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Invest New Drugs. 2017 Aug;35(4):442-450. doi: 10.1007/s10637-016-0413-0. Epub 2017 Feb 4.

Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors.

Author information

1
Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA. patricia.lorusso@yale.edu.
2
Yale Cancer Center, New Haven, CT, USA. patricia.lorusso@yale.edu.
3
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
5
Eli Lilly and Company, Indianapolis, IN, USA.
6
Boehringer Ingelheim, Ridgefield, CT, USA.
7
Merck KGaA, Darmstadt, Germany.
8
Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.

Abstract

Purpose Macrophage-stimulating 1-receptor (RON) is expressed on macrophages, epithelial cells, and a variety of tumors. Narnatumab (IMC-RON8; LY3012219) is a neutralizing monoclonal antibody that blocks RON binding to its ligand, macrophage-stimulating protein (MSP). This study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of narnatumab in patients with advanced solid tumors. Methods Narnatumab was administered intravenously weekly at 5, 10, 15, or 20 mg/kg or every 2 weeks at 15, 20, 30, or 40 mg/kg in 4-week cycles. Results Thirty-nine patients were treated, and 1 dose-limiting toxicity (DLT) (grade 3 hyponatremia, 5 mg/kg) was reported. The most common narnatumab-related adverse events (AEs) were fatigue (20.5%) and decreased appetite, diarrhea, nausea, and vomiting (10.3% each). Except for 2 treatment-related grade 3 AEs (hyponatremia, hypokalemia), all treatment-related AEs were grade 1 or 2. Narnatumab had a short half-life (<7 days). After Cycle 2, no patients had concentrations above 140 μg/mL (concentration that demonstrated antitumor activity in animal models), except for 1 patient receiving 30 mg/kg biweekly. Eleven patients had a best response of stable disease, ranging from 6 weeks to 11 months. Despite only 1 DLT, due to suboptimal drug exposure, the dose was not escalated beyond 40 mg/kg biweekly. This decision was based on published data reporting that mRNA splice variants of RON are highly prevalent in tumors, accumulate in cytoplasm, and are not accessible by large-molecule monoclonal antibodies. Conclusions Narnatumab was well tolerated and showed limited antitumor activity with this dosing regimen.

KEYWORDS:

IMC-RON8; Macrophage-stimulating protein receptor; Narnatumab; Phase 1; RON; Solid tumors

PMID:
28161886
PMCID:
PMC5502198
DOI:
10.1007/s10637-016-0413-0
[Indexed for MEDLINE]
Free PMC Article

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