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Icrucumab, a fully human monoclonal antibody against the vascular endothelial growth factor receptor-1, in the treatment of patients with advanced solid malignancies: a Phase 1 study

  • PHASE I STUDIES
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Summary

Background IMC-18F1 (icrucumab), a human monoclonal antibody against vascular endothelial growth factor receptor-1 (VEGFR-1), potently inhibits ligand-dependent phosphorylation of VEGFR-1 and downstream signaling, making icrucumab an attractive candidate for antitumor activity. Objectives The primary objective was to determine the safety profile and maximum tolerated dose of icrucumab in patients with advanced solid tumors that were previously unresponsive to standard therapy or for which no standard therapy was available. Methods In this open-label, dose-escalation, Phase 1 study, patients received icrucumab intravenously weekly at 2, 3, 6, and 12 mg/kg (Cohorts 1–4), every other week (q2w) at 15 mg/kg (Cohort 5), or every third week at 20 mg/kg (Cohort 6). Patients received icrucumab until evidence of progressive disease or other withdrawal criteria were met. Results Twenty-six patients received icrucumab. The most common adverse events were fatigue, nausea, peripheral edema, anemia, dyspnea, and vomiting. No dose-limiting toxicities (DLTs) were observed in Cohorts 1–5. Two DLTs were observed in Cohort 6 (anemia and hyponatremia), and enrollment was stopped. No patient demonstrated an immunogenic response. Overall, icrucumab exhibited nonlinear pharmacokinetics at doses >6 mg/kg. Six patients (23.1 %) achieved stable disease with median duration of 11.1 weeks (range = 10.3–18.7 weeks); tumor types were thyroid, melanoma, colorectal (3 patients), and small-cell lung cancers. Conclusions Icrucumab was safely administered weekly at doses of 2–12 mg/kg and q2w at a dose of 15 mg/kg with no DLTs. Based on achievement of stable disease, icrucumab has potential for antitumor activity against advanced solid tumors.

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Acknowledgments

This study was sponsored by Eli Lilly and Company. The authors would like to thank Joseph Giaconia of INC Research (Raleigh, NC) for his writing assistance.

Conflicts of interest

Patricia LoRusso, Scot Remick, and Smitha Krishnamurthi declare that they have no conflict of interest. Floyd Fox and Aruna Dontabhaktuni are employees of ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company. Hagop Youssoufian, Nancy Hall, and Dmitri Grebennik were employees of ImClone Systems during the conduct of the trial and/or development of this manuscript.

Ethical standards

The protocol was approved before the start of the study by the relevant independent ethics committees in the participating institutions. The study was performed in accordance with the Declaration of Helsinki, good clinical practice guidelines, and applicable regulatory requirements. Written informed consent was obtained from all patients at initial visit.

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Author notes

  1. Nancy Hall

    Present address: Eisai Inc., Woodcliff Lake, NJ, USA

  2. Dmitri Grebennik

    Present address: Kyowa Hakko Kirin Pharma, Inc., Princeton, NJ, USA

Authors and Affiliations

  1. Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Patricia M. LoRusso

  2. University Hospitals, Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    Smitha Krishnamurthi

  3. Ziopharm, Boston, MA, USA

    Hagop Youssoufian

  4. ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company, Bridgewater, NJ, USA

    Nancy Hall, Floyd Fox, Aruna Dontabhaktuni & Dmitri Grebennik

  5. Mary Babb Randolph Cancer Center, Morgantown, WV, USA

    Scot Remick

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  1. Patricia M. LoRusso
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Correspondence to Patricia M. LoRusso.

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LoRusso, P.M., Krishnamurthi, S., Youssoufian, H. et al. Icrucumab, a fully human monoclonal antibody against the vascular endothelial growth factor receptor-1, in the treatment of patients with advanced solid malignancies: a Phase 1 study. Invest New Drugs 32, 303–311 (2014). https://doi.org/10.1007/s10637-013-9998-8

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  • DOI: https://doi.org/10.1007/s10637-013-9998-8

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