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Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Dana-Farber Cancer Institute
Sponsor:
Collaborators:
Children's Hospital Boston
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
Doernbecher Children's Hospital
Duke University
Johns Hopkins University
Miami Children's Hospital
Nemours Children's Clinic Jacksonville
New York University
Milton S. Hershey Medical Center
Seattle Children's
Stanford University/Lucile Packard Children's Hospital
University of Louisville
UT Southwestern Medical Center
Washington University School of Medicine
Phoenix Children's Hospital
Information provided by (Responsible Party):
Mark W. Kieran, MD, PhD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:
NCT01182350
First received: August 12, 2010
Last updated: November 18, 2014
Last verified: September 2014
  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.


Condition Intervention Phase
Diffuse Intrinsic Pontine Glioma
Drug: Bevacizumab
Drug: Erlotinib
Drug: Temozolomide
Radiation: Irradiation
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Trial of Molecularly Determined Treatment of Children and Young Adults With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas

Resource links provided by NLM:


Further study details as provided by Dana-Farber Cancer Institute:

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) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]

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 [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
  • Toxicity profiles of the 4 treatment strata [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: No ]
  • Molecular pathology analyses [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Estimated Enrollment: 100
Study Start Date: September 2011
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Bevacizumab +irradiation+ erlotinib
  • 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.
Drug: Bevacizumab
• 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.
Other Name: Avastin
Drug: Erlotinib
• The erlotinib dose will be 85 mg/m2/day given continuously during irradiation. Patients will then continue erlotinib at 85 mg/m2/day beginning immediately after completion of radiation therapy through the interim period, and to complete 10 cycles of maintenance therapy
Other Name: Tarceva
Radiation: Irradiation
All patients will receive local radiotherapy(for approximately 7 weeks) to consist of 59.4Gy delivered using conventional conformal or other standard treatment planning with adjuvant bevacizumab
Other Name: Radiation
Experimental: Bevacizumab + Irradiation

(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.
Drug: Bevacizumab
• 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.
Other Name: Avastin
Radiation: Irradiation
All patients will receive local radiotherapy(for approximately 7 weeks) to consist of 59.4Gy delivered using conventional conformal or other standard treatment planning with adjuvant bevacizumab
Other Name: Radiation
Experimental: Bevacizumab+irradiation+temozolomide

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.
Drug: Bevacizumab
• 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.
Other Name: Avastin
Drug: Temozolomide
• The temozolomide dose will be 90 mg/m2/day given continuously during irradiation and then 200mg/m2/day for five days every 28 +/- 5 days to begin approximately 4 weeks after completion of the radiation therapy and to continue for 10 maintenance cycles.
Other Name: Temodar
Radiation: Irradiation
All patients will receive local radiotherapy(for approximately 7 weeks) to consist of 59.4Gy delivered using conventional conformal or other standard treatment planning with adjuvant bevacizumab
Other Name: Radiation
Experimental: Bevacizumab+ irradiation+erlotinib+temozol

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.

Drug: Bevacizumab
• 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.
Other Name: Avastin
Drug: Erlotinib
• The erlotinib dose will be 85 mg/m2/day given continuously during irradiation. Patients will then continue erlotinib at 85 mg/m2/day beginning immediately after completion of radiation therapy through the interim period, and to complete 10 cycles of maintenance therapy
Other Name: Tarceva
Drug: Temozolomide
• The temozolomide dose will be 90 mg/m2/day given continuously during irradiation and then 200mg/m2/day for five days every 28 +/- 5 days to begin approximately 4 weeks after completion of the radiation therapy and to continue for 10 maintenance cycles.
Other Name: Temodar
Radiation: Irradiation
All patients will receive local radiotherapy(for approximately 7 weeks) to consist of 59.4Gy delivered using conventional conformal or other standard treatment planning with adjuvant bevacizumab
Other Name: Radiation

  Eligibility

Ages Eligible for Study:   3 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

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  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01182350

Contacts
Contact: Mark W. Kieran, MD, PhD 617-632-4907 mark_kieran@dfci.harvard.edu

  Show 22 Study Locations
Sponsors and Collaborators
Dana-Farber Cancer Institute
Children&apos;s Hospital Boston
University of California, San Francisco
Ann & Robert H. Lurie Children&apos;s Hospital of Chicago
Children&apos;s Healthcare of Atlanta
Children&apos;s Hospital Colorado
Children&apos;s Hospital Los Angeles
Children&apos;s Hospital of Michigan
Children&apos;s Hospitals and Clinics of Minnesota
Cook Children&apos;s Medical Center
Doernbecher Children&apos;s Hospital
Duke University
Johns Hopkins University
Miami Children&apos;s Hospital
Nemours Children&apos;s Clinic Jacksonville
New York University
Milton S. Hershey Medical Center
Seattle Children&apos;s
Stanford University/Lucile Packard Children&apos;s Hospital
University of Louisville
UT Southwestern Medical Center
Washington University School of Medicine
Phoenix Children&apos;s Hospital
Investigators
Study Chair: Mark W. Kieran, MD, PhD Dana-Farber Cancer Institute
  More Information

No publications provided

Responsible Party: Mark W. Kieran, MD, PhD, Director, Pediatric Neuro-Oncology Program, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT01182350     History of Changes
Other Study ID Numbers: DFCI 10-321
Study First Received: August 12, 2010
Last Updated: November 18, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Dana-Farber Cancer Institute:
Molecularly Determined Treatment

Additional relevant MeSH terms:
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Bevacizumab
Erlotinib
Temozolomide
Alkylating Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Enzyme Inhibitors
Growth Inhibitors
Growth Substances
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on November 23, 2014