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

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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.

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Acknowledgments

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.

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Authors and Affiliations

  1. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Bldg, Room 1M52, 1650 Orleans Street, Baltimore, MD, 21231-1000, USA

    Nilofer Azad, Gretchen E. Taylor, Daniel A. Laheru, Michael A. Carducci, Manuel Hidalgo, Luis A. Diaz Jr., Ross C. Donehower, Ming Zhao & Michelle A. Rudek

  2. University of Colorado Cancer Center, Mailstop 8117, 12801 East 17th Ave, L18-8121, Aurora, CO, 80045, USA

    Arvind Dasari, John Arcaroli, Martine McManus, Kevin Quackenbush & Wells A. Messersmith

  3. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    John J. Wright

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  1. Nilofer Azad
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Correspondence to Michelle A. Rudek or Wells A. Messersmith.

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Funding

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.

Nilofer Azad and Arvind Dasari contribute equally to the work presented.

Presented in part at the American Society of Clinical Oncology (ASCO) Annual Meeting, June 2008, Chicago, IL and ASCO Gastrointestinal Oncology Meeting, January 2011, San Francisco, CA

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Azad, N., Dasari, A., Arcaroli, J. et al. Phase I pharmacokinetic and pharmacodynamic study of cetuximab, irinotecan and sorafenib in advanced colorectal cancer. Invest New Drugs 31, 345–354 (2013). https://doi.org/10.1007/s10637-012-9820-z

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