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

Authors: LoRusso, P. M.; Gounder, M.; Jalal, S. I.; André, V.; Kambhampati, S. R. P.; Loizos, N.; Hall, J.; Holzer, T. R.; Nasir, A.; Cosaert, J.; Kauh, J.; Chiorean, E. G.
Article Title: Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors
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. © 2017, Springer Science+Business Media New York.
Keywords: adult; clinical article; aged; constipation; drug tolerability; fatigue; paresthesia; diarrhea; drug efficacy; drug safety; drug withdrawal; side effect; multiple cycle treatment; pharmacodynamics; anemia; nausea; thrombocytopenia; vomiting; dehydration; peripheral neuropathy; inflammation; cohort analysis; creatinine; antineoplastic activity; arthralgia; coughing; drug dose escalation; drug hypersensitivity; fever; hypomagnesemia; hypokalemia; hyponatremia; insomnia; multicenter study; open study; headache; drug blood level; maximum tolerated dose; phase 1 clinical trial; drug half life; flatulence; amylase; solid tumors; phase 1; dysgeusia; triacylglycerol lipase; decreased appetite; ron; infusion related reaction; human; male; female; priority journal; article; imc-ron8; macrophage-stimulating protein receptor; narnatumab; hypogeusia; solid malignant neoplasm
Journal Title: Investigational New Drugs
Volume: 35
Issue: 4
ISSN: 0167-6997
Publisher: Springer  
Date Published: 2017-08-01
Start Page: 442
End Page: 450
Language: English
DOI: 10.1007/s10637-016-0413-0
PROVIDER: scopus
PMCID: PMC5502198
PUBMED: 28161886
Notes: Article -- Export Date: 1 August 2017 -- Source: Scopus
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MSK Authors
  1. Mrinal M Gounder
    116 Gounder