Study of the Combination of Vorinostat and Radiation Therapy for the Treatment of Patients With Brain Metastases
Vorinostat in combination with radiation therapy can be administered safely and will be tolerated in patients with brain metastases, while providing an assessment of the anti-tumor activity of this combination.
This is a multi-center, open-label, non-randomized Phase I study in patients with brain metastases. Patients will be administered oral Vorinostat and radiation therapy and will be treated for 3 weeks. Patients will be enrolled in cohorts and will be treated at sequentially rising dose levels of Vorinostat combined with radiation therapy. We will initially enter 3 subjects at each dose. If none of the three experiences a dose-limiting toxicity we will proceed to the next dose. If one of the three experiences that level of toxicity, we will accrue 3 more subjects at that dose. If at any time there are two or more dose-limiting toxicities (in the 3-6 subjects) on a given dose, we will drop down to a lower dose. Dose escalation will continue until the MTD of Vorinostat and radiation therapy is established. The MTD will then be one dose below the DLT occurring in at least 1 out of 3 subjects (2 out of 6 patients).
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Study of the Combination of Vorinostat and Radiation Therapy for the Treatment of Patients With Brain Metastases|
- To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Vorinostat and radiotherapy in patients with brain metastases. [ Time Frame: Weekly during treatment On Last day of treatment (30 days after last drug dose) Follow-up (every 3 months) ] [ Designated as safety issue: Yes ]
|Study Start Date:||March 2009|
|Estimated Study Completion Date:||March 2014|
|Primary Completion Date:||January 2013 (Final data collection date for primary outcome measure)|
Experimental: Vorinostat and Radiation
Patients will be treated on a dose escalation model for vorinostat and concurrently receive radiation therapy.
All doses given for 3 weeks
Dose level -2 - 50 mg PO qd (to be used in de-escalation if toxicity occurs) Dose level -1 - 100 mg PO qd (to be used in de-escalation if toxicity occurs) Dose level I - 200 mg PO qd (initial starting dose) Dose level II - 300 mg PO qd Dose level III - 400 mg PO qd
Other Name: ZolinzaRadiation: Radiation Therapy
Patients will take Vorinostat daily during radiation therapy, they will be recommended to swallow the capsule 60-90 minutes prior to estimate time of radiation.
In recent years, a number of investigators have shown that combining signal transduction agents with ionizing radiation results in significant antitumor effects without an increase in normal tissue toxicity. There are numerous lines of evidence that Histone deacetylase (HDAC) inhibitors have been shown to enhance the radiosensitivity of tumor cells in vitro and in vivo 1-6. Vorinostat (Zolinza, suberoylanilide hydroxamic acid - SAHA) a potent histone deacetylase, has recently been approved for clinical use for cutaneous T-cell lymphoma. It has the potential to inhibit tumor growth and proliferation7-13, tumor angiogenesis14 and enhance radiation response15 with minimal toxicity. This phase I study, is based on the range of efficacy of Vorinostat and its ability to cross the blood-brain barrier. This study will evaluate the safety of combination of Vorinostat and daily-fractionated radiation therapy. This information is critical for any combined future combined modality trials that involves radiation therapy to the brain.
Vorinostat was approved by the US Food and Drug Administration (FDA) on 6-Oct-2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies.
Based on preclinical, clinical efficacy and safety data, it is anticipated that Vorinostat in combination with radiation therapy can be administered safely and will be tolerated in patients with brain metastases. In addition, within the recognized limits of a Phase I clinical trial, this study may provide an assessment of the anti-tumor activity of Vorinostat in combination with radiation therapy in patients with brain metastases.
The present study will investigate the safety, tolerability and spectrum of side effects of Vorinostat in combination with radiation therapy. As such, this study will characterize the dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of in combination with radiation therapy in patients with brain metastases.
|United States, Pennsylvania|
|Thomas Jefferson University|
|Philadelphia, Pennsylvania, United States, 19107|
|United States, Texas|
|The University of Texas Southwestern Medical Center|
|Dallas, Texas, United States, 75390|
|Principal Investigator:||Wenyin Shi, MD, PhD||Thomas Jefferson Universtiy|