Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)

NCT01182350 | Terminated Phase 2 Results DMC

• 1 other identifier: DFCI 10-321
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 23

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.

Conditions

Diffuse Intrinsic Pontine Glioma

Keywords

Molecularly Determined Treatment

Outcome Measures

Primary Outcomes (1)

• 9-month Overall Survival (OS) Rate

  9-month overall survival is the percentage of participants remaining alive 9 months from registration.

  9 months

Secondary Outcomes (6)

• Rate of Lethal Complications From Surgery

  2 weeks

• Grade 3-4 Post-Procedural Surgery-Related Toxicity Rate

  2 weeks

• Delay in Radiation Therapy Start

  3 weeks

• Feasibility Rate of Molecular Approach to Therapy

  3 weeks

• Number of Participants With Grade 3-4 Treatment-Related Toxicity Over Chemoradiation Therapy

  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.

Study Arms (4)

radiation + bevacizumab

EXPERIMENTAL

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

Drug: Bevacizumab; Radiation: Radiation

radiation + bevacizumab + erlotinib

EXPERIMENTAL

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

Drug: Bevacizumab; Drug: Erlotinib

radiation + bevacizumab + temozolomide

EXPERIMENTAL

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

Drug: Bevacizumab; Drug: Temozolomide; Radiation: Radiation

radiation + bevacizumab + erlotinib + temozolomide

EXPERIMENTAL

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

Drug: Bevacizumab; Drug: Erlotinib; Drug: Temozolomide; Radiation: Radiation

Interventions

Bevacizumab DRUG

Also known as: Avastin

radiation + bevacizumab; radiation + bevacizumab + erlotinib; radiation + bevacizumab + erlotinib + temozolomide; radiation + bevacizumab + temozolomide

Erlotinib DRUG

Also known as: Tarceva

radiation + bevacizumab + erlotinib; radiation + bevacizumab + erlotinib + temozolomide

Temozolomide DRUG

Also known as: Temodar

radiation + bevacizumab + erlotinib + temozolomide; radiation + bevacizumab + temozolomide

Radiation RADIATION

Also known as: irradiation

radiation + bevacizumab; radiation + bevacizumab + erlotinib + temozolomide; radiation + bevacizumab + temozolomide

Eligibility Criteria

• Age: 3 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Participants must meet the following criteria on screening examination to be eligible to participate in the study:
• Tumor: Newly diagnosed non-disseminated diffuse intrinsic pontine glioma based on classic clinical AND radiographic finding.
• No prior radiation therapy or chemotherapy.
• Age: Patient must be 3 to \< 18 years of age at the time of diagnosis.
• 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.
• 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.
• Female patients of childbearing potential must have negative serum or urine pregnancy test. Patient must not be pregnant or breast feeding.
• 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.
• Ability to understand and the willingness to sign a written informed consent document.

You may not qualify if:

• 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.
• Patients receiving any other anticancer or experimental drug therapy.
• Patients with disseminated intrinsic diffuse brainstem gliomas in either brain or spine (can be based on clinical evaluation).
• 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.
• Use of hematopoietic growth factors within the 2 weeks prior to initiation of therapy.
• Patients with evidence of spontaneous hemorrhage greater than 0.5cm unrelated to surgery.
• 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.
• 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.

Sponsors & Collaborators

• Karen D. Wright MD: lead
• Boston Children's Hospital: collaborator
• University of California, San Francisco: collaborator
• Ann & Robert H Lurie Children's Hospital of Chicago: collaborator
• Children's Healthcare of Atlanta: collaborator
• Children's Hospital Colorado: collaborator
• Children's Hospital Los Angeles: collaborator
• Children's Hospital of Michigan: collaborator
• Children's Hospitals and Clinics of Minnesota: collaborator
• Cook Children's Medical Center: collaborator
• OHSU Doernbecher Children's Hospital: collaborator
• Duke University: collaborator
• Johns Hopkins University: collaborator
• Nicklaus Children's Hospital f/k/a Miami Children's Hospital: collaborator
• Nemours Children's Clinic: collaborator
• New York University: collaborator
• Milton S. Hershey Medical Center: collaborator
• Seattle Children's Hospital: collaborator
• Lucile Packard Children's Hospital: collaborator
• University of Louisville: collaborator
• Children's National Research Institute: collaborator
• Washington University School of Medicine: collaborator
• Phoenix Children's Hospital: collaborator
• Medical University of South Carolina: collaborator

Study Sites (23)

Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Stanford University/Lucile Packard Children's Hospital

Palo Alto, California, 94304, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Nemours Children's Clinic

Jacksonville, Florida, 32207, United States

Location

Miami Children's Hospital

Miami, Florida, 33155, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

Ann & Robert H Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

University of Louisville

Louisville, Kentucky, 40202, United States

Location

Johns Hopkins

Baltimore, Maryland, 21287, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Children's Hospital of Michigan

Detroit, Michigan, 48201, United States

Location

Children's Hospitals and Clinics of Minnesota

Minneapolis, Minnesota, 55404, United States

Location

Washington University Medical Center

St Louis, Missouri, 63110, United States

Location

New York University

New York, New York, 10016, United States

Location

Duke University

Durham, North Carolina, 27710, United States

Location

Doernbecher Children's Hospital

Portland, Oregon, 97239, United States

Location

Penn State Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Cook Children's Medical Center

Fort Worth, Texas, 76104, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Related Publications (1)

• 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.

  PMID: 29741745 RESULT

MeSH Terms

Conditions

Diffuse Intrinsic Pontine Glioma

Interventions

Bevacizumab; Erlotinib Hydrochloride; Temozolomide; Radiation

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Physical Phenomena

Limitations and Caveats

The study was terminated early having met the pre-specified stopping rule which required 3 or more cohorts with at least 10 patients each or 2 cohorts with at least 15 patients each in the first 50 patients with informative biopsies.

Results Point of Contact

• Title: Karen Wright
• Organization: Dana-Farber Cancer Institute

KarenD_Wright@dfci.harvard.edu

617.632.6740

Study Officials

• Karen D. Wright, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prinicipal Investigator

Model Details: This is not a randomized trial rather participants are classified and therapy is directed based on molecular profile obtained from surgical biopsy.

Study Record Dates

• First Submitted: August 12, 2010
• First Posted: August 16, 2010
• Study Start: September 1, 2011
• Primary Completion: June 1, 2016
• Study Completion: June 1, 2016
• Last Updated: September 4, 2019
• Results First Posted: September 4, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (23)