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Phase I Study of Sorafenib and Vorinostat in Advanced Hepatocellular Carcinoma

Gordon, Sarah W. DO*,†; McGuire, William P. III MD*,†; Shafer, Danielle A. DO*,†; Sterling, Richard K. MD; Lee, Hannah M. MD; Matherly, Scott C. MD; Roberts, John D. MD§; Bose, Prithviraj MD; Tombes, Mary B. ANP*,†; Shrader, E. Ellen MS*; Ryan, Alison A. ANP*,†; Kmieciak, Maciej PhD*; Nguyen, Tri PhD*; Deng, Xiaoyan MS; Bandyopadhyay, Dipankar PhD; Dent, Paul PhD*,#; Poklepovic, Andrew S. MD*,†

American Journal of Clinical Oncology: August 2019 - Volume 42 - Issue 8 - p 649–654
doi: 10.1097/COC.0000000000000567
Original Articles: Gastrointestinal

Objectives: Preclinical data suggest histone deacetylase inhibitors improve the therapeutic index of sorafenib. A phase I study was initiated to establish the recommended phase 2 dose of sorafenib combined with vorinostat in patients with unresectable hepatocellular carcinoma.

Materials and Methods: Patients received vorinostat (200 to 400 mg by mouth once daily, 5 of 7 d) and sorafenib at standard or reduced doses (400 mg [cohort A] or 200 mg [cohort B] by mouth twice daily). Patients who received 14 days of vorinostat in cycle 1 were evaluable for dose-limiting toxicity (DLT).

Results: Sixteen patients were treated. Thirteen patients were evaluable for response. Three patients experienced DLTs, 2 in cohort A (grade [gr] 3 hypokalemia; gr 3 maculopapular rash) and 1 in cohort B (gr 3 hepatic failure; gr 3 hypophosphatemia; gr 4 thrombocytopenia). Eleven patients required dose reductions or omissions for non-DLTtoxicity. Ten patients (77%) had stable disease (SD). The median treatment duration was 4.7 months for response-evaluable patients. One patient with SD was on treatment for 29.9 months, and another patient, also with SD, was on treatment for 18.7 months. Another patient electively stopped therapy after 15 months and remains without evidence of progression 3 years later.

Conclusions: Although some patients had durable disease control, the addition of vorinostat to sorafenib led to toxicities in most patients, requiring dose modifications that prevented determination of the recommended phase 2 dose. The combination is not recommended for further exploration with this vorinostat schedule in this patient population.

Departments of *Internal Medicine, Massey Cancer Center


#Biochemistry and Molecular Biology

Division of Hematology, Oncology, and Palliative Care

Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, VA

§Yale Cancer Center, Yale University, New Haven, CT

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

Supported by grants from the National Cancer Institute at the National Institutes of Health by (P30CA016059 [Cancer Center Support Grant to Massey Cancer Center]), a research grant from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK052825 [P.D.]), and in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, or Merck Sharp & Dohme Corp. For the CTC analysis, Flow Cytometry services using Amnis ImageStreamX Mark II in support of the project were provided by the VCU Massey Cancer Center Flow Cytometry Shared Resource, supported, in part, with funding from NIH-NCI Cancer Center Support Grant (P30 CA016059).

The authors declare no conflicts of interest.

Reprints: Sarah W. Gordon, DO, Department of Internal Medicine, Division of Hematology, Oncology, and Palliative Care, Virginia Commonwealth University, P.O. Box 980070, 1201 E. Marshall Street, Richmond, VA 23298-0070. E-mail:

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