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About
This research is being done because melanoma in the brain is very difficult to treat because it does not respond to radiation or to chemotherapy, such as temozolomide. One of the reasons for this is that the melanoma can make chemicals that signal the brain to provide new blood vessels for the tumor. The main signal is called VEGF. Bevacizumab is an antibody that blocks VEGF. The investigators want to see if the combination of bevacizumab and temozolomide will stop the melanoma from growing.
Full description
This study proposes the use of a combination of temozolomide and bevacizumab in a carefully selected group of patients with metastatic melanoma to the brain. This combination has been tested in primary brain tumors and in melanoma not involving the brain. The 6-week on, 2-week off low-dose schedule proposed in this trial capitalizes on preclinical data demonstrating that temozolomide inhibits angiogenesis at low, non-toxic doses that correspond to the plasma concentrations achieved by an oral administration, a so-called 'metronomic' scheduling. The precise mechanism of its antiangiogenic action remains to be elucidated. This potential synergistic mechanism, together with the bulk of evidence for activity presented above suggests that the combination will be well-tolerated, safe and possibly more effective.
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Inclusion criteria
Patients must have histologically or cytologically confirmed malignant melanoma and clinical evidence of metastatic disease to the brain. Mucosal and ocular melanomas are included.
Untreated asymptomatic brain metastases ≤ 2 cm in maximal diameter, with mild or minimal edema, without associated hemorrhage or midline shift.
Progressing brain metastases of any size, not amenable to surgical resection and/or progressing through radiation therapy but without evidence of active associated hemorrhage. Treatment with bevacizumab may not be initiated until 4 weeks after surgical resection or radiation therapy completion.
Hemorrhagic metastases that have resolved after previous resection or radiation therapy do not exclude patients with new non-hemorrhagic metastases meeting the criteria described above from participating.
Patients must have measurable metastases to the brain, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >10 mm in the brain MRI with gadolinium. For disease outside the brain, tumors must be > 20 mm with conventional techniques or > 10 mm with spiral CT scan. Measurable disease outside the brain is NOT required.
Patients with any number of previous systemic therapies are eligible. Previous temozolomide treatment given on a different schedule is allowed, as long as it had not been given in combination with VEGF-targeting drugs.
Age > 18 years. Because no dosing or adverse event data are currently available on the use of bevacizumab in patients <18 years of age, children are excluded from this study.
Life expectancy of 8 weeks or greater.
ECOG performance status < 2 (Karnofsky > 60%).
Patients must have normal organ and marrow function as defined below:
Leukocytes > 3,000/µl
Absolute neutrophil count > 1,500/µl
Platelets > 100,000/µl
Total Bilirubin ** Within institutional upper limit of normal
AST(SGOT)/ALT(SGPT) < 2.5 X institutional upper limit of normal
Creatinine* Within institutional upper limit of normal*
The effects of bevacizumab on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because the anti-angiogenic agent used in this trial may be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
Concomitant use of steroids to treat cerebral edema is allowed.
Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
Subjects meeting any of the following criteria are ineligible for study entry:
Bevacizumab-Specific Exclusions
Previous treatment with bevacizumab.
Inadequately controlled hypertension (defined as systolic blood pressure 150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)
Any prior history of hypertensive crisis or hypertensive encephalopathy
New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E)
History of myocardial infarction or unstable angina within 6 months prior to study enrollment
History of stroke or transient ischemic attack within 6 months prior to study enrollment
Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
Symptomatic peripheral vascular disease
Evidence of bleeding diathesis or coagulopathy
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study
Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment
Serious, non-healing wound, ulcer, or bone fracture
Proteinuria at screening as demonstrated by either
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34 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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