Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)

NCT ID: NCT01182350

Last Updated: 2019-09-04

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 53 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-09-30
• Study Completion Date: 2016-06-30

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).

Conditions

Diffuse Intrinsic Pontine Glioma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: DRUG

Radiation

Intervention Type: RADIATION

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

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: DRUG

Erlotinib

Intervention Type: DRUG

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

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: DRUG

Temozolomide

Intervention Type: DRUG

Radiation

Intervention Type: RADIATION

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

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: DRUG

Erlotinib

Intervention Type: DRUG

Temozolomide

Intervention Type: DRUG

Radiation

Intervention Type: RADIATION

Interventions

Bevacizumab

Intervention Type: DRUG

Erlotinib

Intervention Type: DRUG

Temozolomide

Intervention Type: DRUG

Radiation

Intervention Type: RADIATION

Other Intervention Names

Avastin; Tarceva; Temodar; irradiation

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.

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• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Boston Children's Hospital

OTHER

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: collaborator

Ann & Robert H Lurie Children's Hospital of Chicago

OTHER

Sponsor Role: collaborator

Children's Healthcare of Atlanta

OTHER

Sponsor Role: collaborator

Children's Hospital Colorado

OTHER

Sponsor Role: collaborator

Children's Hospital Los Angeles

OTHER

Sponsor Role: collaborator

Children's Hospital of Michigan

OTHER

Sponsor Role: collaborator

Children's Hospitals and Clinics of Minnesota

OTHER

Sponsor Role: collaborator

Cook Children's Medical Center

OTHER

Sponsor Role: collaborator

OHSU Doernbecher Children's Hospital

OTHER

Sponsor Role: collaborator

Duke University

OTHER

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: collaborator

Nicklaus Children's Hospital f/k/a Miami Children's Hospital

OTHER

Sponsor Role: collaborator

Nemours Children's Clinic

OTHER

Sponsor Role: collaborator

New York University

OTHER

Sponsor Role: collaborator

Milton S. Hershey Medical Center

OTHER

Sponsor Role: collaborator

Seattle Children's Hospital

OTHER

Sponsor Role: collaborator

Lucile Packard Children's Hospital

OTHER

Sponsor Role: collaborator

University of Louisville

OTHER

Sponsor Role: collaborator

Children's National Research Institute

OTHER

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: collaborator

Phoenix Children's Hospital

OTHER

Sponsor Role: collaborator

Medical University of South Carolina

OTHER

Sponsor Role: collaborator

Karen D. Wright MD

OTHER

Sponsor Role: lead

Responsible Party

Karen D. Wright MD

Prinicipal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Karen D. Wright, MD

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber Cancer Institute

Locations

Phoenix Children's Hospital

Phoenix, Arizona, United States

Children's Hospital Los Angeles

Los Angeles, California, United States

Stanford University/Lucile Packard Children's Hospital

Palo Alto, California, United States

University of California, San Francisco

San Francisco, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Nemours Children's Clinic

Jacksonville, Florida, United States

Miami Children's Hospital

Miami, Florida, United States

Children's Healthcare of Atlanta

Atlanta, Georgia, United States

Ann & Robert H Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

University of Louisville

Louisville, Kentucky, United States

Johns Hopkins

Baltimore, Maryland, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Children's Hospital of Michigan

Detroit, Michigan, United States

Children's Hospitals and Clinics of Minnesota

Minneapolis, Minnesota, United States

Washington University Medical Center

St Louis, Missouri, United States

New York University

New York, New York, United States

Duke University

Durham, North Carolina, United States

Doernbecher Children's Hospital

Portland, Oregon, United States

Penn State Hershey Medical Center

Hershey, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

UT Southwestern Medical Center

Dallas, Texas, United States

Cook Children's Medical Center

Fort Worth, Texas, United States

Seattle Children's Hospital

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 29741745 (View on PubMed)

Other Identifiers

DFCI 10-321

Identifier Type: -

Identifier Source: org_study_id