A Randomized Phase II Trial of Vandetanib (ZD6474) in Combination With Carboplatin Versus Carboplatin Alone Followed by Vandetanib Alone in Adults With Recurrent High-Grade Gliomas
- Growth of new blood vessels (angiogenesis) provides many tumors, including brain tumors, with needed nutrients and oxygen for cancer cells to survive. One possible treatment for different kinds of cancer involves treatment with drugs that slow or stop angiogenesis and prevent further tumor growth.
- Vandetanib is an oral medication known to block angiogenesis and has shown significant antitumor activity in laboratory and animal studies. Vandetanib appears to be well tolerated by patients at specific daily doses.
- Carboplatin is a drug that interrupts division of cancer cells and has been shown to be a useful drug in treatment of tumors known as gliomas. It is a useful drug for treating brain tumors, but researchers are interested in gathering more information about how it works as a treatment for patients who have not responded to initial surgery, radiation, or chemotherapy.
- To determine the safety and effectiveness of vandetanib and carboplatin, given together or sequentially, against recurrent high-grade gliomas.
- Adults diagnosed with a malignant glioma who have received standard treatments that no longer appear to be effective.
- Patients will be assigned to one of two groups. Group 1 patients (combination group) will receive oral vandetanib for 28 days and intravenous (IV) carboplatin (once at the beginning of the 28-day cycle). Group 2 patients (sequential group) will receive IV carboplatin alone (once at the beginning of the 28-day cycle) and then oral vandetanib (300 mg daily) for 28 days if the tumor grows or the patient develops unacceptable carboplatin toxicity.
- Treatment will continue in 28-day cycles for 1 year for both groups.
- Patients will undergo a number of tests and procedures during the treatment cycle, including physical examinations, routine laboratory tests, electrocardiograms, and magnetic resonance imaging (MRI) scans
- At the end of 1 year of treatment, patients will be reevaluated for possible continuation of drug therapy.
Anaplastic Mixed Oligoastrocytoma
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Randomized Phase II Trial of Vandetanib (ZD6474) in Combination With Carboplatin Versus Carboplatin Alone Followed by Vandetanib Alone in Adults With Recurrent High-Grade Gliomas|
- To establish data regarding the anti-tumor activity of the combination of vandetanib with carboplatin or carboplatin alone in patients with recurrent high-grade gliomas not taking enzyme-inducing anti-epileptic drugs (EIAEDs). [ Time Frame: +/- 1.5 years ] [ Designated as safety issue: No ]
- To obtain information regarding the spectrum of toxicities of vandetanib with carboplatin or carboplatin alone administered to patients with recurrent high-grade gliomas not taking EIAEDs. [ Time Frame: +/- 1.5 years ] [ Designated as safety issue: Yes ]
|Study Start Date:||September 2009|
|Estimated Study Completion Date:||July 2016|
|Estimated Primary Completion Date:||July 2016 (Final data collection date for primary outcome measure)|
Active Comparator: Group 1
Active Comparator: Group 2
In vivo experiments have documented the ability of vandetanib (ZD6474) to inhibit tumor growth in various preclinical tumor models. Given the pronounced neovasculature associated with malignant gliomas, and abundant published data demonstrating the dependence of glioma growth on the maintenance and proliferation of this neovasculature, vandetanib represents a potentially promising new therapeutic approach to these otherwise refractory tumors. Phase II data of vandetanib for recurrent glioblastomas conducted at the National Institutes of Health showed promising activity but responses were usually short-lasting.
Carboplatin has shown activity as monotherapy in the treatment of recurrent malignant gliomas in adults and preclinical data generated at Dr. Fine s laboratory demonstrate additive anti-glioma activity with vandetanib. The safety profile of carboplatin and the preclinical and clinical data supports its use in combination with vandetanib in patients with malignant gliomas.
Vandetanib is also an EGFR inhibitor and it has been demonstrated that the presence of the EGFRvIII mutant and/or the presence of an intact PTEN and non-phosphorylated AKT predict for a higher likelihood of response to the EGFR inhibitors Tarceva and Iressa.
To establish data regarding the anti-tumor activity of vandetanib in combination with carboplatin and single agent carboplatin and to collect information regarding the spectrum of toxicities.
To determine if the presence of the EGFRvIII mutant and/or the presence of an intact PTEN and non-phosphorylated AKT predict for a higher likelihood of response to vandetanib.
Patients with histologically proven malignant glioma are eligible for this study.
Patients will be randomized (1:1) to one of two groups. Patients in group one will be treated with vandetanib (300 mg daily for patients not on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg daily for patients on EIAEDs) and with carboplatin (area under the concentration-time curve at steady-state [AUC], 6mg/mL x min) once every 4-week cycle ( combination group ). Patients in group two will receive carboplatin alone (AUC 6mg/mL x min) once every 4-week cycle. Patients who develop tumor progression or unacceptable toxicity on carboplatin alone (group 2) can then receive single agent vandetanib (300 mg daily for patients not on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg daily for patients on EIAEDs) in 4-week cycles ( sequential group ). A total of 128 evaluable patients will be analyzed. The total accrual ceiling will allow for 74 patients to be enrolled in the GBM stratum and 74 patients in the AG stratum (total 148) to factor in replacing those patients who come off treatment prior to cycle 1.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00995007
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Katherine E Warren, M.D.||National Cancer Institute (NCI)|