Journal article
A phase I study of vorinostat in combination with bortezomib in patients with advanced malignancies
Investigational new drugs, Vol.31(6), pp.1539-1546
12/01/2013
DOI: 10.1007/s10637-013-0029-6
PMCID: PMC3901262
PMID: 24114121
Abstract
Background A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors. Methods Patients received vorinostat orally once daily on days 1-14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m(2)). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1. Results Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m(2) to 1.5 mg/m(2). The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m(2). DLTs consisted of grade 3 fatigue in three patients (1 mg/m(2),1.3 mg/m(2) and 1.5 mg/m(2)) and grade 3 hyponatremia in one patient (1.5 mg/m(2)). The most common grade 1/2 toxicities included nausea (60.9 %), fatigue (34.8 %), diaphoresis (34.8 %), anorexia (30.4 %) and constipation (26.1 %). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1. Conclusions This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily x 14 days and bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21-day cycle.
Details
- Title: Subtitle
- A phase I study of vorinostat in combination with bortezomib in patients with advanced malignancies
- Creators
- William R. Schelman - University of Wisconsin Carbone Cancer CenterAnne M. Traynor - University of Wisconsin Carbone Cancer CenterKyle D. Holen - University of Wisconsin Carbone Cancer CenterJill M. Kolesar - University of Wisconsin Carbone Cancer CenterSteven Attia - University of Wisconsin Carbone Cancer CenterTien Hoang - University of Wisconsin Carbone Cancer CenterJens Eickhoff - University of Wisconsin Carbone Cancer CenterZhisheng Jiang - University of Wisconsin Carbone Cancer CenterDona Alberti - University of Wisconsin Carbone Cancer CenterRebecca Marnocha - University of Wisconsin Carbone Cancer CenterJoel M. Reid - Mayo ClinicMatthew M. Ames - Mayo ClinicRenee M. McGovern - Mayo ClinicIgor Espinoza-Delgado - NCI, Clin Treatment Evaluat Program, Bethesda, MD 20892 USAJohn J. Wright - NCI, Clin Treatment Evaluat Program, Bethesda, MD 20892 USAGeorge Wilding - University of Wisconsin Carbone Cancer CenterHoward H. Bailey - University of Wisconsin Carbone Cancer Center
- Resource Type
- Journal article
- Publication Details
- Investigational new drugs, Vol.31(6), pp.1539-1546
- DOI
- 10.1007/s10637-013-0029-6
- PMID
- 24114121
- PMCID
- PMC3901262
- NLM abbreviation
- Invest New Drugs
- ISSN
- 0167-6997
- eISSN
- 1573-0646
- Publisher
- Springer Nature
- Number of pages
- 8
- Grant note
- U01CA069912 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) UL1TR000427 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) CTEP Translational Research Initiative 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. UL1RR025011 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) UO1 CA062491 / NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 1UL 1RR025011 / Clinical and Translational Science Award, National Center for Research Resources, NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA U01 CA69912 / Mayo Clinic
- Language
- English
- Date published
- 12/01/2013
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984695786002771
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