Avastin in Combination With Temozolomide for Unresectable or Multifocal GBMs and Gliosarcomas

Phase 2

Completed

• Conditions: Glioblastoma; Gliosarcoma
• Interventions: Drug: Avastin and Temozolomide

• Registration Number: NCT00612339
• Lead Sponsor: Duke University

Brief 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

Detailed Description

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.

Study Timeline

• Study Start: 2007-08
• Study First Submitted: 2008-01-29
• Study First Submitted QC: 2008-02-08
• Study First Posted: 2008-02-11
• Primary Completion: 2012-05
• Study Completion: 2012-05
• Results First Submitted: 2012-08-09
• Results First Submitted QC: 2012-08-09
• Status Verified: 2012-09
• Results First Posted: 2012-09-10
• Last Update Submitted: 2013-05-20
• Last Update Posted: 2013-05-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 41

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Avastin and Temozolomide	Avastin and Temozolomide	Avastin administered at 10 mg/kg every 2 weeks beginning a minimum of 7 days after biopsy or 28 days after craniotomy. Temozolomide dosed at 200 mg/m2 daily for 5 days in a 28-day cycle.

Primary Outcome Measures

Name	Time	Method
Response Rate	4 months	The proportion of subjects with complete or partial response as determined by a modification of the RANO (Response Assessment in Neuro-Oncology) criteria. A confirmation of response was not required. Complete Response was defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. Partial Response was defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks.

Trial Locations

Locations (1)

Duke University Health System; 🇺🇸 Durham, North Carolina, United States