avastin in combination with temozolomide for unresectable or multifocal gbms and gliosarcomas

Conditions: Glioblastoma; Gliosarcoma

Summary: primary objective- to determine efficacy of avastin, 10 mg/kg every other week, in combination with standard 5-day temozolomide in terms of response rate. secondary objective- to determine safety of avastin \& temozolomide in unresectable glioblastoma patients

subjects have histologically confirmed who gr iv primary malignant glioma that is unresectable/multifocal. this is phase ii study where up to 41 subjects will receive up to 4 cycles of avastin \& temozolomide. avastin administered at 10 mg/kg every 14 days beginning a minimum of 7 days after biopsy/28 days after craniotomy. temozolomide dosed at 200 mg/m2 daily for 5 days in 28-day cycle. patients will receive up to 4 cycles of avastin \& temozolomide, then proceed with standard xrt. study will use 2-stage "minimax" study design in which 21 subjects are accrued during 1st stage, with possibility that additional 20 patients accrued during 2nd stage. in initial phase i \& ii trials, 4 potential avastin-associated safety signals were identified: hypertension, proteinuria, thromboembolic events, \& hemorrhage. avastin-associated adverse events in phase iii trials include congestive heart failure, gi perforations, wound healing complications, \& arterial thromboembolic events. most common toxicity associated with temozolomide has been mild myelosuppression.

Eligibility criteria:
inclusion criteria: patients have histologically confirmed diagnosis of who gr iv primary malignant glioma. patients will be unresectable or have multifocal disease. * age ≥ 18years \& life expectancy of \>12 weeks * evidence of measurable primary cns neoplasm on contrast enhanced mri. * interval of \<1 week between prior biopsy/4 weeks from surgical resection \& enrollment on protocol * karnofsky ≥60% * hemoglobin ≥9g/dl, anc ≥1,500 cells/microliter, platelets ≥125,000 cells/microliter * serum creatinine ≤1.5 mg/dl, serum sgot \& bilirubin ≤1.5 x uln * for patients on corticosteroids, they must have been on stable dose for 1 week prior to entry, if clinically possible, \& dose should not be escalated over entry dose level * signed informed consent approved by irb prior to patient entry * no evidence of \> grade 1 cns hemorrhage on baseline mri/ct scan * if sexually active, patients will take contraceptive measures for duration of treatments exclusion criteria: * pregnancy/breast feeding * co-medication that may interfere with study results * active infection requiring iv antibiotics * prior or current treatment w xrt/chemo for brain tumor, irrespective of grade of tumor * evidence of \> grade 1 cns hemorrhage on baseline mri or ct scan avastin-specific concerns: * inadequately controlled hypertension * any prior history of hypertensive crisis/hypertensive encephalopathy * new york heart association grade ii or \> congestive heart failure * history of myocardial infarction/unstable angina \< 6 months prior to study enrollment * history of stroke/transient ischemic attack \< 6 months prior to study enrollment * significant vascular disease * symptomatic peripheral vascular disease * evidence of bleeding diathesis/coagulopathy * major surgical procedure, open biopsy,/significant traumatic injury within 28 days prior to study enrollment/anticipation of need for major surgical procedure during course of study * core biopsy/other minor surgical procedure, excluding placement of vascular access device, \<7 days prior to study enrollment * history of abdominal fistula, gi perforation, /intra-abdominal abscess \<6 months prior to study enrollment * serious, non-healing wound, ulcer, or bone fracture * proteinuria at screening as demonstrated by either * upc ratio ≥1.0 at screening or * urine dipstick for proteinuria ≥2+ * known hypersensitivity to any component of avastin * pregnant/lactating. use of effective means of contraception in subjects of child-bearing potential * current, ongoing treatment with full-dose warfarin or its equivalent

Keywords: glioma temozolomide temodar avastin bevacizumab gbm gliosarcoma multifocal gbm brain tumor unresectable gbm glioblastoma multiforme