NCT01266031

Phase I/II Adaptive Randomized Trial of Bevacizumab Versus Bevacizumab Plus Vorinostat in Adults With Recurrent Glioblastoma

• Status: Completed
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 96 (actual)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years – 99 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Malignant Glioma
• Recurrent Glioblastoma

Interventions

Type	Name	Description
DRUG	vorinostat	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.
DRUG	bevacizumab	Bevacizumab 10mg/kg will be administered on day 1 and 15 intravenously on a 28 day cycle in both arms.

Timeline

• Start date: 2011-07-12
• Primary completion: 2015-06-30
• Completion: 2017-01-31
• First posted: 2010-12-24
• Last updated: 2018-07-31
• Results posted: 2016-09-23

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study