A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation: CALGB 9863

A. P. Venook, C. Enders Klein, G. Fleming, D. Hollis, C. G. Leichman, Raymond Hohl, J. Byrd, D. Budman, M. Villalona, J. Marshall, G. L. Rosner, J. Ramirez, H. Kastrissios, M. J. Ratain

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Abstract

Background: To ascertain if hepatic or renal dysfunction or prior pelvic radiation (XRT) leads to increased toxicity at a given dose of irinotecan and to characterize the pharmacokinetics of irinotecan and its major metabolites in patients with hepatic or renal dysfunction. Patients and methods: Adults with tumors appropriate for irinotecan therapy and who had abnormal liver or renal function tests or had prior radiation to the pelvis were eligible. Patients were assigned to one of four treatment cohorts: I, aspartate aminotransferase (AST) ≥3x upper limit of normal and direct bilirubin <1.0 mg/dl; II, direct bilirubin 1.0-7.0 mg/dl; III, creatinine 1.6-5.0 mg/dl with normal liver function; IV, prior pelvic XRT with normal liver and renal function. Starting with reduced doses of either 145 or 225 mg/m2, irinotecan was administered every 3 weeks to at least three patients within each cohort. Irinotecan and its metabolites in the blood were measured in all patients. Results: Thirty-five patients were evaluable for toxicity. No dose-limiting toxicity was seen in cohort I, although only three patients were treated and at a dose of 225 mg/m2. Patients with elevations of direct bilirubin had dose-limiting toxicities, even though the starting dose was 145 mg/m2. These same patients appeared to have comparable exposure to the active metabolite SN-38 as normal patients treated with full-dose irinotecan. Patients with elevations of creatinine or with prior pelvic radiotherapy did not appear to have increased risk of toxicity at the doses explored in this study. Conclusions: Patients with elevated bilirubin treated with irinotecan have an increased risk of toxicity and a dose reduction is recommended. Patients with elevated AST, creatinine or prior pelvic radiation do not appear to have increased sensitivity to irinotecan, but the data are not adequate to support a specific dosing recommendation.

Original languageEnglish (US)
Pages (from-to)1783-1790
Number of pages8
JournalAnnals of Oncology
Volume14
Issue number12
DOIs
StatePublished - Dec 1 2003

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irinotecan
Pharmacokinetics
Radiation
Kidney
Liver
Bilirubin
Creatinine
Aspartate Aminotransferases

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

Cite this

Venook, A. P. ; Klein, C. Enders ; Fleming, G. ; Hollis, D. ; Leichman, C. G. ; Hohl, Raymond ; Byrd, J. ; Budman, D. ; Villalona, M. ; Marshall, J. ; Rosner, G. L. ; Ramirez, J. ; Kastrissios, H. ; Ratain, M. J. / A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation : CALGB 9863. In: Annals of Oncology. 2003 ; Vol. 14, No. 12. pp. 1783-1790.
@article{c532f63d6f91409c904032e2c38aad41,
title = "A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation: CALGB 9863",
abstract = "Background: To ascertain if hepatic or renal dysfunction or prior pelvic radiation (XRT) leads to increased toxicity at a given dose of irinotecan and to characterize the pharmacokinetics of irinotecan and its major metabolites in patients with hepatic or renal dysfunction. Patients and methods: Adults with tumors appropriate for irinotecan therapy and who had abnormal liver or renal function tests or had prior radiation to the pelvis were eligible. Patients were assigned to one of four treatment cohorts: I, aspartate aminotransferase (AST) ≥3x upper limit of normal and direct bilirubin <1.0 mg/dl; II, direct bilirubin 1.0-7.0 mg/dl; III, creatinine 1.6-5.0 mg/dl with normal liver function; IV, prior pelvic XRT with normal liver and renal function. Starting with reduced doses of either 145 or 225 mg/m2, irinotecan was administered every 3 weeks to at least three patients within each cohort. Irinotecan and its metabolites in the blood were measured in all patients. Results: Thirty-five patients were evaluable for toxicity. No dose-limiting toxicity was seen in cohort I, although only three patients were treated and at a dose of 225 mg/m2. Patients with elevations of direct bilirubin had dose-limiting toxicities, even though the starting dose was 145 mg/m2. These same patients appeared to have comparable exposure to the active metabolite SN-38 as normal patients treated with full-dose irinotecan. Patients with elevations of creatinine or with prior pelvic radiotherapy did not appear to have increased risk of toxicity at the doses explored in this study. Conclusions: Patients with elevated bilirubin treated with irinotecan have an increased risk of toxicity and a dose reduction is recommended. Patients with elevated AST, creatinine or prior pelvic radiation do not appear to have increased sensitivity to irinotecan, but the data are not adequate to support a specific dosing recommendation.",
author = "Venook, {A. P.} and Klein, {C. Enders} and G. Fleming and D. Hollis and Leichman, {C. G.} and Raymond Hohl and J. Byrd and D. Budman and M. Villalona and J. Marshall and Rosner, {G. L.} and J. Ramirez and H. Kastrissios and Ratain, {M. J.}",
year = "2003",
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Venook, AP, Klein, CE, Fleming, G, Hollis, D, Leichman, CG, Hohl, R, Byrd, J, Budman, D, Villalona, M, Marshall, J, Rosner, GL, Ramirez, J, Kastrissios, H & Ratain, MJ 2003, 'A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation: CALGB 9863', Annals of Oncology, vol. 14, no. 12, pp. 1783-1790. https://doi.org/10.1093/annonc/mdg493

A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation : CALGB 9863. / Venook, A. P.; Klein, C. Enders; Fleming, G.; Hollis, D.; Leichman, C. G.; Hohl, Raymond; Byrd, J.; Budman, D.; Villalona, M.; Marshall, J.; Rosner, G. L.; Ramirez, J.; Kastrissios, H.; Ratain, M. J.

In: Annals of Oncology, Vol. 14, No. 12, 01.12.2003, p. 1783-1790.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation

T2 - CALGB 9863

AU - Venook, A. P.

AU - Klein, C. Enders

AU - Fleming, G.

AU - Hollis, D.

AU - Leichman, C. G.

AU - Hohl, Raymond

AU - Byrd, J.

AU - Budman, D.

AU - Villalona, M.

AU - Marshall, J.

AU - Rosner, G. L.

AU - Ramirez, J.

AU - Kastrissios, H.

AU - Ratain, M. J.

PY - 2003/12/1

Y1 - 2003/12/1

N2 - Background: To ascertain if hepatic or renal dysfunction or prior pelvic radiation (XRT) leads to increased toxicity at a given dose of irinotecan and to characterize the pharmacokinetics of irinotecan and its major metabolites in patients with hepatic or renal dysfunction. Patients and methods: Adults with tumors appropriate for irinotecan therapy and who had abnormal liver or renal function tests or had prior radiation to the pelvis were eligible. Patients were assigned to one of four treatment cohorts: I, aspartate aminotransferase (AST) ≥3x upper limit of normal and direct bilirubin <1.0 mg/dl; II, direct bilirubin 1.0-7.0 mg/dl; III, creatinine 1.6-5.0 mg/dl with normal liver function; IV, prior pelvic XRT with normal liver and renal function. Starting with reduced doses of either 145 or 225 mg/m2, irinotecan was administered every 3 weeks to at least three patients within each cohort. Irinotecan and its metabolites in the blood were measured in all patients. Results: Thirty-five patients were evaluable for toxicity. No dose-limiting toxicity was seen in cohort I, although only three patients were treated and at a dose of 225 mg/m2. Patients with elevations of direct bilirubin had dose-limiting toxicities, even though the starting dose was 145 mg/m2. These same patients appeared to have comparable exposure to the active metabolite SN-38 as normal patients treated with full-dose irinotecan. Patients with elevations of creatinine or with prior pelvic radiotherapy did not appear to have increased risk of toxicity at the doses explored in this study. Conclusions: Patients with elevated bilirubin treated with irinotecan have an increased risk of toxicity and a dose reduction is recommended. Patients with elevated AST, creatinine or prior pelvic radiation do not appear to have increased sensitivity to irinotecan, but the data are not adequate to support a specific dosing recommendation.

AB - Background: To ascertain if hepatic or renal dysfunction or prior pelvic radiation (XRT) leads to increased toxicity at a given dose of irinotecan and to characterize the pharmacokinetics of irinotecan and its major metabolites in patients with hepatic or renal dysfunction. Patients and methods: Adults with tumors appropriate for irinotecan therapy and who had abnormal liver or renal function tests or had prior radiation to the pelvis were eligible. Patients were assigned to one of four treatment cohorts: I, aspartate aminotransferase (AST) ≥3x upper limit of normal and direct bilirubin <1.0 mg/dl; II, direct bilirubin 1.0-7.0 mg/dl; III, creatinine 1.6-5.0 mg/dl with normal liver function; IV, prior pelvic XRT with normal liver and renal function. Starting with reduced doses of either 145 or 225 mg/m2, irinotecan was administered every 3 weeks to at least three patients within each cohort. Irinotecan and its metabolites in the blood were measured in all patients. Results: Thirty-five patients were evaluable for toxicity. No dose-limiting toxicity was seen in cohort I, although only three patients were treated and at a dose of 225 mg/m2. Patients with elevations of direct bilirubin had dose-limiting toxicities, even though the starting dose was 145 mg/m2. These same patients appeared to have comparable exposure to the active metabolite SN-38 as normal patients treated with full-dose irinotecan. Patients with elevations of creatinine or with prior pelvic radiotherapy did not appear to have increased risk of toxicity at the doses explored in this study. Conclusions: Patients with elevated bilirubin treated with irinotecan have an increased risk of toxicity and a dose reduction is recommended. Patients with elevated AST, creatinine or prior pelvic radiation do not appear to have increased sensitivity to irinotecan, but the data are not adequate to support a specific dosing recommendation.

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U2 - 10.1093/annonc/mdg493

DO - 10.1093/annonc/mdg493

M3 - Article

C2 - 14630685

AN - SCOPUS:9144256327

VL - 14

SP - 1783

EP - 1790

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 12

ER -