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Phase 1/2 study of KRN330, a fully human anti-A33 monoclonal antibody, plus irinotecan as second-line treatment for patients with metastatic colorectal cancer

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Summary

KRN330 is a recombinant, fully-human monoclonal antibody directed against A33, a surface differentiation antigen that is uniformly expressed in 95 % of colorectal cancers. A previous Phase 1 study of single-agent KRN330 identified a maximum tolerated dose (MTD) of 3 mg/kg q2w and preliminary evidence of clinical activity among patients with advanced and metastatic colorectal cancer (mCRC). This Phase 1/2 trial sought to assess the safety and activity of second-line KRN330 plus irinotecan in patients with mCRC. Patients with mCRC who showed disease progression after FOLFOX/CapOx received intravenous doses of KRN330 (0.5 or 1.0 mg/kg qw or q2w) plus irinotecan (180 mg/m2) in a standard 3 + 3 dose escalation. The MTD of KRN330 with irinotecan in 19 patients was 0.5 mg/kg qw in the Phase 1 study with gastrointestinal effects and neutropenia being the predominant dose-limiting toxicities. In the Phase 2 study, the most frequent treatment-related Grade ≥3 toxicities in 44 patients were fatigue (15.9 %), neutropenia (13.6 %), leukopenia (6.8 %), diarrhea (4.5 %), and dehydration (4.5 %). Objective response rate (ORR) was 4.5 % and disease control rate was 45.5 % for the intent-to-treat population. Median progression-free survival was 87 days (95 % CI, 43–136 days). The prespecified ORR of KRN330 plus irinotecan was not met. Further investigation of KRN330 plus other agents may be warranted.

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Acknowledgements

All authors contributed equally to the data interpretation and writing of the manuscript. The authors would like to thank the study investigators for their invaluable contribution to this study. The authors also acknowledge Janice Briscoe (Kyowa Hakko Kirin Pharma, Inc.) for study management, and Peter Todd, PhD (Tajut Ltd.) for review and critical revisions for important intellectual content and editorial assistance in the preparation of this manuscript. We thank Dr Wu Zhang (University of Southern California Norris Comprehensive Cancer Center) for performing Fc gamma receptor analysis.

Grant support

This work was supported by Kyowa Hakko Kirin Pharma, Inc. (Princeton, NJ) and Kyowa Hakko Kirin Company Limited (Tokyo, Japan). The research conducted was compliant with the current laws of the country in which it was performed.

Conflict of interest

DN is an employee of Kyowa Hakko Kirin Pharma, Inc. (Princeton, NJ). All other authors have confirmed they have no conflict of interest in the publication of this manuscript.

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Authors and Affiliations

  1. Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Suite 110, 250 25th Avenue North, Nashville, TN, 37203, USA

    Johanna C. Bendell

  2. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Heinz-Josef Lenz

  3. Langone Medical Center, New York University, New York, NY, USA

    Theresa Ryan

  4. Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Bassel F. El-Rayes

  5. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    John L. Marshall

  6. ACRC/Arizona Clinical Research Center and Arizona Oncology, Tucson, AZ, USA

    Manuel R. Modiano

  7. Florida Cancer Specialists/Sarah Cannon Research Institute, Fort Myers, FL, USA

    Lowell L. Hart

  8. Clearview Cancer Institute, Huntsville, AL, USA

    Clint D. Kingsley

  9. University of Florida, Gainesville, FL, USA

    Thomas J. George

  10. Kyowa Hakko Kirin Pharma, Inc., Princeton, NJ, USA

    Daisuke Nakashima

  11. Vanderbilt-Ingram Cancer Center, Vanderbilt University, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN, 37232, USA

    Jordan D. Berlin

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  1. Johanna C. Bendell
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Correspondence to Johanna C. Bendell.

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Bendell, J.C., Lenz, HJ., Ryan, T. et al. Phase 1/2 study of KRN330, a fully human anti-A33 monoclonal antibody, plus irinotecan as second-line treatment for patients with metastatic colorectal cancer. Invest New Drugs 32, 682–690 (2014). https://doi.org/10.1007/s10637-014-0088-3

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  • DOI: https://doi.org/10.1007/s10637-014-0088-3

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