Originally published as JCO Early Release 10.1200/JCO.2008.20.0931 on March 2 2009

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Phase I and Pharmacokinetic Study of Sorafenib in Patients With Hepatic or Renal Dysfunction: CALGB 60301

From the Wake Forest University School of Medicine, Winston-Salem; Department of Biostatistics and Bioinformatics, and Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham; University of North Carolina, Chapel Hill, NC; University of Iowa College of Pharmacy; University of Iowa Hospitals, Iowa City, IA; Memorial Sloan-Kettering Cancer Center, New York; Roswell Park Cancer Institute, Buffalo, NY; University of Chicago Medical Center, Chicago, IL; Georgetown University Medical Center, Washington, DC; Ohio State University Medical Center, Columbus, OH; Dartmouth Medical School, Lebanon, NH; University of Maryland Cancer Center, Baltimore, MD; University of California, San Diego, CA; and Whittingham Cancer Center, Norwalk, CT.

Corresponding author: Antonius A. Miller, MD, Comprehensive Cancer Center of Wake Forest University, Medical Center Blvd, Winston-Salem, NC; e-mail: aamiller{at}wfubmc.edu.

Purpose We sought to characterize the pharmacokinetics (PK) and determine a tolerable dose of oral sorafenib in patients with hepatic or renal dysfunction.

Patients and Methods Patients were assigned to one of nine cohorts: cohort 1, bilirubin upper limit of normal (ULN) and AST ULN and creatinine clearance (CC) 60 mL/min; cohort 2, bilirubin more than ULN but 1.5x ULN and/or AST more than ULN; cohort 3, CC between 40 and 59 mL/min; cohort 4, bilirubin more than 1.5x ULN to 3x ULN (any AST); cohort 5, CC between 20 and 39 mL/min; cohort 6, bilirubin more than 3x ULN to 10x ULN (any AST); cohort 7, CC less than 20 mL/min; cohort 8, albumin less than 2.5 mg/dL (any bilirubin/AST); and cohort 9, hemodialysis. Sorafenib was administered as a 400-mg dose on day 1 for PK, and continuous daily dosing started on day 8.

Results Of 150 registered patients, 138 patients were treated. With the exception of cohorts 6 and 7, at least 12 patients per cohort were assessable, and the dose level with prospectively defined dose-limiting toxicity in less than one third of patients by day 29 was considered tolerable. No significant associations between the sorafenib PK and cohort were found.

Conclusion We recommend the following empiric sorafenib starting doses by cohort: cohort 1, 400 mg twice a day; cohort 2, 400 mg twice a day; cohort 3, 400 mg twice a day; cohort 4, 200 mg twice a day; cohort 5, 200 mg twice a day; cohort 6, not even 200 mg every third day tolerable; cohort 7, not defined; cohort 8, 200 mg each day; and cohort 9, 200 mg each day.

Written on behalf of the Cancer and Leukemia Group B.

Supported by National Cancer Institute Grants No. CA31946 (to the Cancer and Leukemia Group B; Richard L. Schilsky, MD, Chair), CA33601 (to the CALGB Statistical Center; Stephen George, PhD), CA77651, CA41287, CA77597, CA03927, CA47559, CA04326, CA02599, CA77658, CA31983, CA11789, CA47642, and CA47577.

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on JCO.org.

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