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

The primary objective of the study is to determine the efficacy of Avastin in combination with temozolomide and irinotecan in terms of response rate and progression-free survival.

The secondary objectives are to describe the overall and progression-free survivals of unresectable patients treated with upfront Avastin, temozolomide and irinotecan and to assess the safety of Avastin, temozolomide and irinotecan in unresectable glioblastoma patients.

This is a phase II study with the combination of Avastin, temozolomide and irinotecan for unresectable or multifocal WHO grade IV malignant glioma patients. Patients will receive up to four cycles of Avastin, temozolomide and irinotecan. Approximately 41 subjects will take part in this study at Duke.

In initial Phase I and II clinical trials, 4 potential Avastin-associated safety signals were identified: hypertension, proteinuria, thromboembolic events, and hemorrhage.

Temozolomide's most common toxicity has been mild myelosuppression. Other, less likely, potential toxicities include nausea and vomiting, constipation, headache, alopecia, rash, burning sensation of skin, esophagitis, pain, diarrhea, lethargy, and hepatotoxicity. The two major toxicities for irinotecan are myelosuppression and diarrhea.

Study Type: Interventional

Study Design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Study Primary Completion Date: November 2010

Intervention(s) in this Clinical Trial

• Drug: Avastin in combination with temozolomide and irinotecan
  • Avastin, by intravenous infusion, 10 mg/kg every 14 days in combination with oral temozolomide at 200 mg/m2 daily for 5 days and irinotecan, by intravenous infusion, every other week (dose dependent upon if taking enzyme-inducing anti-epileptic drugs or if a blood test indicates the patient has the UGT 1A1 polymorphism)

Primary Measures

• Efficacy- Response Rate as seen on MRI and determined by neurologic exam
  • Time Frame: 4 months
    Safety Issue?: No

Secondary Measures

• Efficacy- Progression-free survival
  • Time Frame: 4 months
    Safety Issue?: No
• Safety- Incidence and severity of CNS hemorrhage and systemic hemorrhage, grade 4 or greater hematologic toxicities, grade 3 or greater non-hematologic toxicities
  • Time Frame: 4 months
    Safety Issue?: Yes

Inclusion Criteria:

• Patients must have histologically confirmed diagnosis of WHO grade IV primary malignant glioma (glioblastoma multiforme or gliosarcoma). Patients will be unresectable or have multifocal disease.
• Age > or = to 18 years and a life expectancy of >12 weeks.
• Evidence of measurable primary CNS neoplasm on contrast enhanced MRI.
• An interval of at least one week between prior biopsy or four weeks from surgical resection and enrollment on this protocol.
• Karnofsky > or = to 60%.
• Hemoglobin > or = to 9g/dl, ANC > or = to 1,500 cells/microliter, platelets > or = to 125,000 cells/microliter.
• Serum creatinine ≤ 1.5 mg/dl, serum SGOT and direct bilirubin ≤ 1.5 times upper limit of normal.
• Signed informed consent approved by the Institutional Review Board prior to patient entry.
• If sexually active, patients will take contraceptive measures for the duration of the treatments.

Exclusion Criteria:

• Pregnancy or breast feeding
• Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids.
• Active infection requiring IV antibiotics.
• Treatment with radiotherapy or chemotherapy for a brain tumor, irrespective of the grade of the tumor.
• Evidence of > grade 1 CNS hemorrhage on baseline MRI or CT scan.

Avastin-specific Exclusion Criteria:

• 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
• 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 urine protein:creatinine (UPC) ratio > or = to 1.0 at screening OR urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
• Known hypersensitivity to any component of Avastin
• Pregnant (positive pregnancy test) or lactating. Use of effective means of contraception (men and women) in subjects of child-bearing potential

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  

Overall Contact: James J Vredenburgh, MD 919-681-3824 vrede001@mc.duke.edu

Information obtained from ClinicalTrials.gov on September 01, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00979017

Study ID Number: Pro00019065

ClinicalTrials.gov Identifier: NCT00979017

Health Authority: United States: Food and Drug Administration

The Preston Robert Tisch Brain Tumor Center