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


Diagnosis: Diagnosis via clinical history and MR imaging documentation of a typical diffuse intrinsic brainstem glioma (DiPG).
Surgery: image-guided stereotactic brainstem biopsy.
Tumor Testing: Tumor tissue will be tested for MGMT promoter methylation (MS-PCR based assay) and eGFR expression and a treatment cohort will be subsequently assigned depending on MGMT status and eGFR expression:
Cohort one: Bevacizumab plus irradiation (promoter methylation negative, no eGFR over-expression)
Cohort Two: Bevacizumab plus irradiation plus erlotinib (promoter methylation negative, eGFR over-expressed)
Cohort Three:Bevacizumab plus irradiation plus temozolomide (promoter methylation positive, no eGFR over-expression)
Cohort Four: Bevacizumab plus irradiation plus erlotinib plus temozolomide (promoter methylation positive, eGFR over-expressed)
Length of therapy: Protocol treatment will last approximately 52 weeks from the start of radiation in the absence of significant toxicity. Treatment will be administered based on the 4 strata above. Radiation will last approximately 7 weeks. There will be an approximate 4 week interim period during which bevacizumab will be continued and erlotinib will be continued (if enrolled on cohort two or four). Temozolomide will be held during this interim period. a brain MRi will be obtained, no later than four weeks following completion of irradiation, to assess initial response. Patients will then begin the maintenance phase of therapy based upon cohort assignment. Maintenance will continue for approximately 10 cycles. a cycle will consist of 28 days (+/- 3 days). Bevacizumab will be given every two weeks for all patients; for patients on cohort 2 or 4, erlotinib will be given daily, and for patients on cohort 3 or 4, temozolomide will be given using a five day schedule every 28 days. Disease status will be assessed every 2 cycles using MR imaging. Patients deriving benefit may continue therapy beyond study completion but all protocol specific evaluations (other than survival) will conclude after one year. all patients will be followed with survival as the end point.

Participant Eligibility

--Tumor: Newly diagnosed non-disseminated diffuse intrinsic pontine glioma based on clinical AND radiographic finding.

--No prior radiation therapy or chemotherapy.

--Age: Patient must be 3 to <= 18 years of age at the time of diagnosis.

--Performance Score: Karnofsky Performance Scale >= 12 y/o or Lansky Performance Score for patients < 12y/o must be >= 50 assessed within two-weeks prior to enrollment.

--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; SGPT (ALT) and 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 GFR > 70 ml/min/1.73m2.

-- Female patients of childbearing potential must have negative serum or urine pregnancy test. Patient must not be pregnant or breast feeding.

--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.

-- Ability to understand and the willingness of the patient, parent or legal guardian to provide informed consent.