Clinical Trials /

Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)

NCT01182350

Description:

The primary objective of this study is to estimate the overall survival of children and young adults with diffuse intrinsic pontine glioma treated (DIPG) with a molecularly based treatment strategy, compared to historical controls. Four Biopsies of tumor tissue will be obtained by surgical biopsy prior to treatment stratification if tolerated. An MRI-guided frameless or frame-based stereotactic biopsy will be performed approaching the pontine termentum through a trans-cerebellar or trans-frontal route. The exact biopsy location will be determined by the treating neurosurgeon at the designated participating site with the goal of minimizing procedural risk. Following biopsy,all patients will receive local radiotherapy to consist of 59.4Gy delivered using conventional conformal or other standard treatment planning with adjuvant bevacizumab. Radiation planning can begin with the pre-operative images. Based upon molecular parameters after biopsy, patients will potentially receive erlotinib and/or temozolomide at the start of radiotherapy. Bevacizumab will be given concurrently with radiotherapy beginning at least three weeks from the biopsy and at least two weeks after the start of radiation therapy to ensure that primary wound healing has occurred. Once irradiation is complete, patients will have a four week interim period before beginning the maintenance phase. Adjuvant chemotherapy will be continued during the interim period. The maintenance phase (approxmiately 40 weeks) will last for 10 cycles(28 days +/- 3 days). Based upon molecular parameters as determined at the time of diagnostic biopsy, patients will continue to receive erlotinib and/or temozolomide along with bevacizumab during the maintenance phase. Stratification will be based on O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and epidermal growth factor receptor (EGFR) expression in tumor biopsy samples. If MGMT status and/or EFGR status are not determinable, patients may be treated as per cohort #1(bevacizumab and irradiation) but will be analyzed separately.

Related Conditions:
  • Glioma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)

Title

  • Brief Title: Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)
  • Official Title: Phase II Trial of Molecularly Determined Treatment of Children and Young Adults With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas
  • Clinical Trial IDs

    NCT ID: NCT01182350

    ORG ID: DFCI 10-321

    Trial Conditions

    Diffuse Intrinsic Pontine Glioma

    Trial Interventions

    Drug Synonyms Arms
    Bevacizumab Avastin Bevacizumab +irradiation+ erlotinib, Bevacizumab + Irradiation, Bevacizumab+irradiation+temozolomide, Bevacizumab+ irradiation+erlotinib+temozol
    Erlotinib Tarceva Bevacizumab +irradiation+ erlotinib, Bevacizumab+ irradiation+erlotinib+temozol
    Temozolomide Temodar Bevacizumab+irradiation+temozolomide, Bevacizumab+ irradiation+erlotinib+temozol

    Trial Purpose

    The primary objective of this study is to estimate the overall survival of children and
    young adults with diffuse intrinsic pontine glioma treated (DIPG) with a molecularly based
    treatment strategy, compared to historical controls.

    Four Biopsies of tumor tissue will be obtained by surgical biopsy prior to treatment
    stratification if tolerated. An MRI-guided frameless or frame-based stereotactic biopsy will
    be performed approaching the pontine termentum through a trans-cerebellar or trans-frontal
    route. The exact biopsy location will be determined by the treating neurosurgeon at the
    designated participating site with the goal of minimizing procedural risk.

    Following biopsy,all patients will receive local radiotherapy to consist of 59.4Gy delivered
    using conventional conformal or other standard treatment planning with adjuvant bevacizumab.
    Radiation planning can begin with the pre-operative images. Based upon molecular parameters
    after biopsy, patients will potentially receive erlotinib and/or temozolomide at the start
    of radiotherapy. Bevacizumab will be given concurrently with radiotherapy beginning at least
    three weeks from the biopsy and at least two weeks after the start of radiation therapy to
    ensure that primary wound healing has occurred. Once irradiation is complete, patients will
    have a four week interim period before beginning the maintenance phase. Adjuvant
    chemotherapy will be continued during the interim period.

    The maintenance phase (approxmiately 40 weeks) will last for 10 cycles(28 days +/- 3 days).
    Based upon molecular parameters as determined at the time of diagnostic biopsy, patients
    will continue to receive erlotinib and/or temozolomide along with bevacizumab during the
    maintenance phase.

    Stratification will be based on O6-methylguanine-DNA methyltransferase (MGMT) promoter
    methylation status and epidermal growth factor receptor (EGFR) expression in tumor biopsy
    samples. If MGMT status and/or EFGR status are not determinable, patients may be treated as
    per cohort #1(bevacizumab and irradiation) but will be analyzed separately.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Bevacizumab +irradiation+ erlotinib Experimental Radiation therapy to consist of 59.4Gy delivered using conventional conformal treatment planning. Bevacizumab,and erlotinib will be given according to dosage, time frame listed. Bevacizumab, Erlotinib
    Bevacizumab + Irradiation Experimental (promoter methylation negative, no EGFR over-expression): Bevacizumab plus irradiation: Radiation therapy to consist of 59.4Gy delivered using conventional conformal treatment planning. Bevacizumab, 10 mg/kg IV, will be given at least three weeks from the biopsy and at least two weeks after start of the radiation therapy and then every 14 +/- 3 days concurrently with radiation therapy, during the interim period, and for up to 10 maintenance cycles. Bevacizumab
    Bevacizumab+irradiation+temozolomide Experimental Bevacizumab plus irradiation plus temozolomide (promoter methylation positive, no EGFR over-expression) Radiation therapy to consist of 59.4Gy delivered using conventional conformal treatment planning. Bevacizumab and radiation will be given according to dosage and time frame listed. Bevacizumab, Temozolomide
    Bevacizumab+ irradiation+erlotinib+temozol Experimental Bevacizumab plus irradiation plus erlotinib plus temozolomide (promoter methylation positive, EGFR over-expressed) Radiation therapy to consist of 59.4Gy delivered using conventional conformal treatment planning. Bevacizumab, erlotinib and temozolomide will be given according to dosage, time frame listed. Bevacizumab, Erlotinib, Temozolomide

    Eligibility Criteria

    Inclusion Criteria:

    Participants must meet the following criteria on screening examination to be eligible to
    participate in the study:

    1. Tumor: Newly diagnosed non-disseminated diffuse intrinsic pontine glioma based on
    classic clinical AND radiographic finding.

    2. No prior radiation therapy or chemotherapy.

    3. Age: Patient must be 3 to < 18 years of age at the time of diagnosis.

    4. Performance Score: Karnofsky Performance Scale > 12 y/o >/= 50 or Lansky
    Performance Score for patients < 12y/o 50 assessed within two-weeks prior to
    enrollment.

    5. Participants must have normal organ and marrow function as defined below within two
    week s prior to enrollment:

    - Absolute neutrophil count > 1,000/mcL

    - Platelets > 100,000/mcL (transfusion independent)

    - Hemoglobin > 8gm/dL (can be transfused)

    - Hepatic: Total bilirubin < 1.5 times the upper limit of normal; alanine
    aminotransferase [SGPT (ALT)] and aspartate aminotransferase [SGOT (AST)] < 5
    times the institutional upper limit of normal.

    - Renal: Serum creatinine which is less than 1.5x the upper limit of institutional
    normal for age or Glomerular Filtration Rate (GFR) > 70 ml/min/1.73m2.

    6. Female patients of childbearing potential must have negative serum or urine pregnancy
    test. Patient must not be pregnant or breast feeding.

    7. Patients of childbearing or child-fathering potential must be willing to use a
    medically acceptable form of birth control, which includes abstinence, while being
    treated on this study.

    8. Ability to understand and the willingness to sign a written informed consent
    document.

    Exclusion Criteria:

    1. Patients must not have any significant medical illnesses that in the investigator's
    opinion cannot be adequately controlled with appropriate therapy or would compromise
    the patient's ability to tolerate this therapy.

    2. Patients receiving any other anticancer or experimental drug therapy.

    3. Patients with disseminated intrinsic diffuse brainstem gliomas in either brain or
    spine (can be based on clinical evaluation).

    4. Participants receiving any medications or substances that are strong/intermediate
    inhibitors or inducers of Cytochrome P450 (CYP450), Cytochrome P3A4(CYP3A4) or
    Cytochrome 1A2 (CYP1A2) are ineligible. Lists including medications and substances
    known or with the potential to interact with the CYP450 CYP3A4 or CYP1A2 isoenzymes
    are provided in Appendix I.

    5. Use of hematopoietic growth factors within the 2 weeks prior to initiation of
    therapy.

    6. Patients with evidence of spontaneous hemorrhage greater than 0.5cm unrelated to
    surgery.

    7. Uncontrolled intercurrent illness including, but not limited to ongoing or active
    infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
    arrhythmia, or psychiatric illness/social situations that would limit compliance with
    study requirements.

    8. Pregnant women are excluded from this study because bevacizumab, temozolomide and
    erlotinib can have potential for teratogenic or abortifacient effects. Because there
    is an unknown but potential risk of adverse events in nursing infants secondary to
    treatment of the mother with these agents, breastfeeding should be discontinued.

    -

    Minimum Eligible Age: 3 Years

    Maximum Eligible Age: 18 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Overall survival of children and young adults with diffuse intrinsic pontine glioma treated with a molecularly based treatment strategy, compared to historical controls (COG ACNS0126)

    Secondary Outcome Measures

    Safety and feasibility of performing biopsy and obtaining tissue useful for histologic diagnosis, immunohistochemistry and DNA analyses in newly diagnosed DIPG patients

    Toxicity profiles of the 4 treatment strata

    Progression free survival of children and young adults with diffuse intrinsic pontine glioma treated with a molecularly based treatment strategy, compared to historical controls (COG ACNS0126).

    Molecular pathology analyses

    Correlation of imaging including perfusion/diffusion, diffusion tensor imaging (DTI) and magnetic resonance imaging (MRS) scan with patient response and outcome

    Trial Keywords

    Molecularly Determined Treatment