TY - JOUR
T1 - Vorinostat as a radiosensitizer for brain metastasis
T2 - A phase i clinical trial
AU - Shi, Wenyin
AU - Lawrence, Yaacov Richard
AU - Choy, Hak
AU - Werner-Wasik, Maria
AU - Andrews, David W.
AU - Evans, James J.
AU - Judy, Kevin D.
AU - Farrell, Christopher J.
AU - Moshel, Yaron
AU - Berger, Adam C.
AU - Bar-Ad, Voichita
AU - Dicker, Adam P.
PY - 2014/6
Y1 - 2014/6
N2 - 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.
AB - 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.
KW - Brain metastasis
KW - Phase I
KW - Radiosensitizer
KW - Vorinostat
KW - Whole brain radiation
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U2 - 10.1007/s11060-014-1433-2
DO - 10.1007/s11060-014-1433-2
M3 - Article
C2 - 24728831
AN - SCOPUS:84903894771
SN - 0167-594X
VL - 118
SP - 313
EP - 319
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
IS - 2
ER -