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
Condition: Glioblastoma Multiforme; Gliosarcoma; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Anaplastic Mixed Oligoastrocytoma
MeSH terms: Glioblastoma; Astrocytoma; Gliosarcoma; Oligodendroglioma
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

        -  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.

      Objective:

      - To determine the safety and effectiveness of vandetanib and carboplatin, given together or
      sequentially, against recurrent high-grade gliomas.

      Eligibility:

      - Adults diagnosed with a malignant glioma who have received standard treatments that no
      longer appear to be effective.

      Design:

        -  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.
    

Detailed description: 
      Background:

      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. Fines' 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 epidermal growth factor receptor (EGFR) inhibitor and it has been
      demonstrated that the presence of the EGFRvIII mutant and/or the presence of an intact
      phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and non-phosphorylated protein
      kinase B (AKT) predict for a higher likelihood of response to the EGFR inhibitors Tarceva and
      Iressa.

      Objectives:

      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.

      Eligibility:

      Patients with histologically proven malignant glioma are eligible for this study.

      Design:

      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 [area under curve (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
      glioblastoma multiforme (GBM) stratum and 74 patients in the anaplastic gliomas (AG) stratum
      (total 148) to factor in replacing those patients who come off treatment prior to cycle 1.
    

Intervention name(s): ZD6474 (Vandetanib); Carboplatin
Intervention type(s): Drug; Drug
Intervention description(s): 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.
Intervention MeSH terms: Carboplatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Brain Tumor; Chemotherapy; Antiangiogenesis; Radiation; Progression; Glioma; Glioblastoma Multiforme