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

• ClinicalTrials.gov Identifier: NCT00612339
• Recruitment Status: Completed
• First Posted: February 11, 2008
• Results First Posted: September 10, 2012
• Last Update Posted: May 27, 2013
• Sponsor: Duke University
• Collaborators: Genentech, Inc.; Schering-Plough
• Information provided by (Responsible Party): Duke University

Study Description

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

Condition or disease	Intervention/treatment	Phase
Glioblastoma; Gliosarcoma	Drug: Avastin and Temozolomide	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 41 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Avastin in Combination With Temozolomide for Unresectable or Multifocal Glioblastoma Multiformes and Gliosarcomas
• Study Start Date: August 2007
• Actual Primary Completion Date: May 2012
• Actual Study Completion Date: May 2012

Arms and Interventions

Arm

Intervention/treatment

Experimental: 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.

Drug: Avastin and Temozolomide; This is Phase II study with the combination of Avastin & Temozolomide for unresectable or multifocal WHO grade IV malignant glioma patients. Patients 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. Patients 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, patient non-compliance or patient withdraws consent to continue therapy & requests discontinuation, patients 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 patient & treating physicians.; Other Names: Avastin - Bevacizumab; Temozolomide - Temodar

Outcome Measures

Primary Outcome Measures :

1. Response Rate [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, North Carolina

Duke University Health System

Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Duke University

Genentech, Inc.

Schering-Plough

Investigators

• Principal Investigator: Katherine B Peters, MD, PhD; Duke University Health System

More Information

Additional Information:

The Preston Robert Tisch Brain Tumor Center at DUKE 

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT00612339
• Other Study ID Numbers: Pro00001022
• First Posted: February 11, 2008
• Results First Posted: September 10, 2012
• Last Update Posted: May 27, 2013
• Last Verified: September 2012

Keywords provided by Duke University:

Glioma; Temozolomide; Temodar; Avastin; Bevacizumab; GBM; Gliosarcoma; Multifocal GBM; Brain tumor; Unresectable GBM; Glioblastoma multiforme

Additional relevant MeSH terms:

Glioblastoma; Gliosarcoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Bevacizumab; Temozolomide; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action