Investigational New Drugs

, Volume 31, Issue 2, pp 345–354 | Cite as

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. DiazJr.
  • Ross C. Donehower
  • Ming Zhao
  • Michelle A. RudekEmail author
  • Wells A. MessersmithEmail author


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.


Sorafenib Cetuximab Irinotecan Pharmacokinetics Colorectal cancer 



The authors would like to thank Sharyn Baker for helpful scientific discussions. The authors would also like to thank the patients and their families for participating in the study.

Disclosure of potential conflicts of interest

Dr. Messersmith has received commercial clinical research grant support from Bayer (major) via University of Colorado Cancer Center.

Supplementary material

10637_2012_9820_MOESM1_ESM.docx (1.4 mb)
ESM 1 (DOCX 1.37 mb)


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Nilofer Azad
    • 1
  • Arvind Dasari
    • 2
  • John Arcaroli
    • 2
  • Gretchen E. Taylor
    • 1
  • Daniel A. Laheru
    • 1
  • Michael A. Carducci
    • 1
  • Martine McManus
    • 2
  • Kevin Quackenbush
    • 2
  • John J. Wright
    • 3
  • Manuel Hidalgo
    • 1
  • Luis A. DiazJr.
    • 1
  • Ross C. Donehower
    • 1
  • Ming Zhao
    • 1
  • Michelle A. Rudek
    • 1
    Email author
  • Wells A. Messersmith
    • 2
    Email author
  1. 1.The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA
  2. 2.University of Colorado Cancer CenterAuroraUSA
  3. 3.Cancer Therapy Evaluation ProgramNational Cancer InstituteBethesdaUSA

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