Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301.
OBJECTIVE
We sought to characterize the pharmacokinetics (PK) and determine a tolerable dose of oral sorafenib in patients with hepatic or renal dysfunction.


METHODS
Patients were assigned to one of nine cohorts: cohort 1, bilirubin < or = upper limit of normal (ULN) and AST < or = ULN and creatinine clearance (CC) > or = 60 mL/min; cohort 2, bilirubin more than ULN but < or = 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 < or = 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.


CONCLUSIONS
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.
Miller
Antonius A
AA
Comprehensive Cancer Center of Wake Forest University, Wake Forest University School of Medicine, Winston-Salem, NC, USA. aamiller@wfubmc.edu
Murry
Daryl J
DJ
Owzar
Kouros
K
Hollis
Donna R
DR
Kennedy
Erin B
EB
Abou-Alfa
Ghassan
G
Desai
Apurva
A
Hwang
Jimmy
J
Villalona-Calero
Miguel A
MA
Dees
E Claire
EC
Lewis
Lionel D
LD
Fakih
Marwan G
MG
Edelman
Martin J
MJ
Millard
Fred
F
Frank
Richard C
RC
Hohl
Raymond J
RJ
Ratain
Mark J
MJ
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D048550:Hepatic Insufficiency / Q000150:complications*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051437:Renal Insufficiency / Q000150:complications*; D000077157:Sorafenib; D016896:Treatment Outcome; D055815:Young Adult
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib