Official Title: “Avastin in Combination With Temozolomide for Unresectable or Multifocal Glioblastoma Multiformes and Gliosarcomas”

Primary objective- To determine efficacy of Avastin, 10 mg/kg Q O wk in combo w standard 5-day temozolomide in terms of response rate & progression-free survival.

Secondary objective- To determine safety of Avastin & Temozolomide in unresectable glioblastoma pts.

Study Type: Interventional

Study Design: Allocation: Non-Randomized, Control: Active Control, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Study Primary Completion Date: August 2008

Subjects have histologically confirmed WHO gr IV primary malignant glioma that is unresectable/multifocal. This is ph 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 mini of 7 days after biopsy/28 days after craniotomy. Temozolomide dosed at 200 mg/m2 daily for 5 days in 28-day cycle. Pts will receive up to 4 cycles of Avastin & Temozolomide , then proceed w standard XRT. Study will use 2-stage "minimax" study design in which 21 subjects are accrued during 1st stage, w possibility that additional 20 pts accrued during 2nd stage. In initial Ph I & II trials, 4 potential Avastin-associated safety signals were identified: hypertension, proteinuria, thromboembolic events, & hemorrhage.

Avastin-associated adverse events in ph III trials include congestive heart failure, GI perforations, wound healing complications, & arterial thromboembolic events. Most common toxicity associated w temo has been mild myelosuppression.

Intervention(s) in this Clinical Trial

• Drug: Avastin, & temozolomide
  • This is ph II study with combo of Avastin & Temozolomide for unresectable or multifocal WHO grade IV malignant glioma pts. Pts will receive up to 4 cycles of Avastin & Temozolomide . Avastin administered at 10 mg/kg every 14 days beginning minimum of 7 days after biopsy or 28 days after craniotomy. Temozolomide will be dosed at 200 mg/m2 daily x 5 days in 28-day cycle. Pts will have baseline MRI & repeat MRI every 4 weeks. If there is no evidence of disease progression after each cycle, or unacceptable toxicity, or as determined by investigators, pt non-compliance or pt withdraws consent to continue therapy & requests discontinuation, pts will receive up to 4 cycles of Avastin & Temozolomide , then proceed with standard XRT therapy, & future therapy after 4 cycles will be at discretion of pt & treating physicians.

Primary Measures

• Response rate
  • Time Frame: 6 months
    Safety Issue?: No

Secondary Measures

• Progression-free survival
  • Time Frame: 6 months
    Safety Issue?: No
• Incidence & severity of CNS hemorrhage & systemic hemorrhage. Incidence of > gr4 hematologic & > gr3 non-hematologic toxicities
  • Time Frame: 6 months
    Safety Issue?: Yes

Inclusion Criteria:

• Pts have histologically confirmed diagnosis of WHO gr IV primary malignant glioma. Pts will be unresectable or have multifocal disease.
• Age ≥ 18yrs & life expectancy of >12 wks
• Evidence of measurable primary CNS neoplasm on contrast enhanced MRI.
• Interval of <1 wk between prior biopsy/4 wks from surgical resection & enrollment on protocol
• Karnofsky ≥60 percent
• 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 pts on corticosteroids, they must have been on stable dose for 1wk prior to entry, if clinically possible, & dose should not be escalated over entry dose level
• Signed informed consent approved by IRB prior to pt entry
• No evidence of > gr1 CNS hemorrhage on baseline MRI/CT scan
• If sexually active, pts 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 gr of tumor
• Evidence of > gr1 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 Gr II / > congestive heart failure
• History of myocardial infarction/unstable angina < 6mths prior to study enrollment
• History of stroke/transient ischemic attack < 6mths 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 mths prior to study enrollment
• Serious, non-healing wound, ulcer, /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 w full-dose warfarin/its equivalent

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Duke University

Overall Clinical Trial Officials and Contacts

James J Vredenburgh, MD Principal Investigator Duke University Health System  

Information obtained from ClinicalTrials.gov on September 01, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00612339

Study ID Number: 00001022

ClinicalTrials.gov Identifier: NCT00612339

Health Authority: United States: Institutional Review Board

The Preston Robert Tisch Brain Tumor Center at DUKE