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Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01182350
Recruitment Status : Terminated (Per design: Stop if fewer than 3 cohorts by molecular classification were with 10 participants or only 1 cohort enrolled at least 15 participants of 50.)
First Posted : August 16, 2010
Results First Posted : September 4, 2019
Last Update Posted : September 4, 2019
Sponsor:
Collaborators:
Boston Children's Hospital
University of California, San Francisco
Ann & Robert H Lurie Children's Hospital of Chicago
Children's Healthcare of Atlanta
Children's Hospital Colorado
Children's Hospital Los Angeles
Children's Hospital of Michigan
Children's Hospitals and Clinics of Minnesota
Cook Children's Medical Center
OHSU Doernbecher Children's Hospital
Duke University
Johns Hopkins University
Nicklaus Children's Hospital f/k/a Miami Children's Hospital
Nemours Children's Clinic
New York University
Milton S. Hershey Medical Center
Seattle Children's Hospital
Lucile Packard Children's Hospital
University of Louisville
Children's National Research Institute
Washington University School of Medicine
Phoenix Children's Hospital
Medical University of South Carolina
Information provided by (Responsible Party):
Karen D. Wright MD, Dana-Farber Cancer Institute

Tracking Information
First Submitted Date  ICMJE August 12, 2010
First Posted Date  ICMJE August 16, 2010
Results First Submitted Date  ICMJE June 27, 2019
Results First Posted Date  ICMJE September 4, 2019
Last Update Posted Date September 4, 2019
Actual Study Start Date  ICMJE September 2011
Actual Primary Completion Date June 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 13, 2019)
9-month Overall Survival (OS) Rate [ Time Frame: 9 months ]
9-month overall survival is the percentage of participants remaining alive 9 months from registration.
Original Primary Outcome Measures  ICMJE
 (submitted: August 13, 2010)
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) [ Time Frame: 52 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 13, 2019)
  • Rate of Lethal Complications From Surgery [ Time Frame: 2 weeks ]
    The rate of lethal complications from surgery is the percentage of participants dying as a result of surgery.
  • Grade 3-4 Post-Procedural Surgery-Related Toxicity Rate [ Time Frame: 2 weeks ]
    Grade 3-4 post-procedural surgery-related toxicity rate is the percentage of participants experiencing at least one grade 3-4 adverse event (AE) during the post-procedural time frame of 14 days attributable to the surgical procedure based on NCI Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4).
  • Delay in Radiation Therapy Start [ Time Frame: 3 weeks ]
    The number of participants delaying the start of radiation therapy by more than 3 weeks due to complications as a result of surgical biopsy to obtain diagnostic tumor sample.
  • Feasibility Rate of Molecular Approach to Therapy [ Time Frame: 3 weeks ]
    Feasibility rate of the molecular strategy is based on the percentage of participants either with inadequate tissue from surgical biopsy to confirm DIPG diagnosis and/or with uninterpretable results for identification of EGFR overexpression and MGMT methylation status.
  • Number of Participants With Grade 3-4 Treatment-Related Toxicity Over Chemoradiation Therapy [ Time Frame: Adverse events were routinely throughout treatment. Treatment duration was a median of 6.4 months (range 0.4-13.4 months) in this study cohort. ]
    Counts any participant experiencing at least one treatment-related grade 3 or 4 adverse event (AE) with treatment attribution of possibly, probably or definite based on NCI Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4) over chemoradiation therapy as reported on case report forms.
  • Median Progression Free Survival (PFS) [ Time Frame: Disease assessments using a standard CNS imaging protocol occurred chemoradiation cycles 1 and 2, every other maintenance cycle, every 3 months post-treatment year 1 then annually until PD or therapy change; In this study cohort, follow-up was up to 34m. ]
    PFS based on the Kaplan-Meier method is defined as the duration of time [months (m)] from study entry to documented disease progression (PD) or death. Participants alive without PD are censored at the date of last disease assessment. For intrinsic pontine brainstem gliomas, only one lesion/mass is present at diagnosis. Comparisons of maximal 2-dimensional measurements, TxW (product of the longest diameter [width (W)] and its longest perpendicular diameter [transverse (T)]) are used to assess response for this target lesion. PD is 25% or more increase, taking as reference the smallest product observed since the start of treatment, or the appearance of one or more new lesions.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 13, 2010)
  • Safety and feasibility of performing biopsy and obtaining tissue useful for histologic diagnosis, immunohistochemistry and DNA analyses in newly diagnosed DIPG patients [ Time Frame: 52 weeks ]
  • Toxicity profiles of the 4 treatment strata [ Time Frame: 52 weeks ]
  • 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). [ Time Frame: 52 weeks ]
  • Molecular pathology analyses [ Time Frame: 52 weeks ]
  • Correlation of imaging including perfusion/diffusion, diffusion tensor imaging (DTI) and magnetic resonance imaging (MRS) scan with patient response and outcome [ Time Frame: 52 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)
Official Title  ICMJE Phase II Trial of Molecularly Determined Treatment of Children and Young Adults With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas
Brief Summary Diagnosis of diffuse intrinsic pontine glioma (DIPG) for decades has relied on imaging studies and clinical findings. Histologic confirmation has been absent with surgical biopsy of brainstem tumors not believed to have acceptable safety. The prognosis of DIPG has remained quite poor and novel therapeutic strategies are needed. This DIPG Biology and Treatment Study (DIPG-BATS) study incorporates a surgical biopsy at presentation using strict preoperative neurosurgical planning and stratifies participants to receive FDA-approved agents chosen on the basis of specific biologic targets. This is the first prospective national clinical trial to examine the feasibility and safety of incorporating surgical biopsy into potential treatment strategies for children with DIPG.
Detailed Description The primary objective of this study is to estimate the overall survival of children and young adults with DIPG in the context of a molecularly based treatment strategy, compared to historical controls (COG ACNS0126). Secondary objectives were to determine the safety and potential morbidity associated with biopsy of classic DIPGs based on imaging and clinical history as well as ability to perform biologic analyses on the biopsy material obtained to guide therapy. At study entry, a 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. Treatment directed based on tumor biopsy results requires classification of patients into 1 of 4 potential cohorts: O^6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status (negative versus positive) and epidermal growth factor receptor (EGFR) overexpression status (negative versus positive).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
This is not a randomized trial rather participants are classified and therapy is directed based on molecular profile obtained from surgical biopsy.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Diffuse Intrinsic Pontine Glioma
Intervention  ICMJE
  • Drug: Bevacizumab
    Other Name: Avastin
  • Drug: Erlotinib
    Other Name: Tarceva
  • Drug: Temozolomide
    Other Name: Temodar
  • Radiation: Radiation
    Other Name: irradiation
Study Arms  ICMJE
  • Experimental: radiation + bevacizumab

    Cohort 1: MGMT-/EGFR-

    Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

    Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/-5.4 Gy for approximately 7 weeks beginning 7-21 days after biopsy

    Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles

    Interventions:
    • Drug: Bevacizumab
    • Radiation: Radiation
  • Experimental: radiation + bevacizumab + erlotinib

    Cohort 2: MGMT-/EGFR+

    Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

    Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/-5.4 Gy for approximately 7 weeks beginning 7-21 days after biopsy

    Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles

    Erlotinib: Administered orally at 85 mg/m2 daily continuously during radiation therapy, through the interim period and for up to 10 maintenance cycles

    Interventions:
    • Drug: Bevacizumab
    • Drug: Erlotinib
  • Experimental: radiation + bevacizumab + temozolomide

    Cohort 3. MGMT+/EGFR-

    Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

    Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/-5.4 Gy for approximately 7 weeks beginning 7-21 days after biopsy

    Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles

    Temozolomide: Administered orally at 90 mg/m2/day continuously during radiation therapy, held through the interim period and then 200 mg/m2/day for 5 days for up to 10 maintenance cycles

    Interventions:
    • Drug: Bevacizumab
    • Drug: Temozolomide
    • Radiation: Radiation
  • Experimental: radiation + bevacizumab + erlotinib + temozolomide

    Cohort 4. MGMT+/EGFR+

    Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).

    Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/-5.4 Gy for approximately 7 weeks beginning 7-21 days after biopsy

    Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles

    Erlotinib: Administered orally at 85 mg/m2 daily continuously during radiation therapy, through the interim period and for up to 10 maintenance cycles

    Interventions:
    • Drug: Bevacizumab
    • Drug: Erlotinib
    • Drug: Temozolomide
    • Radiation: Radiation
Publications * Gupta N, Goumnerova LC, Manley P, Chi SN, Neuberg D, Puligandla M, Fangusaro J, Goldman S, Tomita T, Alden T, DiPatri A, Rubin JB, Gauvain K, Limbrick D, Leonard J, Geyer JR, Leary S, Browd S, Wang Z, Sood S, Bendel A, Nagib M, Gardner S, Karajannis MA, Harter D, Ayyanar K, Gump W, Bowers DC, Weprin B, MacDonald TJ, Aguilera D, Brahma B, Robison NJ, Kiehna E, Krieger M, Sandler E, Aldana P, Khatib Z, Ragheb J, Bhatia S, Mueller S, Banerjee A, Bredlau AL, Gururangan S, Fuchs H, Cohen KJ, Jallo G, Dorris K, Handler M, Comito M, Dias M, Nazemi K, Baird L, Murray J, Lindeman N, Hornick JL, Malkin H, Sinai C, Greenspan L, Wright KD, Prados M, Bandopadhayay P, Ligon KL, Kieran MW. Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma. Neuro Oncol. 2018 Oct 9;20(11):1547-1555. doi: 10.1093/neuonc/noy070.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: October 17, 2015)
53
Original Estimated Enrollment  ICMJE
 (submitted: August 13, 2010)
100
Actual Study Completion Date  ICMJE June 2016
Actual Primary Completion Date June 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

    -

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01182350
Other Study ID Numbers  ICMJE DFCI 10-321
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Karen D. Wright MD, Dana-Farber Cancer Institute
Study Sponsor  ICMJE Karen D. Wright MD
Collaborators  ICMJE
  • Boston Children's Hospital
  • University of California, San Francisco
  • Ann & Robert H Lurie Children's Hospital of Chicago
  • Children's Healthcare of Atlanta
  • Children's Hospital Colorado
  • Children's Hospital Los Angeles
  • Children's Hospital of Michigan
  • Children's Hospitals and Clinics of Minnesota
  • Cook Children's Medical Center
  • OHSU Doernbecher Children's Hospital
  • Duke University
  • Johns Hopkins University
  • Nicklaus Children's Hospital f/k/a Miami Children's Hospital
  • Nemours Children's Clinic
  • New York University
  • Milton S. Hershey Medical Center
  • Seattle Children's Hospital
  • Lucile Packard Children's Hospital
  • University of Louisville
  • Children's National Research Institute
  • Washington University School of Medicine
  • Phoenix Children's Hospital
  • Medical University of South Carolina
Investigators  ICMJE
Principal Investigator: Karen D. Wright, MD Dana-Farber Cancer Institute
PRS Account Dana-Farber Cancer Institute
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP