Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Diffuse Intrinsic Pontine Glioma

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Erlotinib
* Drug: Temozolomide
* Radiation: Radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must meet the following criteria on screening examination to be eligible to participate in the study: Tumor: Newly diagnosed non-disseminated diffuse intrinsic pontine glioma based on classic 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 >/= 50 or Lansky Performance Score for patients < 12y/o 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; 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. 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 to sign a written informed consent document. Exclusion Criteria: 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. Patients receiving any other anticancer or experimental drug therapy. Patients with disseminated intrinsic diffuse brainstem gliomas in either brain or spine (can be based on clinical evaluation). 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. Use of hematopoietic growth factors within the 2 weeks prior to initiation of therapy. Patients with evidence of spontaneous hemorrhage greater than 0.5cm unrelated to surgery. 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. 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. -

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is not a randomized trial rather participants are classified and therapy is directed based on molecular profile obtained from surgical biopsy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: radiation + bevacizumab<br>Cohort 1: MGMT-/EGFR- Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days). Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/-5.4 Gy for approximately 7 weeks beginning 7-21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles | Drug: Bevacizumab<br> <br> * Other names: Avastin;Radiation: Radiation<br> <br> * Other names: irradiation;|
| Experimental: radiation + bevacizumab + erlotinib<br>Cohort 2: MGMT-/EGFR+ Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days). Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/-5.4 Gy for approximately 7 weeks beginning 7-21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles Erlotinib: Administered orally at 85 mg/m2 daily continuously during radiation therapy, through the interim period and for up to 10 maintenance cycles | Drug: Bevacizumab<br> <br> * Other names: Avastin;Drug: Erlotinib<br> <br> * Other names: Tarceva;|
| Experimental: radiation + bevacizumab + temozolomide<br>Cohort 3. MGMT+/EGFR- Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days). Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/-5.4 Gy for approximately 7 weeks beginning 7-21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles Temozolomide: Administered orally at 90 mg/m2/day continuously during radiation therapy, held through the interim period and then 200 mg/m2/day for 5 days for up to 10 maintenance cycles | Drug: Bevacizumab<br> <br> * Other names: Avastin;Drug: Temozolomide<br>* •<br>* Other names: Temodar;Radiation: Radiation<br> <br> * Other names: irradiation;|
| Experimental: radiation + bevacizumab + erlotinib + temozolomide<br>Cohort 4. MGMT+/EGFR+ Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days). Radiation therapy: Given in 180 cGy fractions to a total dose of 59.4 + 1.8 Gy/-5.4 Gy for approximately 7 weeks beginning 7-21 days after biopsy Bevacizumab: Administered intravenously at 10 mg/kg beginning no sooner than 21 days from biopsy and every 14 days concurrent with radiation therapy, through the interim period and for up to 10 maintenance cycles Erlotinib: Administered orally at 85 mg/m2 daily continuously during radiation therapy, through the interim period and for up to 10 maintenance cycles | Drug: Bevacizumab<br> <br> * Other names: Avastin;Drug: Erlotinib<br> <br> * Other names: Tarceva;Drug: Temozolomide<br>* •<br>* Other names: Temodar;Radiation: Radiation<br> <br> * Other names: irradiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 9-month Overall Survival (OS) Rate | 9-month overall survival is the percentage of participants remaining alive 9 months from registration. | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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. | 
| 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Molecularly Determined Treatment