Phase I/II Adaptive Randomized Trial of Bevacizumab Versus Bevacizumab Plus Vorinostat in Adults With Recurrent Glioblastoma
Condition: Malignant Glioma; Recurrent Glioblastoma
MeSH terms: Glioblastoma; Glioma; Recurrence
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The goal of this Phase I portion of this clinical research study is to find the highest
      tolerable dose of bevacizumab with or without vorinostat, that can be given to patients with
      malignant gliomas. The safety of these drug combinations will also be studied.

      The goal of this Phase II part of this clinical research study is to learn if bevacizumab
      when given with or without vorinostat can help to control malignant gliomas. The safety of
      these drug combinations will also be studied.
    

Detailed description: 
      Background

        -  Glioblastoma (GBM) is the most common primary brain tumor. With optimal treatment,
           consisting of focal radiotherapy with concurrent chemotherapy, followed by adjuvant
           chemotherapy, median survival is 14.6 months. Most patients have evidence of tumor
           progression within one year of diagnosis despite treatment. At progression, treatment
           options are limited and mostly ineffective.

        -  Given the importance of angiogenesis in GBM, anti-angiogenic therapy is a promising
           strategy in recurrent GBM. Bevacizumab, the first angiogenesis inhibitor approved
           against cancer by FDA based on improved survival of advanced colon cancer patient, has
           recently been studied in the GBM.

        -  The present study aims to determine the potential of vorinostat, an HDAC inhibitor plus
           bevacizumab, versus bevacizumab alone, in an attempt to increase the anti-angiogenic
           effects of VEGF by blocking the evasive resistance by combination with vorinostat and to
           also not only provide the potential of the independent effects of both agents but also
           the potential for synergy.

      Objectives

        -  To determine the maximum tolerated dose (MTD) of vorinostat plus bevacizumab in adult
           patients with malignant glioma.

        -  To determine the efficacy of vorinostat plus bevacizumab versus bevacizumab alone in
           patients with recurrent WHO grade IV glioma (glioblastoma and gliosarcoma) as determined
           by progression free survival (PFS) using an adaptive randomization phase II trial
           design.

      Eligibility

        -  Patients must have histologically proven glioblastoma, gliosarcoma or anaplastic glioma
           to be eligible for the Phase I component of this protocol. Anaplastic gliomas include
           anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed
           oligoastrocytoma (AMO), or malignant glioma NOS (not otherwise specified). Patients will
           be eligible if the original histology was low-grade glioma and a subsequent histological
           diagnosis of a malignant glioma is made. Only patients with histologically proven or
           imaging proven recurrent glioblastoma or gliosarcoma will be eligible for the Phase II
           component.

        -  Patients must have shown unequivocal evidence for tumor progression as determined by an
           MRI scan done prior to study entry which will be reviewed by the treating physician to
           confirm and document recurrence.

        -  No prior treatment with bevacizumab or Vorinostat

      Design

      The phase I component will assess the MTD of Vorinostat in combination with Bevacizumab. A
      conventional phase I design will be used and the MTD will be selected using a 3+3 accrual
      design at each dose level until MTD is determined. A maximum of 18 patients will be recruited
      to this component of the study.

      The phase II component of the trial compares Bevacizumab to Vorinostat+ Bevacizumab in
      patients with recurrent GBM. The primary outcome is progression free survival. Patients will
      be randomized between the two arms using a Bayesian adaptive algorithm. Patients will be
      randomized fairly between the two arms at the start of the trial (for the first 20 patients).
      Thereafter, as the trial progresses and data accrue, the randomization will become unbalanced
      in favor of the treatment that, on average, has better results in terms of failure time.
      Therefore, each successive patient is more likely to receive the treatment with better
      results, on average. A minimum of 20 and a maximum of 90 patients will be accrued.
    

Intervention name(s): vorinostat; bevacizumab
Intervention type(s): Drug; Drug
Intervention description(s): Vorinostat 400mg/day will be administered on day 1 to 7 and day 15 to 21 orally on a 28 day cycle in the arm with combination of vorinostat and bevacizumab. Vorinostat will be administered orally. Vorinostat capsules should not be opened or crushed and must be administered whole.; Bevacizumab 10mg/kg will be administered on day 1 and 15 intravenously on a 28 day cycle in both arms.
Other intervention name(s): Zolinza; Avastin
Intervention MeSH terms: Bevacizumab; Vorinostat
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Glioblastoma Multiforme