Aflibercept, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed or Recurrent Glioblastoma Multiforme, Gliosarcoma, or Other Malignant Glioma
- Conditions
- Adult Anaplastic AstrocytomaAdult Anaplastic OligodendrogliomaAdult Giant Cell GlioblastomaAdult GlioblastomaAdult GliosarcomaAdult Mixed GliomaRecurrent Adult Brain Tumor
- Interventions
- Procedure: radiation therapyProcedure: pharmacological studyProcedure: laboratory biomarker analysis
- Registration Number
- NCT00650923
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
This phase I trial is studying the side effects and best dose of aflibercept when given together with radiation therapy and temozolomide in treating patients with newly diagnosed or recurrent glioblastoma multiforme, gliosarcoma, or other malignant glioma. Aflibercept may stop the growth of tumor cells by blocking blood flow to the tumor. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving aflibercept together with radiation therapy and temozolomide may kill more tumor cells.
- Detailed Description
PRIMARY OBJECTIVES:
I. To define the maximum tolerated dose (MTD) of aflibercept (VEGF Trap) with radiotherapy (RT) and concurrent temozolomide (TMZ) when administered in patients with newly-diagnosed glioblastoma (GBM) or gliosarcoma.
II. To define the MTD of aflibercept with adjuvant TMZ administered at 150mg/m2once daily for 5 days every 28 days in patients with stable or recurrent malignant glioma (MG) after RT.
III. To define the MTD of aflibercept with adjuvant TMZ administered at 100 mg/m2 once daily for 21 days every 28 days in patients with stable or recurrent MG after RT.
IV. To characterize the safety profile of aflibercept in combination with RT and concomitant TMZ in patients with newly-diagnosed GBM.
V. To characterize the safety profile of aflibercept in combination with adjuvant TMZ in patients with stable or recurrent MG after RT.
SECONDARY OBJECTIVE:
I. To characterize the pharmacokinetic profiles of free and bound aflibercept and TMZ in these patients
OUTLINE: This is a multicenter, dose-escalation study of aflibercept. Patients are assigned to 1 of 3 treatment groups according to prior treatment and diagnosis.
Group 1 (newly diagnosed glioblastoma multiforme or gliosarcoma): Patients undergo involved field partial brain radiotherapy (RT) once daily, 5 days a week (total of 30 fractions) and receive concurrent oral temozolomide (TMZ) once daily for 6 weeks. Beginning 2 weeks after the initiation of RT patients also receive aflibercept IV over 1 hour on days 1 and 15 and continue until the end of RT. Beginning 4 weeks after completion of radiotherapy, patients receive adjuvant oral TMZ once daily on days 1-5. Treatment with adjuvant TMZ repeats every 28 days for up to 12 courses.
Group 2 (stable or recurrent malignant glioma): Patients undergo radiotherapy as in group 1. Patients receive oral TMZ on days 1-5. Treatment repeats every 28 days for up to 12\* courses. Patients also receive aflibercept IV over 1 hour on days 1 and 15 beginning on the first day of TMZ treatment.
\[Note: \*The 12 course maximum includes adjuvant TMZ courses administered prior to enrollment.\]
Group 3 (stable or recurrent malignant glioma): Patients undergo radiotherapy as in group 1. Patients receive oral TMZ on days 1-5. Treatment repeats every 21 days for up to 12\* courses. Patients also receive aflibercept IV over 1 hour on days 1 and 15 beginning on the first day of TMZ treatment.
\[Note: \*The 12 course maximum includes adjuvant TMZ courses administered prior to enrollment.\]
In all groups, treatment continues in the absence of disease progression or unacceptable toxicity.
Blood samples are collected periodically for analysis of pharmacokinetics by ELISA. Tumor biomarkers and plasma angiogenic peptides are analyzed for correlation with response, and tumor MGMT promoter methylation status is determined using methylation-specific PCR.
After completion of study treatment, patients are followed every 3 months.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 61
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Arm 1 ziv-aflibercept See Detailed Description Arm 1 radiation therapy See Detailed Description Arm 1 pharmacological study See Detailed Description Arm 1 laboratory biomarker analysis See Detailed Description Arm 1 temozolomide See Detailed Description
- Primary Outcome Measures
Name Time Method Maximum tolerated dose of aflibercept defined as the dose at which fewer than one-third of patients experience DLT based on the CTC severity grading 28 days
- Secondary Outcome Measures
Name Time Method Plasma aflibercept (VEGF Trap) concentrations and PK parameters such as Cmax, Tmax, area under the plasma concentration-time curve (AUCo-t and AUC), clearance (CL), apparent volume of distribution at steady state (Vdss), and terminal half-life (t1/2) Baseline and days 15, 16, 22, 29, 57, 85 of course 1 for patients in Arm I; baseline and days 2, 8, 15, 43, 71 of course 1 for patients in Arms 2 and 3 Will be determined using non-compartmental methods. Dose proportionality in PK parameters will be determined by performing a one-way analysis of variance (ANOVA) on dose-normalized parameters. In addition, summary tables depicting individual patient concentrations and individual and mean PK parameters will be provided.
Efficacy in terms of antitumor activity based on clinical, radiographic, and biologic assessments Up to 3 months Descriptive analysis will be provided.
Trial Locations
- Locations (9)
University of California San Francisco Medical Center-Parnassus
🇺🇸San Francisco, California, United States
Adult Brain Tumor Consortium
🇺🇸Baltimore, Maryland, United States
University of California at Los Angeles (UCLA )
🇺🇸Los Angeles, California, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
UCSF-Mount Zion
🇺🇸San Francisco, California, United States
M D Anderson Cancer Center
🇺🇸Houston, Texas, United States
Massachusetts General Hospital
🇺🇸Charlestown, Massachusetts, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸New York, New York, United States
University of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States