Clinical trial NCT01182350: Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)
Official title: Phase II Trial of Molecularly Determined Treatment of Children and Young Adults With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Diffuse Intrinsic Pontine Glioma
Keywords: Molecularly Determined Treatment
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Boston Children's Hospital
name: University of California, San Francisco
name: Ann & Robert H Lurie Children's Hospital of Chicago
name: Children's Healthcare of Atlanta
name: Children's Hospital Colorado
name: Children's Hospital Los Angeles
name: Children's Hospital of Michigan
name: Children's Hospitals and Clinics of Minnesota
name: Cook Children's Medical Center
name: OHSU Doernbecher Children's Hospital
name: Duke University
name: Johns Hopkins University
name: Nicklaus Children's Hospital f/k/a Miami Children's Hospital
name: Nemours Children's Clinic
name: New York University
name: Milton S. Hershey Medical Center
name: Seattle Children's Hospital
name: Lucile Packard Children's Hospital
name: University of Louisville
name: Children's National Research Institute
name: Washington University School of Medicine
name: Phoenix Children's Hospital
name: Medical University of South Carolina
First posted: 2010-08-16
Enrollment: 53
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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).

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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Primary outcomes:
measure: 9-month Overall Survival (OS) Rate
timeFrame: 9 months
Secondary outcomes:
measure: Rate of Lethal Complications From Surgery
timeFrame: 2 weeks
measure: Grade 3-4 Post-Procedural Surgery-Related Toxicity Rate
timeFrame: 2 weeks
measure: Delay in Radiation Therapy Start
timeFrame: 3 weeks
measure: Feasibility Rate of Molecular Approach to Therapy
timeFrame: 3 weeks
measure: Number of Participants With Grade 3-4 Treatment-Related Toxicity Over Chemoradiation Therapy
timeFrame: 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.
measure: Median Progression Free Survival (PFS)
timeFrame: 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.
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford University/Lucile Packard Children's Hospital
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Jacksonville
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Miami
country: United States
facility: Miami Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H Lurie Children's Hospital of Chicago
state: Illinois
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University Medical Center
state: Missouri
city: New York
country: United States
facility: New York University
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Portland
country: United States
facility: Doernbecher Children's Hospital
state: Oregon
city: Hershey
country: United States
facility: Penn State Hershey Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Karen D. Wright, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.