Journal article
A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors
Investigational new drugs, Vol.32(2), pp.323-329
04/01/2014
DOI: 10.1007/s10637-013-0035-8
PMCID: PMC3949160
PMID: 24114123
Abstract
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.
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.
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.
The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m(2) 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.
Details
- Title: Subtitle
- A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors
- Creators
- Dustin A Deming - University of Wisconsin Carbone Cancer CenterJacob Ninan - University of Wisconsin Carbone Cancer CenterHoward H Bailey - University of Wisconsin Carbone Cancer CenterJill M Kolesar - University of Wisconsin Carbone Cancer CenterJens Eickhoff - University of Wisconsin Carbone Cancer CenterJoel M Reid - Mayo Clinic in FloridaMatthew M Ames - Mayo ClinicRenee M McGovern - Mayo ClinicDona Alberti - University of Wisconsin Carbone Cancer CenterRebecca Marnocha - University of Wisconsin Carbone Cancer CenterIgor Espinoza-DelgadoJohn WrightGeorge Wilding - University of Wisconsin Carbone Cancer CenterWilliam R Schelman - University of Wisconsin Carbone Cancer Center
- Resource Type
- Journal article
- Publication Details
- Investigational new drugs, Vol.32(2), pp.323-329
- DOI
- 10.1007/s10637-013-0035-8
- PMID
- 24114123
- PMCID
- PMC3949160
- ISSN
- 0167-6997
- eISSN
- 1573-0646
- Grant note
- T32 CA009614 / NCI NIH HHS CA062491 / NCI NIH HHS U01 CA069912 / NCI NIH HHS P30 CA014520 / NCI NIH HHS U01 CA69912 / NCI NIH HHS UL1 TR000427 / NCATS NIH HHS U01 CA062491 / NCI NIH HHS CA014520 / NCI NIH HHS P30 CA015083 / NCI NIH HHS 1ULRR025011 / PHS HHS
- Language
- English
- Date published
- 04/01/2014
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984695798002771
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