title: A phase I study of the human monoclonal anti-NRP1 antibody MNRP1685A in patients with advanced solid tumors.
abstract: The human monoclonal antibody MNRP1685A targets the VEGF binding domain of neuropilin-1 (NRP1), a multi-domain receptor necessary for neural development and blood vessel maturation. In nonclinical studies, MNRP1685A prevents vascular maturation by keeping blood vessels in an immature, highly VEGF-dependent state. We explored the safety and tolerability of MNRP1685A in patients with advanced solid tumors. Patients were treated with MNRP1685A given intravenously every 3 weeks using a 3 + 3 dose-escalation design with 7 dose-escalation cohorts. Twenty-four of 35 patients (69 %) experienced drug-related adverse events (AEs) of infusion-related reaction on the day of MNRP1685A administration. With premedication including dexamethasone, infusions were well-tolerated with main symptoms of pruritus and rash. Outside the day of infusion, most common (≥ 2 patients) related AEs were fatigue (17 %), pruritus (9 %), myalgia and thrombocytopenia (both 6 %) (all were Grade 1-2). MNRP1685A-related Grade ≥ 3 AEs consisted of one dose-limiting toxicity of Grade 3 upper gastrointestinal bleeding and one related Grade 3 thrombocytopenia, coinciding with unrelated Grade 3 fungemia and duodenal obstruction. MNRP1685A showed nonlinear PK with more-than-dose proportional increases in exposure, consistent with broad target expression. Transient platelet count reductions (≥ 30 % from predose) were observed in 56 % of evaluable patients. Nine patients were on study for ≥ 4 cycles, one colorectal cancer patient for one year. MNRP1685A was generally well-tolerated. The primary MNRP1685A-related AE was infusion-related reaction, which were attenuated by premedication including dexamethasone. Transient platelet count reductions were frequent but did not impact MNRP1685A dosing.
authors.affiliation: University of Colorado School of Medicine and Developmental Therapeutics Program, University of Colorado Cancer Center, Mail Stop 8117, RC1 South, Rm 8123, 12801 E. 17th Avenue, Aurora, CO, 80045, USA, colin.weekes@ucdenver.edu.
authors.forename: Colin D
authors.initials: CD
authors.lastname: Weekes
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
authors.forename: Priti
authors.initials: P
authors.lastname: Hegde
authors.forename: Yan
authors.initials: Y
authors.lastname: Xin
authors.forename: Ron
authors.initials: R
authors.lastname: Yu
authors.forename: L Mason
authors.initials: LM
authors.lastname: Shih
authors.forename: Hong
authors.initials: H
authors.lastname: Xiang
authors.forename: Rainer K
authors.initials: RK
authors.lastname: Brachmann
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D039942:Neuropilin-1; C574067:vesencumab