal radiation therapy and chemotherapy may kill tumor
    cells and may also reduce the late side effects of treatment.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To estimate the progression-free survival (PFS) of children >= 3 years of age with
    wingless-type MMTV integration site family (WNT)/WNT-driven average-risk medulloblastoma
    using reduced craniospinal radiotherapy (CSI) (18 Gray [Gy]) with a limited target volume
    boost to the tumor bed of 36 Gy for a total of 54 Gy and reduced chemotherapy approach (no
    vincristine [vincristine sulfate] during radiotherapy and reduced-dose maintenance
    chemotherapy) and to monitor the PFS for early evidence that the outcome is unacceptable.

    SECONDARY OBJECTIVES:

    I. To prospectively test the hypothesis that deoxyribonucleic acid (DNA) methylation
    profiling will result in "real-time" classification of WNT-driven medulloblastoma.

    II. To use the ALTE07C1 protocol to prospectively evaluate and longitudinally model the
    cognitive, social, emotional and behavioral functioning of children who are treated with
    reduced CSI (18 Gy) with a limited target volume boost to the tumor bed (to a total of 54
    Gy) and reduced chemotherapy (reduced cisplatin, vincristine and lomustine [CCNU]).

    TERTIARY OBJECTIVES:

    I. To explore whether DNA methylation profiling of medulloblastoma samples will result in a
    "real-time" predictive classification scheme for the Sonic Hedgehog (SHH), Group 3 and Group
    4 medulloblastoma subgroups according to the Heidelberg classifier.

    OUTLINE:

    RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal
    radiation therapy 5 days a week for 6 weeks.

    MAITENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation
    therapy patients receive lomustine orally (PO) on day 1, vincristine sulfate intravenously
    (IV) over 1 minute or via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day
    1. Treatment repeats every 42 days in the absence of disease progression or unacceptable
    toxicity.

    MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60
    minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine
    sulfate IV over 1 minute or via minibag on days 1 and 8. Treatment repeats every 28 days in
    the absence of disease progression or unacceptable toxicity.

    After completion of study treatment, patients are followed up every 3 months for 2 years,
    every 6 months for 2 years, and then annually for 6 years.

    Trial Arms

    Name Type Description Interventions
    Treatment (reduced radiation therapy and chemotherapy) Experimental RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks. MAITENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine PO on day 1, vincristine sulfate IV over 1 minute or via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day 1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV over 1 minute or via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Cisplatin, Cyclophosphamide, Lomustine, Vincristine Sulfate

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must be newly diagnosed and have a confirmed molecular diagnosis of
    classical histologic type (non large cell/anaplastic [LC/A]) WNT medulloblastoma from
    rapid central pathology screening review on APEC14B1 (immunohistochemistry
    [IHC]/molecular screening [positive nuclear beta (B)-catenin by IHC and positive for
    catenin beta 1 [CTNNB1] mutation) and confirmation of =< 1.5 cm^2 maximal
    cross-sectional area of residual tumor from rapid central imaging review

    - Patient must have negative lumbar cerebrospinal fluid (CSF) cytology; CSF cytology
    for staging should be performed preferably no sooner than 14 days post operatively to
    avoid false positive CSF; ideally, CSF should be obtained between day 14 and day 21
    to allow for final staging status before enrollment onto the study

    - Note: patients with positive CSF cytology obtained prior to 14 days after
    surgery may have cytology repeated to determine eligibility and final CSF status

    - Patients must have eligibility confirmed by rapid central imaging review on APEC14B1;
    standard whole brain magnetic resonance imaging (MRI) with and without contrast
    (gadolinium) and spine MRI with contrast (gadolinium) must be performed at the
    following time points:

    - Pre-operative to include an MRI of the brain with and without contrast
    (including post-contrast three-dimensional [3D] T1-weighted image [T1WI] and
    post-contrast fluid-attenuated inversion recovery [FLAIR])

    - Pre-operative spinal MRI with gadolinium; post-operative staging spinal MRI may
    be obtained if pre-operative imaging is not possible or is suboptimal;
    pre-operative spine imaging is strongly preferred, due to the potential of
    post-operative sequelae, which could affect metastasis detection

    - Post-operative brain MRI within 72 hours of surgery

    - Patients must be enrolled on ALTE07C1 prior to enrollment on ACNS1422

    - Patients must be enrolled within 36 days of definitive diagnostic surgery (day
    0)

    - Note: patients must begin treatment within 36 days of definitive surgery

    - Patients must have no previous radiotherapy or chemotherapy other than
    corticosteroids

    - Peripheral absolute neutrophil count (ANC) >= 1000/uL

    - Platelet count >= 100,000/uL (transfusion independent)

    - Hemoglobin >= 10.0 g/dL (may receive red blood cell [RBC] transfusions)

    - Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
    mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

    - 3 to < 6 years of age: maximum (max) serum creatinine 0.8 mg/dL (males and
    females)

    - 6 to < 10 years of age: max serum creatinine 1 mg/dL (males and females)

    - 10 to < 13 years of age: max serum creatinine 1.2 mg/dL (males and females)

    - 13 to < 16 years of age: max serum creatinine 1.5 md/dL (males) and 1.4 md/dL
    (females)

    - >= 16 years of age: max serum creatinine 1.7 mg/dL (males) and 1.4 mg/dL
    (females)

    - The threshold creatinine values were derived from the Schwartz formula for
    estimating GFR utilizing child length and stature data published by the
    Centers for Disease Control and Prevention (CDC)

    - Total or direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and

    - Serum glutamate pyruvate (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L (for the
    purpose of this study, the upper limit of normal [ULN] for SGPT is 45 U/L)

    - Central nervous system function defined as:

    - Patients with seizure disorder may be enrolled if on anticonvulsants and well
    controlled

    - Patients must not be in status epilepticus, a coma or on assisted ventilation at
    the time of study enrollment

    - All patients and/or their parents or legal guardians must sign a written informed
    consent; assent, when appropriate, will be obtained according to institutional
    guidelines

    - All institutional, Food and Drug Administration (FDA), and National Cancer Institute
    (NCI) requirements for human studies must be met

    Exclusion Criteria:

    - Patients with metastatic disease by either MRI evaluation (brain and spine) or lumbar
    CSF cytology are not eligible; patients who are unable to undergo a lumbar puncture
    for assessment of CSF cytology are ineligible

    - Patients must not have received any prior tumor-directed therapy other than surgical
    intervention and corticosteroids

    - Female patients who are pregnant are ineligible

    - Lactating females are not eligible unless they have agreed not to breastfeed their
    infants

    - Female patients of childbearing potential are not eligible unless a negative
    pregnancy test result has been obtained

    - Sexually active patients of reproductive potential are not eligible unless they have
    agreed to use an effective contraceptive method for the duration of their study
    participation

    Minimum Eligible Age: 3 Years

    Maximum Eligible Age: 21 Years

    Eligible Gender: Both

    Primary Outcome Measures

    PFS

    Secondary Outcome Measures

    Change in neurocognitive function (cognitive, social, emotional and behavioral) according to Children Oncology Group Standard Neuropsychological Battery

    DNA methylation profiling as real-time classification of WNT-driven medulloblastoma

    Trial Keywords