title: Vorinostat as a radiosensitizer for brain metastasis: a phase I clinical trial.
abstract: Perform a phase I study to evaluate the safety, and tolerability of vorinostat, an HDAC inhibitor, when combined with whole brain radiation treatment (WBRT) in patients with brain metastasis. A multi-institutional phase I clinical trial enrolled patients with a histological diagnosis of malignancy and radiographic evidence of brain metastasis. WBRT was 37.5 Gy in 2.5 Gy fractions delivered over 3 weeks. Vorinostat was administrated by mouth, once daily, Monday through Friday, concurrently with radiation treatment. The vorinostat dose was escalated from 200 to 400 mg daily using a 3+3 trial design. Seventeen patients were enrolled, 4 patients were excluded from the analysis due to either incorrect radiation dose (n = 1), or early treatment termination due to disease progression (n = 3). There were no treatment related grade 3 or higher toxicities in the 200 and 300 mg dose levels. In the 400 mg cohort there was a grade 3 pulmonary embolus and one death within 30 days of treatment. Both events were most likely related to disease progression rather than treatment; nonetheless, we conservatively classified the death as a dose limiting toxicity. We found Vorinostat administered with concurrent WBRT to be well tolerated to a dose of 300 mg once daily. This is the recommended dose for phase II study.
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA. wenyin.shi@jefferson.edu.
authors.forename: Wenyin
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.|Department of Radiation Oncology, Sheba Medical Center, Tel HaShomer, Israel.
authors.forename: Yaacov Richard
authors.initials: YR
authors.lastname: Lawrence
authors.affiliation: Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
authors.forename: Hak
authors.initials: H
authors.lastname: Choy
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Werner-Wasik
authors.affiliation: Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Andrews
authors.affiliation: Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Evans
authors.affiliation: Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Judy
authors.affiliation: Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Farrell
authors.affiliation: Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Moshel
authors.affiliation: Department of Surgery, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Berger
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Voichita
authors.initials: V
authors.lastname: Bar-Ad
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
mesh_terms: D000368:Aged; D001932:Brain Neoplasms / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D059248:Chemoradiotherapy; D015331:Cohort Studies; D018450:Disease Progression; D005185:Fallopian Tube Neoplasms / Q000473:pathology; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011838:Radiation-Sensitizing Agents; D000077337:Vorinostat
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