Phase II Trial of Molecularly Determined Treatment of Children and Young Adults with Newly Diagnosed Diffuse Intrinsic Pontine Gliomas
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.
Ages Eligible for Study: 3 Years to 18 Years Genders Eligible for Study: Both Accepts Healthy Volunteers: No 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 less than 18 years of age at the time of diagnosis. 4.Performance Score: Karnofsky Performance Scale greater than 12 y/o greater than / equal to 50 or Lansky Performance Score for patients less than 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: â?¦Absolute neutrophil count greater than 1,000/mcL â?¦Platelets greater than 100,000/mcL (transfusion independent) â?¦Hemoglobin greater than 8gm/dL (can be transfused) â?¦Hepatic: Total bilirubin less than 1.5 times the upper limit of normal; alanine aminotransferase [SGPT (ALT)] and aspartate aminotransferase [SGOT (AST)] less than 5 times the institutional upper limit of normal. â?¦Renal: Serum creatinine which is less than 1.5x the upper limit of institutional normal for age or Glomerular Filtration Rate (GFR) greater than 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.
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.
09/19/2014 04:03 AM