title: A Phase Ib study evaluating MNRP1685A, a fully human anti-NRP1 monoclonal antibody, in combination with bevacizumab and paclitaxel in patients with advanced solid tumors.
abstract: OBJECTIVE
  MNRP1685A is a human monoclonal antibody that blocks binding of vascular endothelial growth factor (VEGF), VEGF-B, and placental growth factor 2 to neuropilin-1 resulting in vessel immaturity and VEGF dependency. The safety of combining MNRP1685A with bevacizumab, with or without paclitaxel, was examined.
  
  
  METHODS
  Patients with advanced solid tumors received escalating doses of MNRP1685A (7.5, 15, 24, and 36 mg/kg) with bevacizumab 15 mg/kg every 3 weeks in Arm A (n = 14). Arm B (n = 10) dosing consisted of MNRP1685A (12 and 16 mg/kg) with bevacizumab 10 mg/kg (every 2 weeks) and paclitaxel 90 mg/m(2) (weekly, 3 of 4 weeks). Objectives were to determine safety, pharmacokinetics, pharmacodynamics, and the maximum tolerated dose of MNRP1685A.
  
  
  RESULTS
  Infusion reactions (88 %) and transient thrombocytopenia (67 %) represent the most frequent study drug-related adverse events (AEs). Drug-related Grade 2 or 3 proteinuria occurred in 13 patients (54 %). Additional study drug-related AEs occurring in >20 % of patients included neutropenia, alopecia, dysphonia, fatigue, and nausea. Neutropenia occurred only in Arm B. Grade ≥3 study drug-related AEs in ≥3 patients included neutropenia (Arm B), proteinuria, and thrombocytopenia. Two confirmed and three unconfirmed partial responses were observed.
  
  
  CONCLUSIONS
  The safety profiles were consistent with the single-agent profiles of all study drugs. However, a higher than expected rate of clinically significant proteinuria was observed that does not support further testing of MNRP1685A in combination with bevacizumab.
authors.affiliation: South Texas Accelerated Research Therapeutics, 4383 Medical Drive, San Antonio, TX, 78229, USA, amita.patnaik@start.stoh.com.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.forename: Vanitha
authors.initials: V
authors.lastname: Ramakrishnan
authors.forename: Amy H
authors.initials: AH
authors.lastname: Kim
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Beyer
authors.forename: L
authors.initials: L
authors.lastname: Mason Shih
authors.forename: Walter C
authors.initials: WC
authors.lastname: Darbonne
authors.forename: Yan
authors.initials: Y
authors.lastname: Xin
authors.forename: Ron
authors.initials: R
authors.lastname: Yu
authors.forename: Hong
authors.initials: H
authors.lastname: Xiang
authors.forename: Rainer K
authors.initials: RK
authors.lastname: Brachmann
authors.forename: Colin D
authors.initials: CD
authors.lastname: Weekes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000068258:Bevacizumab; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D039942:Neuropilin-1 / Q000008:administration & dosage / Q000627:therapeutic use*; D017239:Paclitaxel / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D039942:Neuropilin-1; D000068258:Bevacizumab; C574067:vesencumab; D017239:Paclitaxel