PMID- 24349470
OWN - NLM
STAT- MEDLINE
DCOM- 20150330
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 12
DP  - 2013
TI  - First-in-human phase I study of PRS-050 (Angiocal), an Anticalin targeting and 
      antagonizing VEGF-A, in patients with advanced solid tumors.
PG  - e83232
LID - 10.1371/journal.pone.0083232 [doi]
LID - e83232
AB  - BACKGROUND: To report the nonrandomized first-in-human phase I trial of PRS-050, 
      a novel, rationally engineered Anticalin based on human tear lipocalin that 
      targets and antagonizes vascular endothelial growth factor A (VEGF-A). METHODS: 
      Patients with advanced solid tumors received PRS-050 at 0.1 mg/kg to 10 mg/kg by 
      IV in successive dosing cohorts according to the 3+3 escalation scheme. The 
      primary end point was safety. RESULTS: Twenty-six patients were enrolled; 25 were 
      evaluable. Two patients experienced dose-limiting toxicity, comprising grade (G) 
      3 hypertension and G3 pyrexia, respectively. The maximum tolerated dose was not 
      reached. Most commonly reported treatment-emergent adverse events (AEs) included 
      chills (52%; G3, 4%), fatigue (52%; G3, 4%), hypertension (44%; G3, 16%), and 
      nausea (40%, all G1/2). No anti-PRS-050 antibodies following multiple 
      administration of the drug were detected. PRS-050 showed dose-proportional 
      pharmacokinetics (PK), with a terminal half-life of approximately 6 days. Free 
      VEGF-A was detectable at baseline in 9/25 patients, becoming rapidly undetectable 
      after PRS-050 infusion for up to 3 weeks. VEGF-A/PRS-050 complex was detectable 
      for up to 3 weeks at all dose levels, including in patients without detectable 
      baseline-free VEGF-A. We also detected a significant reduction in circulating 
      matrix metalloproteinase 2, suggesting this end point could be a pharmacodynamic 
      (PD) marker of the drug's activity. CONCLUSIONS: PRS-050, a novel Anticalin with 
      high affinity for VEGF-A, was well-tolerated when administered at the highest 
      dose tested, 10 mg/kg. Based on target engagement and PK/PD data, the recommended 
      phase II dose is 5 mg/kg every 2 weeks administered as a 120-minute infusion. 
      TRIAL REGISTRATION: ClinicalTrials.gov NCT01141257 
      http://clinicaltrials.gov/ct2/show/NCT01141257.
FAU - Mross, Klaus
AU  - Mross K
AD  - Klinik fur Tumorbiologie, Albert-Ludwigs Universitat, Freiburg, Germany.
FAU - Richly, Heike
AU  - Richly H
AD  - Department of Medical Oncology, West German Cancer Center, University Hospital, 
      University Duisburg-Essen, Essen, Germany.
FAU - Fischer, Richard
AU  - Fischer R
AD  - Department of Gastroenterology, University Medical Center, Freiburg, German.
FAU - Scharr, Dirk
AU  - Scharr D
AD  - Klinik fur Tumorbiologie, Albert-Ludwigs Universitat, Freiburg, Germany.
FAU - Buchert, Martin
AU  - Buchert M
AD  - Magnetic Resonance Development and Application Center, University Medical Center, 
      Freiburg, Germany.
FAU - Stern, Angelika
AU  - Stern A
AD  - Stern Consult, Basel, Switzerland.
FAU - Gille, Hendrik
AU  - Gille H
AD  - Pieris AG, Freising, Germany.
FAU - Audoly, Laurent P
AU  - Audoly LP
AD  - Pieris AG, Freising, Germany.
FAU - Scheulen, Max E
AU  - Scheulen ME
AD  - Department of Medical Oncology, West German Cancer Center, University Hospital, 
      University Duisburg-Essen, Essen, Germany.
LA  - eng
SI  - ClinicalTrials.gov/NCT01141257
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20131213
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Lipocalin 1)
RN  - 0 (Lipocalins)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (angiocal protein)
RN  - EC 3.4.24.24 (MMP2 protein, human)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Angiogenesis Inhibitors/*administration & dosage/adverse 
      effects/*pharmacokinetics
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - *Lipocalin 1
MH  - Lipocalins/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Matrix Metalloproteinase 2/blood
MH  - Middle Aged
MH  - Neoplasms/blood/*drug therapy
MH  - Time Factors
MH  - Vascular Endothelial Growth Factor A/*antagonists & inhibitors/blood
PMC - PMC3862718
COIS- Competing Interests: This study was sponsored by Pieris AG, the employer of HG 
      and LPA. AS is affiliated to Stern Consult. There is a pending patent 
      (PCT/EP2012/072406) relating to this study: "Novel uses of VEGF antagonists", 
      inventors HG and LPA. KM and MES have received a travel grant from Pieris AG, and 
      AS and MES have consulted for Pieris AG. There are no further patents, products 
      in development or marketed products to declare. This does not alter the authors' 
      adherence to all the PLOS ONE policies on sharing data and materials, as detailed 
      online in the guide for authors.
EDAT- 2013/12/19 06:00
MHDA- 2015/03/31 06:00
PMCR- 2013/12/13
CRDT- 2013/12/19 06:00
PHST- 2013/07/01 00:00 [received]
PHST- 2013/10/30 00:00 [accepted]
PHST- 2013/12/19 06:00 [entrez]
PHST- 2013/12/19 06:00 [pubmed]
PHST- 2015/03/31 06:00 [medline]
PHST- 2013/12/13 00:00 [pmc-release]
AID - PONE-D-13-29240 [pii]
AID - 10.1371/journal.pone.0083232 [doi]
PST - epublish
SO  - PLoS One. 2013 Dec 13;8(12):e83232. doi: 10.1371/journal.pone.0083232. 
      eCollection 2013.