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Investigational New Drugs

, Volume 32, Issue 4, pp 682–690 | Cite as

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

  • Johanna C. BendellEmail author
  • Heinz-Josef Lenz
  • Theresa Ryan
  • Bassel F. El-Rayes
  • John L. Marshall
  • Manuel R. Modiano
  • Lowell L. Hart
  • Clint D. Kingsley
  • Thomas J. George
  • Daisuke Nakashima
  • Jordan D. Berlin
PHASE I STUDIES

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.

Keywords

A33 antibody Phase 1/2 Solid tumors KRN330 Irinotecan 

Notes

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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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Johanna C. Bendell
    • 1
    Email author
  • Heinz-Josef Lenz
    • 2
  • Theresa Ryan
    • 3
  • Bassel F. El-Rayes
    • 4
  • John L. Marshall
    • 5
  • Manuel R. Modiano
    • 6
  • Lowell L. Hart
    • 7
  • Clint D. Kingsley
    • 8
  • Thomas J. George
    • 9
  • Daisuke Nakashima
    • 10
  • Jordan D. Berlin
    • 11
  1. 1.Sarah Cannon Research Institute/Tennessee Oncology, PLLCNashvilleUSA
  2. 2.Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaLos AngelesUSA
  3. 3.Langone Medical CenterNew York UniversityNew YorkUSA
  4. 4.Winship Cancer InstituteEmory UniversityAtlantaUSA
  5. 5.Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashingtonUSA
  6. 6.ACRC/Arizona Clinical Research Center and Arizona OncologyTucsonUSA
  7. 7.Florida Cancer Specialists/Sarah Cannon Research InstituteFort MyersUSA
  8. 8.Clearview Cancer InstituteHuntsvilleUSA
  9. 9.University of FloridaGainesvilleUSA
  10. 10.Kyowa Hakko Kirin Pharma, Inc.PrincetonUSA
  11. 11.Vanderbilt-Ingram Cancer CenterVanderbilt UniversityNashvilleUSA

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