PMID- 28161886 OWN - NLM STAT- MEDLINE DCOM- 20180501 LR - 20220331 IS - 1573-0646 (Electronic) IS - 0167-6997 (Print) IS - 0167-6997 (Linking) VI - 35 IP - 4 DP - 2017 Aug TI - Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors. PG - 442-450 LID - 10.1007/s10637-016-0413-0 [doi] AB - 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 mug/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. FAU - LoRusso, Patricia M AU - LoRusso PM AD - Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA. patricia.lorusso@yale.edu. AD - Yale Cancer Center, New Haven, CT, USA. patricia.lorusso@yale.edu. FAU - Gounder, Mrinal AU - Gounder M AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Jalal, Shadia I AU - Jalal SI AD - Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA. FAU - Andre, Valerie AU - Andre V AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Kambhampati, Siva Rama Prasad AU - Kambhampati SRP AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Loizos, Nick AU - Loizos N AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Hall, Jennifer AU - Hall J AD - Eli Lilly and Company, Indianapolis, IN, USA. AD - Boehringer Ingelheim, Ridgefield, CT, USA. FAU - Holzer, Timothy R AU - Holzer TR AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Nasir, Aejaz AU - Nasir A AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Cosaert, Jan AU - Cosaert J AD - Eli Lilly and Company, Indianapolis, IN, USA. AD - Merck KGaA, Darmstadt, Germany. FAU - Kauh, John AU - Kauh J AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Chiorean, E Gabriela AU - Chiorean EG AD - Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA. AD - Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States GR - UL1 TR001863/TR/NCATS NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20170204 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Cytokines) RN - EC 2.7.10.1 (RON protein) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) SB - IM MH - Administration, Intravenous MH - Adult MH - Aged MH - Aged, 80 and over MH - Antibodies, Monoclonal/adverse effects/pharmacokinetics/pharmacology/*therapeutic use MH - Antineoplastic Agents/adverse effects/pharmacokinetics/pharmacology/*therapeutic use MH - Cytokines/blood MH - Female MH - Humans MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasms/blood/*drug therapy/metabolism/pathology MH - Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors MH - Treatment Outcome MH - Young Adult PMC - PMC5502198 MID - NIHMS860747 OTO - NOTNLM OT - IMC-RON8 OT - Macrophage-stimulating protein receptor OT - Narnatumab OT - Phase 1 OT - RON OT - Solid tumors COIS- Compliance with Ethical Standards Conflict of Interest Disclosures P. M. LoRusso, M. Gounder, S. I. Jalal, and E. G. Chiorean disclosed no potential conflicts of interest. V. Andre, S. R. P. Kambhampati, N. Loizos, T. R. Holzer, A. Nasir, and J. Kauh are employees of Eli Lilly and Company. J. Cosaert and J. Hall were employed by Eli Lilly and Company during the conduct of the study but are now employed by Sotio (Prague, Czech Republic) and Boehringer Ingelheim (Ridgefield, CT), respectively. EDAT- 2017/02/06 06:00 MHDA- 2018/05/02 06:00 PMCR- 2018/08/01 CRDT- 2017/02/06 06:00 PHST- 2016/09/08 00:00 [received] PHST- 2016/11/22 00:00 [accepted] PHST- 2017/02/06 06:00 [pubmed] PHST- 2018/05/02 06:00 [medline] PHST- 2017/02/06 06:00 [entrez] PHST- 2018/08/01 00:00 [pmc-release] AID - 10.1007/s10637-016-0413-0 [pii] AID - 10.1007/s10637-016-0413-0 [doi] PST - ppublish SO - Invest New Drugs. 2017 Aug;35(4):442-450. doi: 10.1007/s10637-016-0413-0. Epub 2017 Feb 4.