Phase i and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301

Antonius A. Miller, Daryl J. Murry, Kouros Owzar, Donna R. Hollis, Erin B. Kennedy, Ghassan Abou-Alfa, Apurva Desai, Jimmy Hwang, Miguel A. Villalona-Calero, E. Claire Dees, Lionel D. Lewis, Marwan G. Fakih, Martin J. Edelman, Fred Millard, Richard C. Frank, Raymond J. Hohl, Mark J. Ratain

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1800-1805
Number of pages6
JournalJournal of Clinical Oncology
Volume27
Issue number11
DOIs
StatePublished - Apr 10 2009

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Pharmacokinetics
Bilirubin
Kidney
Liver
Creatinine
sorafenib
Renal Dialysis
Albumins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Miller, A. A., Murry, D. J., Owzar, K., Hollis, D. R., Kennedy, E. B., Abou-Alfa, G., ... Ratain, M. J. (2009). Phase i and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. Journal of Clinical Oncology, 27(11), 1800-1805. https://doi.org/10.1200/JCO.2008.20.0931
Miller, Antonius A. ; Murry, Daryl J. ; Owzar, Kouros ; Hollis, Donna R. ; Kennedy, Erin B. ; Abou-Alfa, Ghassan ; Desai, Apurva ; Hwang, Jimmy ; Villalona-Calero, Miguel A. ; Dees, E. Claire ; Lewis, Lionel D. ; Fakih, Marwan G. ; Edelman, Martin J. ; Millard, Fred ; Frank, Richard C. ; Hohl, Raymond J. ; Ratain, Mark J. / Phase i and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction : CALGB 60301. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 11. pp. 1800-1805.
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title = "Phase i and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301",
abstract = "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.",
author = "Miller, {Antonius A.} and Murry, {Daryl J.} and Kouros Owzar and Hollis, {Donna R.} and Kennedy, {Erin B.} and Ghassan Abou-Alfa and Apurva Desai and Jimmy Hwang and Villalona-Calero, {Miguel A.} and Dees, {E. Claire} and Lewis, {Lionel D.} and Fakih, {Marwan G.} and Edelman, {Martin J.} and Fred Millard and Frank, {Richard C.} and Hohl, {Raymond J.} and Ratain, {Mark J.}",
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Miller, AA, Murry, DJ, Owzar, K, Hollis, DR, Kennedy, EB, Abou-Alfa, G, Desai, A, Hwang, J, Villalona-Calero, MA, Dees, EC, Lewis, LD, Fakih, MG, Edelman, MJ, Millard, F, Frank, RC, Hohl, RJ & Ratain, MJ 2009, 'Phase i and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301', Journal of Clinical Oncology, vol. 27, no. 11, pp. 1800-1805. https://doi.org/10.1200/JCO.2008.20.0931

Phase i and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction : CALGB 60301. / Miller, Antonius A.; Murry, Daryl J.; Owzar, Kouros; Hollis, Donna R.; Kennedy, Erin B.; Abou-Alfa, Ghassan; Desai, Apurva; Hwang, Jimmy; Villalona-Calero, Miguel A.; Dees, E. Claire; Lewis, Lionel D.; Fakih, Marwan G.; Edelman, Martin J.; Millard, Fred; Frank, Richard C.; Hohl, Raymond J.; Ratain, Mark J.

In: Journal of Clinical Oncology, Vol. 27, No. 11, 10.04.2009, p. 1800-1805.

Research output: Contribution to journalArticle

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T1 - Phase i and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction

T2 - CALGB 60301

AU - Miller, Antonius A.

AU - Murry, Daryl J.

AU - Owzar, Kouros

AU - Hollis, Donna R.

AU - Kennedy, Erin B.

AU - Abou-Alfa, Ghassan

AU - Desai, Apurva

AU - Hwang, Jimmy

AU - Villalona-Calero, Miguel A.

AU - Dees, E. Claire

AU - Lewis, Lionel D.

AU - Fakih, Marwan G.

AU - Edelman, Martin J.

AU - Millard, Fred

AU - Frank, Richard C.

AU - Hohl, Raymond J.

AU - Ratain, Mark J.

PY - 2009/4/10

Y1 - 2009/4/10

N2 - 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.

AB - 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.

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