Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction: A National Cancer Institute Organ Dysfunction Working Group study

Suresh S. Ramalingam, Shivaani Kummar, John Sarantopoulos, Stephen Shibata, Patricia LoRusso, Mara Yerk, Julianne Holleran, Yan Lin, Jan H. Beumer, R. Donald Harvey, S. Percy Ivy, Chandra P. Belani, Merrill J. Egorin

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Abstract

Purpose: Vorinostat is the first US Food and Drug Administration-approved histone deacetylase inhibitor and is indicated for the treatment of refractory cutaneous T-cell lymphoma. We conducted a phase I study to determine the maximum-tolerated dose and pharmacokinetics of vorinostat in patients with hepatic dysfunction. Patients and Methods: Patients had solid malignancies and acceptable bone marrow and renal function. Hepatic dysfunction was categorized as mild, moderate, or severe by the National Cancer Institute Organ Dysfunction Working Group criteria. Fifteen patients with normal liver function were enrolled as controls. All patients received a single 400-mg dose of vorinostat for pharmacokinetic studies. One week later, daily vorinostat dosing was begun and continued until toxicity or disease progression occurred. The daily vorinostat dose was escalated within each hepatic dysfunction category. Vorinostat plasma concentrations were quantitated by a validated liquid chromatography-tandem mass spectrometry assay and modeled noncompartmentally. Results: Fifty-seven patients were enrolled (median age, 59 years; females, n = 24); 42 patients had hepatic dysfunction (16 mild, 15 moderate, and 11 severe). Eight of nine patients with dose-limiting toxicity had grade 4 thrombocytopenia. The recommended vorinostat doses in mild, moderate, and severe hepatic dysfunction were 300, 200, and 100 mg, respectively, on the daily continuous schedule. There were no significant differences in vorinostat pharmacokinetic parameters among the normal or hepatic dysfunction categories. Disease stabilization was noted in 12 patients. Of five patients with adenoid cystic carcinoma, one patient had a partial response, and four patients had stable disease. A patient with papillary thyroid carcinoma had stable disease for more than 2 years. Conclusion: Patients with varying degrees of hepatic dysfunction require appropriate dose reduction even though vorinostat pharmacokinetics are unaltered.

Original languageEnglish (US)
Pages (from-to)4507-4512
Number of pages6
JournalJournal of Clinical Oncology
Volume28
Issue number29
DOIs
StatePublished - Oct 10 2010

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National Cancer Institute (U.S.)
Liver
Neoplasms
Pharmacokinetics
vorinostat
Cutaneous T-Cell Lymphoma
Adenoid Cystic Carcinoma
Histone Deacetylase Inhibitors
Maximum Tolerated Dose
United States Food and Drug Administration
Tandem Mass Spectrometry
Liquid Chromatography
Disease Progression
Appointments and Schedules

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Ramalingam, Suresh S. ; Kummar, Shivaani ; Sarantopoulos, John ; Shibata, Stephen ; LoRusso, Patricia ; Yerk, Mara ; Holleran, Julianne ; Lin, Yan ; Beumer, Jan H. ; Harvey, R. Donald ; Ivy, S. Percy ; Belani, Chandra P. ; Egorin, Merrill J. / Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction : A National Cancer Institute Organ Dysfunction Working Group study. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 29. pp. 4507-4512.
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abstract = "Purpose: Vorinostat is the first US Food and Drug Administration-approved histone deacetylase inhibitor and is indicated for the treatment of refractory cutaneous T-cell lymphoma. We conducted a phase I study to determine the maximum-tolerated dose and pharmacokinetics of vorinostat in patients with hepatic dysfunction. Patients and Methods: Patients had solid malignancies and acceptable bone marrow and renal function. Hepatic dysfunction was categorized as mild, moderate, or severe by the National Cancer Institute Organ Dysfunction Working Group criteria. Fifteen patients with normal liver function were enrolled as controls. All patients received a single 400-mg dose of vorinostat for pharmacokinetic studies. One week later, daily vorinostat dosing was begun and continued until toxicity or disease progression occurred. The daily vorinostat dose was escalated within each hepatic dysfunction category. Vorinostat plasma concentrations were quantitated by a validated liquid chromatography-tandem mass spectrometry assay and modeled noncompartmentally. Results: Fifty-seven patients were enrolled (median age, 59 years; females, n = 24); 42 patients had hepatic dysfunction (16 mild, 15 moderate, and 11 severe). Eight of nine patients with dose-limiting toxicity had grade 4 thrombocytopenia. The recommended vorinostat doses in mild, moderate, and severe hepatic dysfunction were 300, 200, and 100 mg, respectively, on the daily continuous schedule. There were no significant differences in vorinostat pharmacokinetic parameters among the normal or hepatic dysfunction categories. Disease stabilization was noted in 12 patients. Of five patients with adenoid cystic carcinoma, one patient had a partial response, and four patients had stable disease. A patient with papillary thyroid carcinoma had stable disease for more than 2 years. Conclusion: Patients with varying degrees of hepatic dysfunction require appropriate dose reduction even though vorinostat pharmacokinetics are unaltered.",
author = "Ramalingam, {Suresh S.} and Shivaani Kummar and John Sarantopoulos and Stephen Shibata and Patricia LoRusso and Mara Yerk and Julianne Holleran and Yan Lin and Beumer, {Jan H.} and Harvey, {R. Donald} and Ivy, {S. Percy} and Belani, {Chandra P.} and Egorin, {Merrill J.}",
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Ramalingam, SS, Kummar, S, Sarantopoulos, J, Shibata, S, LoRusso, P, Yerk, M, Holleran, J, Lin, Y, Beumer, JH, Harvey, RD, Ivy, SP, Belani, CP & Egorin, MJ 2010, 'Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction: A National Cancer Institute Organ Dysfunction Working Group study', Journal of Clinical Oncology, vol. 28, no. 29, pp. 4507-4512. https://doi.org/10.1200/JCO.2010.30.2307

Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction : A National Cancer Institute Organ Dysfunction Working Group study. / Ramalingam, Suresh S.; Kummar, Shivaani; Sarantopoulos, John; Shibata, Stephen; LoRusso, Patricia; Yerk, Mara; Holleran, Julianne; Lin, Yan; Beumer, Jan H.; Harvey, R. Donald; Ivy, S. Percy; Belani, Chandra P.; Egorin, Merrill J.

In: Journal of Clinical Oncology, Vol. 28, No. 29, 10.10.2010, p. 4507-4512.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction

T2 - A National Cancer Institute Organ Dysfunction Working Group study

AU - Ramalingam, Suresh S.

AU - Kummar, Shivaani

AU - Sarantopoulos, John

AU - Shibata, Stephen

AU - LoRusso, Patricia

AU - Yerk, Mara

AU - Holleran, Julianne

AU - Lin, Yan

AU - Beumer, Jan H.

AU - Harvey, R. Donald

AU - Ivy, S. Percy

AU - Belani, Chandra P.

AU - Egorin, Merrill J.

PY - 2010/10/10

Y1 - 2010/10/10

N2 - Purpose: Vorinostat is the first US Food and Drug Administration-approved histone deacetylase inhibitor and is indicated for the treatment of refractory cutaneous T-cell lymphoma. We conducted a phase I study to determine the maximum-tolerated dose and pharmacokinetics of vorinostat in patients with hepatic dysfunction. Patients and Methods: Patients had solid malignancies and acceptable bone marrow and renal function. Hepatic dysfunction was categorized as mild, moderate, or severe by the National Cancer Institute Organ Dysfunction Working Group criteria. Fifteen patients with normal liver function were enrolled as controls. All patients received a single 400-mg dose of vorinostat for pharmacokinetic studies. One week later, daily vorinostat dosing was begun and continued until toxicity or disease progression occurred. The daily vorinostat dose was escalated within each hepatic dysfunction category. Vorinostat plasma concentrations were quantitated by a validated liquid chromatography-tandem mass spectrometry assay and modeled noncompartmentally. Results: Fifty-seven patients were enrolled (median age, 59 years; females, n = 24); 42 patients had hepatic dysfunction (16 mild, 15 moderate, and 11 severe). Eight of nine patients with dose-limiting toxicity had grade 4 thrombocytopenia. The recommended vorinostat doses in mild, moderate, and severe hepatic dysfunction were 300, 200, and 100 mg, respectively, on the daily continuous schedule. There were no significant differences in vorinostat pharmacokinetic parameters among the normal or hepatic dysfunction categories. Disease stabilization was noted in 12 patients. Of five patients with adenoid cystic carcinoma, one patient had a partial response, and four patients had stable disease. A patient with papillary thyroid carcinoma had stable disease for more than 2 years. Conclusion: Patients with varying degrees of hepatic dysfunction require appropriate dose reduction even though vorinostat pharmacokinetics are unaltered.

AB - Purpose: Vorinostat is the first US Food and Drug Administration-approved histone deacetylase inhibitor and is indicated for the treatment of refractory cutaneous T-cell lymphoma. We conducted a phase I study to determine the maximum-tolerated dose and pharmacokinetics of vorinostat in patients with hepatic dysfunction. Patients and Methods: Patients had solid malignancies and acceptable bone marrow and renal function. Hepatic dysfunction was categorized as mild, moderate, or severe by the National Cancer Institute Organ Dysfunction Working Group criteria. Fifteen patients with normal liver function were enrolled as controls. All patients received a single 400-mg dose of vorinostat for pharmacokinetic studies. One week later, daily vorinostat dosing was begun and continued until toxicity or disease progression occurred. The daily vorinostat dose was escalated within each hepatic dysfunction category. Vorinostat plasma concentrations were quantitated by a validated liquid chromatography-tandem mass spectrometry assay and modeled noncompartmentally. Results: Fifty-seven patients were enrolled (median age, 59 years; females, n = 24); 42 patients had hepatic dysfunction (16 mild, 15 moderate, and 11 severe). Eight of nine patients with dose-limiting toxicity had grade 4 thrombocytopenia. The recommended vorinostat doses in mild, moderate, and severe hepatic dysfunction were 300, 200, and 100 mg, respectively, on the daily continuous schedule. There were no significant differences in vorinostat pharmacokinetic parameters among the normal or hepatic dysfunction categories. Disease stabilization was noted in 12 patients. Of five patients with adenoid cystic carcinoma, one patient had a partial response, and four patients had stable disease. A patient with papillary thyroid carcinoma had stable disease for more than 2 years. Conclusion: Patients with varying degrees of hepatic dysfunction require appropriate dose reduction even though vorinostat pharmacokinetics are unaltered.

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JF - Journal of Clinical Oncology

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