Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)

Phase II Trial of Molecularly Determined Treatment of Children and Young Adults With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas

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.

Study Overview

• Status: Terminated
• Conditions: Diffuse Intrinsic Pontine Glioma
• Intervention / Treatment: Drug: Erlotinib; Drug: Bevacizumab; Radiation: Radiation; Drug: Temozolomide

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: Interventional
• Enrollment (Actual): 53
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Palo Alto, California, United States, 94304
      • Stanford University/Lucile Packard Children's Hospital
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H Lurie Children's Hospital of Chicago
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University Medical Center
  • New York
    • New York, New York, United States, 10016
      • New York University
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Doernbecher Children's Hospital
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	Drug: Bevacizumab; Other Names: Avastin; Radiation: Radiation; Other Names: irradiation
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	Drug: Erlotinib; Other Names: Tarceva; Drug: Bevacizumab; Other Names: Avastin
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	Drug: Bevacizumab; Other Names: Avastin; Radiation: Radiation; Other Names: irradiation; Drug: Temozolomide; •; Other Names: Temodar
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	Drug: Erlotinib; Other Names: Tarceva; Drug: Bevacizumab; Other Names: Avastin; Radiation: Radiation; Other Names: irradiation; Drug: Temozolomide; •; Other Names: Temodar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
9-month Overall Survival (OS) Rate	9-month overall survival is the percentage of participants remaining alive 9 months from registration.	9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Lethal Complications From Surgery	The rate of lethal complications from surgery is the percentage of participants dying as a result of surgery.	2 weeks
Grade 3-4 Post-Procedural Surgery-Related Toxicity Rate	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).	2 weeks
Delay in Radiation Therapy Start	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.	3 weeks
Feasibility Rate of Molecular Approach to Therapy	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.	3 weeks
Number of Participants With Grade 3-4 Treatment-Related Toxicity Over Chemoradiation Therapy	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.	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.
Median Progression Free Survival (PFS)	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.	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.

Collaborators and Investigators

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

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2011
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: August 12, 2010
• First Submitted That Met QC Criteria: August 13, 2010
• First Posted (Estimate): August 16, 2010

Study Record Updates

• Last Update Posted (Actual): September 4, 2019
• Last Update Submitted That Met QC Criteria: August 13, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Molecularly Determined Treatment
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Stem Neoplasms; Infratentorial Neoplasms; Glioma; Diffuse Intrinsic Pontine Glioma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Erlotinib Hydrochloride; Temozolomide; Bevacizumab
• Other Study ID Numbers: DFCI 10-321

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No