Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 14015
© 2007 American Society of Clinical Oncology

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Abstract

A phase I and pharmacokinetic/pharmacodynamic study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in Japanese patients with solid tumor

National Cancer Center Hospital, Tokyo, Japan; Tokyo Metropolitan Komagome Hospital, Tokyo, Japan; Kinki University School of Medicine, Osaka, Japan; Banyu Pharmaceutical, Tokyo, Japan; Merck & Co., Inc., North Wales, PA

14015

Background: Vorinostat (Zolinza^TM), a potent inhibitor of histone deacetylase (HDAC), induces tumor growth inhibition, differentiation, and apoptosis in vitro. Increasing evidence has revealed clinical activity of vorinostat in patients (pts) with various types of cancer including cutaneous T-cell lymphoma. Methods: Japanese pts with solid tumor who failed standard therapy were enrolled in a single institution, National Cancer Center hospital, Phase I study. Pts were dosed with vorinostat BID for 14 consecutive days followed by 7 day-rest starting at 100 mg and escalated by 100 mg BID until MTD was established. Subsequently single daily dosing was tested at 400 and 500 mg. PK was measured at total of 41 timepoints. Response was also evaluated according to the international workshop criteria. Results: MTD was established as 200 mg BID and 500 mg QD for 14 consecutive days followed by a 7 day-rest. All 18 enrolled pts were assessed for safety and PK. Median age was 58 yrs [25–72]. Ten of 18 pts had lung cancer. Two of 6 pts receiving 200 mg BID experienced DLTs: Grade 4 thrombocytopenia, and Grade 4 thrombocytopenia and Grade 3 anorexia. None of 3 pts receiving 400 mg QD experienced DLT. One of 6 pts receiving 500 mg QD experienced Grade 3 anorexia and fatigue. AUC of vorinostat increased generally proportional to dose in the range of 100–500 mg. PK was not greatly affected by multiple doses. Intact drug was hardly excreted in urine (<1% of dose). PK profile is similar to that established in US pts. As of Dec 2006, 1 pt with invasive thymoma received 200 mg BID for 1 yr. Nine pts achieved SD as best response. Conclusions: This study demonstrates the safety of vorinostat 200 mg BID and 500 mg QD for 14 consecutive days followed by 7 day-rest. These would be the RD for Phase II studies on this schedule.

No significant financial relationships to disclose.