PMID- 24604265
OWN - NLM
STAT- MEDLINE
DCOM- 20150302
LR  - 20211021
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Linking)
VI  - 32
IP  - 4
DP  - 2014 Aug
TI  - A phase I study of the human monoclonal anti-NRP1 antibody MNRP1685A in patients 
      with advanced solid tumors.
PG  - 653-60
LID - 10.1007/s10637-014-0071-z [doi]
AB  - 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.
FAU - Weekes, Colin D
AU  - Weekes CD
AD  - 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.
FAU - Beeram, Muralidhar
AU  - Beeram M
FAU - Tolcher, Anthony W
AU  - Tolcher AW
FAU - Papadopoulos, Kyriakos P
AU  - Papadopoulos KP
FAU - Gore, Lia
AU  - Gore L
FAU - Hegde, Priti
AU  - Hegde P
FAU - Xin, Yan
AU  - Xin Y
FAU - Yu, Ron
AU  - Yu R
FAU - Shih, L Mason
AU  - Shih LM
FAU - Xiang, Hong
AU  - Xiang H
FAU - Brachmann, Rainer K
AU  - Brachmann RK
FAU - Patnaik, Amita
AU  - Patnaik A
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20140307
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Antibodies, Monoclonal)
RN  - 144713-63-3 (Neuropilin-1)
RN  - 7SF22186WT (vesencumab)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal/adverse effects/*therapeutic use
MH  - Dose-Response Relationship, Drug
MH  - Drug Administration Schedule
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy/metabolism
MH  - Neuropilin-1/*antagonists & inhibitors/metabolism
EDAT- 2014/03/08 06:00
MHDA- 2015/03/03 06:00
CRDT- 2014/03/08 06:00
PHST- 2013/10/15 00:00 [received]
PHST- 2014/02/03 00:00 [accepted]
PHST- 2014/03/08 06:00 [entrez]
PHST- 2014/03/08 06:00 [pubmed]
PHST- 2015/03/03 06:00 [medline]
AID - 10.1007/s10637-014-0071-z [doi]
PST - ppublish
SO  - Invest New Drugs. 2014 Aug;32(4):653-60. doi: 10.1007/s10637-014-0071-z. Epub 
      2014 Mar 7.