Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Diffuse Intrinsic Pontine Glioma |
Drug: Bevacizumab Drug: Erlotinib Drug: Temozolomide Radiation: Irradiation |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Phase II Trial of Molecularly Determined Treatment of Children and Young Adults With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas |
- 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 ] [ Designated as safety issue: No ]
- 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 ] [ Designated as safety issue: Yes ]
- Toxicity profiles of the 4 treatment strata [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
- 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 ] [ Designated as safety issue: No ]
- Molecular pathology analyses [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
- 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 ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 100 |
| Study Start Date: | September 2011 |
| Estimated Primary Completion Date: | September 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
Experimental: Bevacizumab +irradiation+ erlotinib
|
Drug: Bevacizumab
• 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.
Other Name: Avastin
Drug: Erlotinib
• 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
Other Name: Tarceva
Radiation: Irradiation
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
Other Name: Radiation
|
|
Experimental: Bevacizumab + Irradiation
(promoter methylation negative, no EGFR over-expression): Bevacizumab plus irradiation:
|
Drug: Bevacizumab
• 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.
Other Name: Avastin
Radiation: Irradiation
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
Other Name: Radiation
|
|
Experimental: Bevacizumab+irradiation+temozolomide
Bevacizumab plus irradiation plus temozolomide (promoter methylation positive, no EGFR over-expression)
|
Drug: Bevacizumab
• 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.
Other Name: Avastin
Drug: Temozolomide
• 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.
Other Name: Temodar
Radiation: Irradiation
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
Other Name: Radiation
|
|
Experimental: Bevacizumab+ irradiation+erlotinib+temozol
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. |
Drug: Bevacizumab
• 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.
Other Name: Avastin
Drug: Erlotinib
• 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
Other Name: Tarceva
Drug: Temozolomide
• 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.
Other Name: Temodar
Radiation: Irradiation
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
Other Name: Radiation
|
Eligibility| Ages Eligible for Study: | 3 Years to 18 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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.
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Contacts and Locations| Contact: Mark W. Kieran, MD, PhD | 617-632-4907 | mark_kieran@dfci.harvard.edu |
Show 19 Study Locations| Study Chair: | Mark W. Kieran, MD, PhD | Dana-Farber Cancer Institute |
More Information
No publications provided
| Responsible Party: | Mark W. Kieran, MD, PhD, Director, Pediatric Neuro-Oncology Program, Dana-Farber Cancer Institute |
| ClinicalTrials.gov Identifier: | NCT01182350 History of Changes |
| Other Study ID Numbers: | DFCI 10-321 |
| Study First Received: | August 12, 2010 |
| Last Updated: | May 18, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by Dana-Farber Cancer Institute:
|
Molecularly Determined Treatment |
Additional relevant MeSH terms:
|
Glioma Pontine Glioma Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue Astrocytoma Temozolomide Dacarbazine Bevacizumab Erlotinib |
Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Antineoplastic Agents Therapeutic Uses Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Physiological Effects of Drugs Growth Inhibitors Protein Kinase Inhibitors Enzyme Inhibitors |
ClinicalTrials.gov processed this record on May 23, 2013