Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)

Diffuse Intrinsic Pontine Glioma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01182350
• Other study ID #: DFCI 10-321
• Status: Terminated
• Phase: Phase 2
• Start date: September 2011
• Est. completion date: June 2016

Study information

• Verified date: August 2019
• Source: Dana-Farber Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 53
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 18 Years

Eligibility

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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Related Conditions & MeSH terms

• Diffuse Intrinsic Pontine Glioma
• Glioma

Intervention

Drug:
• Bevacizumab

• Erlotinib

• Temozolomide
•

Radiation:
• Radiation

Locations

Country	Name	City	State
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Johns Hopkins	Baltimore	Maryland
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Ann & Robert H Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Duke University	Durham	North Carolina
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Penn State Hershey Medical Center	Hershey	Pennsylvania
United States	Nemours Children's Clinic	Jacksonville	Florida
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	University of Louisville	Louisville	Kentucky
United States	Miami Children's Hospital	Miami	Florida
United States	Children's Hospitals and Clinics of Minnesota	Minneapolis	Minnesota
United States	New York University	New York	New York
United States	Stanford University/Lucile Packard Children's Hospital	Palo Alto	California
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Doernbecher Children's Hospital	Portland	Oregon
United States	Washington University Medical Center	Saint Louis	Missouri
United States	University of California, San Francisco	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington

Sponsors (24)

Lead Sponsor

Collaborator

Karen D. Wright MD

Ann & Robert H Lurie Children's Hospital of Chicago, Boston Children’s Hospital, 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, Children's Research Institute, Cook Children's Medical Center, Duke University, Johns Hopkins University, Lucile Packard Children's Hospital, Medical University of South Carolina, Milton S. Hershey Medical Center, Nemours Children's Clinic, New York University, Nicklaus Children's Hospital f/k/a Miami Children's Hospital, OHSU Doernbecher Children's Hospital, Phoenix Children's Hospital, Seattle Children's Hospital, University of California, San Francisco, University of Louisville, Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & 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, H — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	9-month Overall Survival (OS) Rate	9-month overall survival is the percentage of participants remaining alive 9 months from registration.	9 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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.