A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors
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Background Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. Methods Vorinostat was initially administered orally twice daily on days 1–14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1–4 and 8–11. Results 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3–4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. Conclusions The MTD was established at vorinostat 300 mg BID on days 1–4 and 8–11 and bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.
KeywordsSAHA Vorinostat PS-341 Bortezomib Phase I
The authors would like to thank the University of Wisconsin Carbone Cancer Center (UWCCC) Analytical Instrumentation Laboratory for Pharmacokinetics, Pharmacodynamics, & Pharmacogenetics (3P Lab) for support in the acquisition of pharmacokinetic data for this research.
The authors also would like to thank the patients who participated in this clinical trial, and the nurses and research specialist of the UWCCC Cancer Therapy Discovery and Development Program for their efforts in conducting and managing this trial.
No potential conflicts of interest were disclosed.
NCI, UO1, CA062491, NCI P30, CA014520, SAIC 25XS097, and 1ULRR025011. U01 CA69912, Phase I Trials of Anticancer Agents (Mayo Clinic); 23XS026, CTEP Translational Research Initiative - Support Subcontracts, Correlative Studies Core Laboratory for SAHA Phase I and Phase II Clinical Protocols (Mayo Clinic), SAIC-FREDERICK, INC.; funding from Merck.
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