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Phase 1 study of the anti-vascular endothelial growth factor receptor 3 monoclonal antibody LY3022856/IMC-3C5 in patients with advanced and refractory solid tumors and advanced colorectal cancer

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Abstract

Purpose

Metastasis of solid tumors to regional lymph nodes is facilitated by tumor lymphangiogenesis, which is primarily mediated by the vascular endothelial growth factor receptor 3 (VEGFR-3). We conducted a phase 1 dose-escalation (part A) study of the VEGFR-3 human immunoglobulin G subclass 1 monoclonal antibody LY3022856 in advanced solid tumors, followed by a colorectal cancer (CRC) expansion (part B).

Methods

Part A evaluated the safety profile and maximum tolerated dose (MTD) of LY3022856 in patients treated intravenously at doses of 5–30 mg/kg weekly (qwk). Part B further evaluated tolerability in CRC patients treated with 30 mg/kg. Secondary objectives were pharmacokinetics, anti-tumor activity, and pharmacodynamics (exploratory).

Results

A total of 44 patients (23 in part A; 21 in part B) were treated; only one dose-limiting toxicity was observed at the lowest dose level. The MTD was not reached. Treatment-emergent adverse events (TEAEs) of any grade included in ≥15 % of all patients were: nausea (41 %), fatigue (32 %), vomiting (30 %), decreased appetite (27 %), pyrexia (25 %), peripheral edema (23 %), and urinary tract infection (UTI, 20 %). The most common grade 3/4 TEAEs included UTI and small intestinal obstruction (7 % each). No radiographic responses were noted. Median progression-free survival in part B was 6.3 weeks (95 % confidence interval: 5.1, 14.4), and a best overall response of stable disease was observed in 4 CRC patients (19.0 %).

Conclusions

LY3022856 was well tolerated up to a dose of 30 mg/kg qwk, but with minimal anti-tumor activity in CRC.

ClinicalTrials.gov identifier

NCT01288989.

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Acknowledgments

We thank the patients, their families, the study sites, and the study personnel who participated in this clinical trial. Eli Lilly and Company contracted with inVentiv Health Clinical for writing and editorial support, provided by Emily Cullinan, Ph.D., and Noelle Gasco, respectively.

Funding

This study was funded by Eli Lilly and Company (NCT01288989).

Author information

Authors and Affiliations

  1. Tufts Cancer Center - Medical Center, Tufts University School of Medicine, 800 Washington St., Ste. 7099, 7-South, Boston, MA, 02111, USA

    Muhammad Wasif Saif

  2. Illinois CancerCare, Peoria, IL, USA

    James A. Knost

  3. University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    E. Gabriela Chiorean

  4. Eli Lilly and Company, Bridgewater, NJ, USA

    Siva Rama Prasad Kambhampati, Amy Qin & John S. Kauh

  5. Eli Lilly and Company, Indianapolis, IN, USA

    Danni Yu

  6. Eli Lilly and Company, New York, NY, USA

    Bronislaw Pytowski

  7. Indiana University, Indianapolis, IN, USA

    Bert H. O’Neil

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  1. Muhammad Wasif Saif
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Corresponding author

Correspondence to Muhammad Wasif Saif.

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Conflict of interest

Dr Saif received research grants from Eli Lilly and Company; served on speaker bureaus for Celgene, Genentech, Ipsen, and Sirtex; and received research funding from Celgene, Genentech, Taiho, Eli Lilly and Company, Merrimack Pharmaceuticals, and Gilead. Dr Chiorean declares her institution received a research grant from Eli Lilly and Company. Dr O’Neil received honorarium from Eli Lilly and Company. Dr Knost has no conflicts to declare. Dr Kambhampati, Dr Yu, Dr Pytowski, Dr Qin, and Dr Kauh are employed by Eli Lilly and Company and are minor stockholders in Eli Lilly and Company.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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Saif, M.W., Knost, J.A., Chiorean, E.G. et al. Phase 1 study of the anti-vascular endothelial growth factor receptor 3 monoclonal antibody LY3022856/IMC-3C5 in patients with advanced and refractory solid tumors and advanced colorectal cancer. Cancer Chemother Pharmacol 78, 815–824 (2016). https://doi.org/10.1007/s00280-016-3134-3

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  • DOI: https://doi.org/10.1007/s00280-016-3134-3

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