Phase i pharmacokinetic and pharmacodynamic study of cetuximab, irinotecan and sorafenib in advanced colorectal cancer

Nilofer Azad; Arvind Dasari; John Arcaroli; Gretchen E. Taylor; Daniel A. Laheru; Michael A. Carducci; Martine McManus; Kevin Quackenbush; John J. Wright; Manuel Hidalgo; Luis A. Diaz; Ross C. Donehower; Ming Zhao; Michelle A. Rudek; Wells A. Messersmith

doi:10.1007/s10637-012-9820-z

Phase i pharmacokinetic and pharmacodynamic study of cetuximab, irinotecan and sorafenib in advanced colorectal cancer

Nilofer Azad, Arvind Dasari, John Arcaroli, Gretchen E. Taylor, Daniel A. Laheru, Michael A. Carducci, Martine McManus, Kevin Quackenbush, John J. Wright, Manuel Hidalgo, Luis A. Diaz, Ross C. Donehower, Ming Zhao, Michelle A. Rudek, Wells A. Messersmith

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

Summary: Background This phase Ib study was designed to determine the maximum tolerated doses (MTD) and dose limiting toxicities (DLTs) of irinotecan and cetuximab with sorafenib. Secondary objectives included characterizing the pharmacokinetics and pharmacodynamics and evaluating preliminary antitumor activity in patients with advanced colorectal cancer (CRC). Methods Patients with metastatic, pretreated CRC were treated at five dose levels. Results Eighteen patients were recruited with median age 56.5 years. In the first five patients treated, 2 irinotecan related DLTs were observed. With reduced dose intensity irinotecan, there were no further DLTs. The most common toxicities were diarrhea, nausea/vomiting, fatigue, anorexia and rash. DLTs included neutropenia and thrombocytopenia. Two patients had partial responses (one with a KRAS mutation) and 8 had stable disease (8-36 weeks). The median progression free survival (PFS) and overall survival (OS) were 2.5 and 4.7 months respectively. Pharmacokinetic analyses suggest sorafenib and metabolite exposure correlate with OS and DLTs. Conclusions The recommended phase II dose (RP2D) is irinotecan 100 mg/m² i.v. days 1, 8; cetuximab 400 mg/m² i.v. days 1 and 250 mg/m² i.v. weekly; and sorafenib 400 mg orally twice daily in advanced, pretreated CRC. The combination resulted in a modest response rate.

Original language	English (US)
Pages (from-to)	345-354
Number of pages	10
Journal	Investigational New Drugs
Volume	31
Issue number	2
DOIs	https://doi.org/10.1007/s10637-012-9820-z
State	Published - Apr 2013
Externally published	Yes

Keywords

Cetuximab
Colorectal cancer
Irinotecan
Pharmacokinetics
Sorafenib

ASJC Scopus subject areas

Oncology
Pharmacology
Pharmacology (medical)

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10.1007/s10637-012-9820-z

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Azad, N., Dasari, A., Arcaroli, J., Taylor, G. E., Laheru, D. A., Carducci, M. A., McManus, M., Quackenbush, K., Wright, J. J., Hidalgo, M., Diaz, L. A., Donehower, R. C., Zhao, M., Rudek, M. A., & Messersmith, W. A. (2013). Phase i pharmacokinetic and pharmacodynamic study of cetuximab, irinotecan and sorafenib in advanced colorectal cancer. Investigational New Drugs, 31(2), 345-354. https://doi.org/10.1007/s10637-012-9820-z

Azad, N, Dasari, A, Arcaroli, J, Taylor, GE, Laheru, DA, Carducci, MA, McManus, M, Quackenbush, K, Wright, JJ, Hidalgo, M, Diaz, LA, Donehower, RC, Zhao, M, Rudek, MA & Messersmith, WA 2013, 'Phase i pharmacokinetic and pharmacodynamic study of cetuximab, irinotecan and sorafenib in advanced colorectal cancer', Investigational New Drugs, vol. 31, no. 2, pp. 345-354. https://doi.org/10.1007/s10637-012-9820-z

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title = "Phase i pharmacokinetic and pharmacodynamic study of cetuximab, irinotecan and sorafenib in advanced colorectal cancer",

abstract = "Summary: Background This phase Ib study was designed to determine the maximum tolerated doses (MTD) and dose limiting toxicities (DLTs) of irinotecan and cetuximab with sorafenib. Secondary objectives included characterizing the pharmacokinetics and pharmacodynamics and evaluating preliminary antitumor activity in patients with advanced colorectal cancer (CRC). Methods Patients with metastatic, pretreated CRC were treated at five dose levels. Results Eighteen patients were recruited with median age 56.5 years. In the first five patients treated, 2 irinotecan related DLTs were observed. With reduced dose intensity irinotecan, there were no further DLTs. The most common toxicities were diarrhea, nausea/vomiting, fatigue, anorexia and rash. DLTs included neutropenia and thrombocytopenia. Two patients had partial responses (one with a KRAS mutation) and 8 had stable disease (8-36 weeks). The median progression free survival (PFS) and overall survival (OS) were 2.5 and 4.7 months respectively. Pharmacokinetic analyses suggest sorafenib and metabolite exposure correlate with OS and DLTs. Conclusions The recommended phase II dose (RP2D) is irinotecan 100 mg/m2 i.v. days 1, 8; cetuximab 400 mg/m2 i.v. days 1 and 250 mg/m2 i.v. weekly; and sorafenib 400 mg orally twice daily in advanced, pretreated CRC. The combination resulted in a modest response rate.",

keywords = "Cetuximab, Colorectal cancer, Irinotecan, Pharmacokinetics, Sorafenib",

author = "Nilofer Azad and Arvind Dasari and John Arcaroli and Taylor, {Gretchen E.} and Laheru, {Daniel A.} and Carducci, {Michael A.} and Martine McManus and Kevin Quackenbush and Wright, {John J.} and Manuel Hidalgo and Diaz, {Luis A.} and Donehower, {Ross C.} and Ming Zhao and Rudek, {Michelle A.} and Messersmith, {Wells A.}",

note = "Funding Information: This research was supported by NIH/NCI grant 1K23CA115500 (WM), 1R21CA117125 (WM), U01 CA070095 (MC), and the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 RR025005). This publication was made possible by Grant Number UL1RR025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Funding Information: Disclosure of potential conflicts of interest Dr. Messersmith has received commercial clinical research grant support from Bayer (major) via University of Colorado Cancer Center.",

year = "2013",

month = apr,

doi = "10.1007/s10637-012-9820-z",

language = "English (US)",

volume = "31",

pages = "345--354",

journal = "Investigational New Drugs",

issn = "0167-6997",

publisher = "Kluwer Academic Publishers",

number = "2",

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TY - JOUR

T1 - Phase i pharmacokinetic and pharmacodynamic study of cetuximab, irinotecan and sorafenib in advanced colorectal cancer

AU - Azad, Nilofer

AU - Dasari, Arvind

AU - Arcaroli, John

AU - Taylor, Gretchen E.

AU - Laheru, Daniel A.

AU - Carducci, Michael A.

AU - McManus, Martine

AU - Quackenbush, Kevin

AU - Wright, John J.

AU - Hidalgo, Manuel

AU - Diaz, Luis A.

AU - Donehower, Ross C.

AU - Zhao, Ming

AU - Rudek, Michelle A.

AU - Messersmith, Wells A.

N1 - Funding Information: This research was supported by NIH/NCI grant 1K23CA115500 (WM), 1R21CA117125 (WM), U01 CA070095 (MC), and the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 RR025005). This publication was made possible by Grant Number UL1RR025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Funding Information: Disclosure of potential conflicts of interest Dr. Messersmith has received commercial clinical research grant support from Bayer (major) via University of Colorado Cancer Center.

PY - 2013/4

Y1 - 2013/4

N2 - Summary: Background This phase Ib study was designed to determine the maximum tolerated doses (MTD) and dose limiting toxicities (DLTs) of irinotecan and cetuximab with sorafenib. Secondary objectives included characterizing the pharmacokinetics and pharmacodynamics and evaluating preliminary antitumor activity in patients with advanced colorectal cancer (CRC). Methods Patients with metastatic, pretreated CRC were treated at five dose levels. Results Eighteen patients were recruited with median age 56.5 years. In the first five patients treated, 2 irinotecan related DLTs were observed. With reduced dose intensity irinotecan, there were no further DLTs. The most common toxicities were diarrhea, nausea/vomiting, fatigue, anorexia and rash. DLTs included neutropenia and thrombocytopenia. Two patients had partial responses (one with a KRAS mutation) and 8 had stable disease (8-36 weeks). The median progression free survival (PFS) and overall survival (OS) were 2.5 and 4.7 months respectively. Pharmacokinetic analyses suggest sorafenib and metabolite exposure correlate with OS and DLTs. Conclusions The recommended phase II dose (RP2D) is irinotecan 100 mg/m2 i.v. days 1, 8; cetuximab 400 mg/m2 i.v. days 1 and 250 mg/m2 i.v. weekly; and sorafenib 400 mg orally twice daily in advanced, pretreated CRC. The combination resulted in a modest response rate.

AB - Summary: Background This phase Ib study was designed to determine the maximum tolerated doses (MTD) and dose limiting toxicities (DLTs) of irinotecan and cetuximab with sorafenib. Secondary objectives included characterizing the pharmacokinetics and pharmacodynamics and evaluating preliminary antitumor activity in patients with advanced colorectal cancer (CRC). Methods Patients with metastatic, pretreated CRC were treated at five dose levels. Results Eighteen patients were recruited with median age 56.5 years. In the first five patients treated, 2 irinotecan related DLTs were observed. With reduced dose intensity irinotecan, there were no further DLTs. The most common toxicities were diarrhea, nausea/vomiting, fatigue, anorexia and rash. DLTs included neutropenia and thrombocytopenia. Two patients had partial responses (one with a KRAS mutation) and 8 had stable disease (8-36 weeks). The median progression free survival (PFS) and overall survival (OS) were 2.5 and 4.7 months respectively. Pharmacokinetic analyses suggest sorafenib and metabolite exposure correlate with OS and DLTs. Conclusions The recommended phase II dose (RP2D) is irinotecan 100 mg/m2 i.v. days 1, 8; cetuximab 400 mg/m2 i.v. days 1 and 250 mg/m2 i.v. weekly; and sorafenib 400 mg orally twice daily in advanced, pretreated CRC. The combination resulted in a modest response rate.

KW - Cetuximab

KW - Colorectal cancer

KW - Irinotecan

KW - Pharmacokinetics

KW - Sorafenib

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AN - SCOPUS:84877587140

SN - 0167-6997

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Phase i pharmacokinetic and pharmacodynamic study of cetuximab, irinotecan and sorafenib in advanced colorectal cancer

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