PMID- 22370972
OWN - NLM
STAT- MEDLINE
DCOM- 20130731
LR  - 20211021
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 31
IP  - 1
DP  - 2013 Feb
TI  - Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory 
      solid tumors.
PG  - 77-84
LID - 10.1007/s10637-012-9801-2 [doi]
AB  - BACKGROUND: Targeting the cell-surface receptor EphA2, which is highly expressed 
      in some solid tumors, is a novel approach for cancer therapy. We aimed to 
      evaluate the safety profile, maximum tolerated dose (MTD), pharmacokinetics, and 
      antitumor activity of MEDI-547, an antibody drug conjugate composed of the 
      cytotoxic drug auristatin (toxin) linked to a human anti-EphA2 monoclonal 
      antibody (1C1), in patients with solid tumors relapsed/refractory to standard 
      therapy. METHODS: In this phase 1, open-label study with planned dose-escalation 
      and dose-expansion cohorts, patients received a 1-h intravenous infusion of 
      MEDI-547 (0.08 mg/kg) every 3 weeks. RESULTS: Six patients received 0.08 mg/kg; 
      all discontinued treatment. Dose escalation was not pursued. The study was 
      stopped before cohort 2 enrollment due to treatment-related bleeding and 
      coagulation events (hemorrhage-related, n = 3; epistaxis, n = 2). Therefore, 
      lower doses were not explored and an MTD could not be selected. The most 
      frequently reported treatment-related adverse events (AEs) were increased liver 
      enzymes, decreased hemoglobin, decreased appetite, and epistaxis. Three patients 
      (50%) experienced treatment-related serious AEs, including conjunctival 
      hemorrhage, pain (led to study drug discontinuation), liver disorder, and 
      hemorrhage. Best response included progressive disease (n = 5; 83.3%) and stable 
      disease (n = 1; 16.7%). Minimal or no dissociation of toxin from 1C1 conjugate 
      occurred in the blood. Serum MEDI-547 concentrations decreased rapidly, ~70% by 3 
      days post-dose. No accumulation of MEDI-547 was observed at 0.08 mg/kg upon 
      administration of a second dose 3 weeks following dose 1. CONCLUSIONS: The safety 
      profile of MEDI-547 does not support further clinical investigation in patients 
      with advanced solid tumors.
FAU - Annunziata, Christina M
AU  - Annunziata CM
AD  - Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      National Institutes of Health, 10 Center Drive, Room 12 N226, Bethesda, MD 
      20892-1906, USA. annunzic@mail.nih.gov
FAU - Kohn, Elise C
AU  - Kohn EC
FAU - LoRusso, Patricia
AU  - LoRusso P
FAU - Houston, Nicole D
AU  - Houston ND
FAU - Coleman, Robert L
AU  - Coleman RL
FAU - Buzoianu, Manuela
AU  - Buzoianu M
FAU - Robbie, Gabriel
AU  - Robbie G
FAU - Lechleider, Robert
AU  - Lechleider R
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20120228
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Aminobenzoates)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (MEDI-547)
RN  - EC 2.7.10.1 (Receptor, EphA2)
SB  - IM
MH  - Aged
MH  - Aminobenzoates/*administration & dosage/adverse effects
MH  - Antibodies, Monoclonal/*administration & dosage/adverse effects
MH  - Antineoplastic Agents/*administration & dosage/adverse effects/pharmacokinetics
MH  - Drug Resistance, Neoplasm
MH  - Epistaxis/chemically induced
MH  - Female
MH  - Hemorrhage/chemically induced
MH  - Humans
MH  - Middle Aged
MH  - Neoplasms/*drug therapy/metabolism
MH  - Receptor, EphA2/immunology
PMC - PMC3553417
EDAT- 2012/03/01 06:00
MHDA- 2013/08/01 06:00
PMCR- 2012/02/28
CRDT- 2012/02/29 06:00
PHST- 2011/12/22 00:00 [received]
PHST- 2012/02/09 00:00 [accepted]
PHST- 2012/02/29 06:00 [entrez]
PHST- 2012/03/01 06:00 [pubmed]
PHST- 2013/08/01 06:00 [medline]
PHST- 2012/02/28 00:00 [pmc-release]
AID - 9801 [pii]
AID - 10.1007/s10637-012-9801-2 [doi]
PST - ppublish
SO  - Invest New Drugs. 2013 Feb;31(1):77-84. doi: 10.1007/s10637-012-9801-2. Epub 2012 
      Feb 28.