Phase I and pharmacodynamic study of vorinostat combined with capecitabine and cisplatin as first-line chemotherapy in advanced gastric cancer.

Abstract

A phase I trial of first-line vorinostat, an orally bio-available histone deacetylase inhibitor, in combination with capecitabine plus cisplatin (XP) was performed to assess recommend phase II trial dose in patients with advanced gastric cancer. Five dose levels of three-weekly vorinostat-XP were tested; vorinostat was dosed at 300-400 mg once daily on Days 1-14, capecitabine at 800-1,000 mg/m(2) twice daily on Days 1-14, and cisplatin at 60-80 mg/m(2) on Day 1. To assess the pharmacodynamics of vorinostat, histone H3 acetylation was assessed in peripheral blood mononuclear cells before the study treatment and at Day 8 of cycle 1. In total, 30 patients with unresectable or metastatic gastric adenocarcinoma were included. Dose-limiting toxicities were thrombocytopenia, fatigue, stomatitis, and anorexia. The following doses were recommended for phase II trial: 400 mg of vorinostat once daily, 1,000 mg/m(2) of capecitabine twice daily, and 60 mg/m(2) of cisplatin. The most common grade 3-4 toxicities were neutropenia (47 %), anorexia (20 %), thrombocytopenia (17 %), and fatigue (13 %). In overall, response rate was 56 % (95 % confidence interval [CI]: 32-81). With a median follow-up of 14.1 months, the median progression-free survival and overall survival were 7.1 months (95 % CI: 3.8-10.3) and 18.0 months (95 % CI: 4.8-31.1), respectively. The change in H3 acetylation after treatment with vorinostat correlated significantly with the vorinostat dose (300 vs. 400 mg/day) and the baseline level of H3 acetylation before treatment. Three-weekly vorinostat-XP regimen is feasible and recommended for further development in advanced gastric cancer.

• Authors: Changhoon Yoo, Min-Hee Ryu, Young-Soon Na, Baek-Yeol Ryoo, Chae-Won Lee, Jeheon Maeng, Se-Yeon Kim, Dong Hoe Koo, Inkeun Park, Yoon-Koo Kang
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 2 Pg. 271-8 (Apr 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 23712440 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histone Deacetylase Inhibitors
• Histones
• Hydroxamic Acids
• Deoxycytidine
• Vorinostat
• Capecitabine
• Cisplatin
• Fluorouracil

Topics

• Acetylation
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Capecitabine
• Cisplatin (administration & dosage, adverse effects)
• Deoxycytidine (administration & dosage, adverse effects, analogs & derivatives)
• Female
• Fluorouracil (administration & dosage, adverse effects, analogs & derivatives)
• Histone Deacetylase Inhibitors (administration & dosage, adverse effects)
• Histones (metabolism)
• Humans
• Hydroxamic Acids (administration & dosage, adverse effects)
• Male
• Middle Aged
• Stomach Neoplasms (drug therapy, metabolism)
• Vorinostat