Avastin in Combination With Radiation (XRT) & Temozolomide, Followed by Avastin, Temozolomide and Irinotecan for Glioblastoma (GBM) and Gliosarcomas

Glioblastoma Clinical Trial

Official title:

Avastin in Combination With Radiation and Temozolomide, Followed by Avastin, Temozolomide and Irinotecan for Glioblastoma Multiformes and Gliosarcomas

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00597402
• Other study ID #: Pro00000458
• Status: Completed
• Phase: Phase 2
• First received: January 10, 2008
• Last updated: April 22, 2014
• Start date: July 2007
• Est. completion date: May 2013

Study information

• Verified date: April 2014
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

Primary objective: To use overall survival to assess the efficacy of the combination of radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and irinotecan in the treatment of grade IV malignant glioma patients following surgical resection.

Secondary objective: To determine the progression-free survival following the combination of radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and irinotecan.

Exploratory Objective: To explore the relationship between biomarkers and outcome (overall survival and progression-free survival) among patients with grade IV malignant glioma treated with radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and irinotecan.

To describe the toxicity of radiation therapy,temozolomide and Avastin followed by Avastin, temozolomide, and irinotecan.

Description:

The standard of care for grade IV gliomas is radiation therapy with daily temozolomide, followed by 6 months of temozolomide. The majority of patients progress and die of their tumor. Many glioma patients are resistant to temozolomide because the tumors have high O(6)-methylguanine-DNA methyltransferase (MGMT), conferring resistance. Irinotecan is synergistic with temozolomide, and the combination may overcome high MGMT. Vascular endothelial growth factor (VEGF) is present on the cell surface and around malignant gliomas. It appears that the presence of vascular endothelial growth factor is a prognostic growth factor with more VEGF expression correlating with a poor prognosis. Monoclonal antibodies to VEGF have inhibited growth of malignant gliomas in a mouse xenograft. Avastin is a humanized monoclonal immunoglobulin G (IGG) 1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor. The combination of Avastin and irinotecan was safe and demonstrated high activity against recurrent malignant gliomas. The combination of Avastin, temozolomide, and irinotecan as the initial therapy may maximize the chance for long-term survival. There are other studies completed or ongoing for newly diagnosed glioblastoma (GBM) patients, including a Radiation Therapy Oncology Group (RTOG) study that added irinotecan to temozolomide following standard radiation therapy and temozolomide, and a University of California, Los Angeles (UCLA) study that added Avastin to standard radiation therapy and temozolomide followed by Avastin and temozolomide.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 125
• Est. completion date: May 2013
• Est. primary completion date: August 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients must have histologically confirmed diagnosis of World Health Organization (WHO) grade IV primary malignant glioma (glioblastoma multiforme or gliosarcoma). Patients have to be within 4 weeks of the last major surgical procedure.

• Age > 18 years.

• An interval of at least 2 weeks and not > 6 weeks between prior major surgical procedure and study enrollment.

• No prior radiotherapy or chemotherapy for a brain tumor

• Karnofsky = 60 percent.

• Hemoglobin = 9.0 g/deciliter (dl), absolute neutrophil count (ANC) = 1,500 cells/ microliter, platelets = 125,000 cells/microliter.

• Serum creatinine = 1.5 mg/dl, serum serum glutamic-oxaloacetic transaminase (SGOT) and bilirubin = 1.5 times upper limit of normal (ULN).

• For patients on corticosteroids, they must be on a stable or decreasing dose for 1 week prior to entry, and the dose should not be escalated over entry dose level, if clinically possible.

• Signed informed consent approved by the Institutional Review Board

• No evidence of > grade 1 central nervous system (CNS) hemorrhage on the baseline MRI or CT scan.

• If sexually active, patients will take contraceptive measures for the duration of treatment as stated in the informed consent.

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 intravenous (IV) antibiotics.

• Prior 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 on CT scan.

Avastin-Specific Concerns:

Subjects meeting any of the following criteria are ineligible for study entry:

• Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study

• Blood pressure of 150/100 mmHg

• Unstable angina

• New York Heart Association (NYHA) Grade II or greater congestive heart failure

• History of myocardial infarction within 6 months

• History of stroke within 6 months

• Clinically significant peripheral vascular disease

• Evidence of bleeding diathesis

• Coagulopathy (prothrombin time (PT) or partial thromboplastin time (PTT) >1.5x normal or a history of > three grade 2 or greater hemorrhages)

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to first Avastin infusion during XRT/Temodar or anticipation of need for major surgical procedure during the course of the study

• Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to first Avastin infusion during XRT/Temodar

• Pregnant (positive pregnancy test) or lactating

• Urine protein >1.0 + at screening

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to first Avastin infusion during XRT/Temodar

• Serious, non-healing wound, ulcer, or bone fractures.

• Inability to comply with study and/or follow-up procedures.

Study Design

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

Related Conditions & MeSH terms

• Brain Neoplasms
• Brain Tumor
• Glioblastoma
• Gliosarcoma

Intervention

Drug:
• Avastin
Avastin will be administered 10 mg/kg every other week beginning a minimum of 28 days after last major surgical procedure, open biopsy, or significant traumatic injury. Following completion of XRT, patients will receive treatment that includes 6 cycles of Avastin, beginning a minimum of 14 days after last XRT.
• Temozolomide
Daily temozolomide 75 mg/m2/day for 6.5 weeks of radiation treatment. Following completion of XRT, patients will receive treatment including temozolomide 200 mg/m2/day on the 1st 5 days of each 28-day cycle.

Radiation:
• Radiation Therapy (XRT)
Treatment with standard XRT (radiation) for 6.5 weeks.

Drug:
• Irinotecan
Following completion of XRT, patients will receive 6 cycles of treatment that includes irinotecan. Beginning a minimum of 14 days after last XRT, the irinotecan dose will depend on whether the patient is on enzyme-inducing antiepileptic drugs (EIAED). (EIAED:340 mg/m2 every other week, non-EIAED: 125 mg/m2.)

Locations

Country	Name	City	State
United States	Duke University Health System	Durham	North Carolina

Sponsors (3)

Lead Sponsor	Collaborator
Duke University	Genentech, Inc., Schering-Plough

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	16-month Overall Survival (OS)	Percentage of participants surviving sixteen months from the start of study treatment. OS was defined as the time from the date of study treatment initiation to the date of death due to any cause.	16 months	No
Secondary	12-month Progression-free Survival (PFS)	Percentage of participants surviving twelve months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause.	12 months	No
Secondary	Number of Patients Experiencing a Central Nervous System (CNS) Hemorrhage or a Systemic Hemorrhage	Number of times a CNS hemorrhage or systemic hemorrhage was experienced	55 months	Yes
Secondary	Number of Patients Experiencing a Grade = 4 Hematologic or Grade = 3 Non-hematologic Toxicity	Number of times a grade = 4 hematologic or grade = 3 non-hematologic toxicity was experienced	55 months	Yes

External Links

•   The Preston Robert Tisch Brain Tumor Center at DUKE