Overview

This trial is active, not recruiting.

Condition diffuse intrinsic pontine glioma
Treatments bevacizumab, erlotinib, temozolomide, irradiation
Phase phase 2
Targets VEGF, EGFR
Sponsor Dana-Farber Cancer Institute
Collaborator Children's Hospital Boston
Start date September 2011
End date March 2017
Trial size 53 participants
Trial identifier NCT01182350, DFCI 10-321

Summary

The primary objective of this study is to estimate the overall survival of children and young adults with diffuse intrinsic pontine glioma treated (DIPG) with a molecularly based treatment strategy, compared to historical controls.

Four Biopsies of tumor tissue will be obtained by surgical biopsy prior to treatment stratification if tolerated. An 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.

Following biopsy,all patients will receive local radiotherapy to consist of 59.4Gy delivered using conventional conformal or other standard treatment planning with adjuvant bevacizumab. Radiation planning can begin with the pre-operative images. Based upon molecular parameters after biopsy, patients will potentially receive erlotinib and/or temozolomide at the start of radiotherapy. Bevacizumab will be given concurrently with radiotherapy beginning at least three weeks from the biopsy and at least two weeks after the start of radiation therapy to ensure that primary wound healing has occurred. Once irradiation is complete, patients will have a four week interim period before beginning the maintenance phase. Adjuvant chemotherapy will be continued during the interim period.

The maintenance phase (approxmiately 40 weeks) will last for 10 cycles(28 days +/- 3 days). Based upon molecular parameters as determined at the time of diagnostic biopsy, patients will continue to receive erlotinib and/or temozolomide along with bevacizumab during the maintenance phase.

Stratification will be based on O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and epidermal growth factor receptor (EGFR) expression in tumor biopsy samples. If MGMT status and/or EFGR status are not determinable, patients may be treated as per cohort #1(bevacizumab and irradiation) but will be analyzed separately.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation non-randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Radiation therapy to consist of 59.4Gy delivered using conventional conformal treatment planning. Bevacizumab,and erlotinib will be given according to dosage, time frame listed.
bevacizumab Avastin
• Bevacizumab, 10 mg/kg IV, will be given at least three weeks from the biopsy and at least two weeks after start of the radiation therapy and then every 14 +/- 3 days concurrently with radiation therapy, during the interim period, and for up to 10 maintenance cycles.
erlotinib Tarceva
• The erlotinib dose will be 85 mg/m2/day given continuously during irradiation. Patients will then continue erlotinib at 85 mg/m2/day beginning immediately after completion of radiation therapy through the interim period, and to complete 10 cycles of maintenance therapy
irradiation Radiation
All patients will receive local radiotherapy(for approximately 7 weeks) to consist of 59.4Gy delivered using conventional conformal or other standard treatment planning with adjuvant bevacizumab
(Experimental)
(promoter methylation negative, no EGFR over-expression): Bevacizumab plus irradiation: Radiation therapy to consist of 59.4Gy delivered using conventional conformal treatment planning. Bevacizumab, 10 mg/kg IV, will be given at least three weeks from the biopsy and at least two weeks after start of the radiation therapy and then every 14 +/- 3 days concurrently with radiation therapy, during the interim period, and for up to 10 maintenance cycles.
bevacizumab Avastin
• Bevacizumab, 10 mg/kg IV, will be given at least three weeks from the biopsy and at least two weeks after start of the radiation therapy and then every 14 +/- 3 days concurrently with radiation therapy, during the interim period, and for up to 10 maintenance cycles.
irradiation Radiation
All patients will receive local radiotherapy(for approximately 7 weeks) to consist of 59.4Gy delivered using conventional conformal or other standard treatment planning with adjuvant bevacizumab
(Experimental)
Bevacizumab plus irradiation plus temozolomide (promoter methylation positive, no EGFR over-expression) Radiation therapy to consist of 59.4Gy delivered using conventional conformal treatment planning. Bevacizumab and radiation will be given according to dosage and time frame listed.
bevacizumab Avastin
• Bevacizumab, 10 mg/kg IV, will be given at least three weeks from the biopsy and at least two weeks after start of the radiation therapy and then every 14 +/- 3 days concurrently with radiation therapy, during the interim period, and for up to 10 maintenance cycles.
temozolomide Temodar
• The temozolomide dose will be 90 mg/m2/day given continuously during irradiation and then 200mg/m2/day for five days every 28 +/- 5 days to begin approximately 4 weeks after completion of the radiation therapy and to continue for 10 maintenance cycles.
irradiation Radiation
All patients will receive local radiotherapy(for approximately 7 weeks) to consist of 59.4Gy delivered using conventional conformal or other standard treatment planning with adjuvant bevacizumab
(Experimental)
Bevacizumab plus irradiation plus erlotinib plus temozolomide (promoter methylation positive, EGFR over-expressed) • Radiation therapy to consist of 59.4Gy delivered using conventional conformal treatment planning. Bevacizumab, erlotinib and temozolomide will be given according to dosage, time frame listed.
bevacizumab Avastin
• Bevacizumab, 10 mg/kg IV, will be given at least three weeks from the biopsy and at least two weeks after start of the radiation therapy and then every 14 +/- 3 days concurrently with radiation therapy, during the interim period, and for up to 10 maintenance cycles.
erlotinib Tarceva
• The erlotinib dose will be 85 mg/m2/day given continuously during irradiation. Patients will then continue erlotinib at 85 mg/m2/day beginning immediately after completion of radiation therapy through the interim period, and to complete 10 cycles of maintenance therapy
temozolomide Temodar
• The temozolomide dose will be 90 mg/m2/day given continuously during irradiation and then 200mg/m2/day for five days every 28 +/- 5 days to begin approximately 4 weeks after completion of the radiation therapy and to continue for 10 maintenance cycles.
irradiation Radiation
All patients will receive local radiotherapy(for approximately 7 weeks) to consist of 59.4Gy delivered using conventional conformal or other standard treatment planning with adjuvant bevacizumab

Primary Outcomes

Measure
Overall survival of children and young adults with diffuse intrinsic pontine glioma treated with a molecularly based treatment strategy, compared to historical controls (COG ACNS0126)
time frame: 52 weeks

Secondary Outcomes

Measure
Safety and feasibility of performing biopsy and obtaining tissue useful for histologic diagnosis, immunohistochemistry and DNA analyses in newly diagnosed DIPG patients
time frame: 52 weeks
Toxicity profiles of the 4 treatment strata
time frame: 52 weeks
Progression free survival of children and young adults with diffuse intrinsic pontine glioma treated with a molecularly based treatment strategy, compared to historical controls (COG ACNS0126).
time frame: 52 weeks
Molecular pathology analyses
time frame: 52 weeks
Correlation of imaging including perfusion/diffusion, diffusion tensor imaging (DTI) and magnetic resonance imaging (MRS) scan with patient response and outcome
time frame: 52 weeks

Eligibility Criteria

Male or female participants from 3 years up to 18 years old.

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.

Additional Information

Official title Phase II Trial of Molecularly Determined Treatment of Children and Young Adults With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas
Trial information was received from ClinicalTrials.gov and was last updated in October 2015.
Information provided to ClinicalTrials.gov by Dana-Farber Cancer Institute.
Location data was received from the National Cancer Institute and was last updated in August 2016.