PMID- 25012508
OWN - NLM
STAT- MEDLINE
DCOM- 20150227
LR  - 20231104
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 14
DP  - 2014 Jul 11
TI  - Vascular effects, efficacy and safety of nintedanib in patients with advanced, 
      refractory colorectal cancer: a prospective phase I subanalysis.
PG  - 510
LID - 10.1186/1471-2407-14-510 [doi]
AB  - BACKGROUND: Nintedanib is a potent, oral angiokinase inhibitor that targets VEGF, 
      PDGF and FGF signalling, as well as RET and Flt3. The maximum tolerated dose of 
      nintedanib was evaluated in a phase I study of treatment-refractory patients with 
      advanced solid tumours. In this preplanned subanalysis, the effect of nintedanib 
      on the tumour vasculature, along with efficacy and safety, was assessed in 30 
      patients with colorectal cancer (CRC). METHODS: Patients with advanced CRC who 
      had failed conventional treatment, or for whom no therapy of proven efficacy 
      existed, were treated with nintedanib ranging from 50-450 mg once-daily (n = 14) 
      or 150-250 mg twice-daily (n = 16) for 28 days. After a 1-week rest, further 
      courses were permitted in the absence of progression or undue toxicity. The 
      primary objective was the effect on the tumour vasculature using dynamic 
      contrast-enhanced magnetic resonance imaging (DCE-MRI) and expressed as the 
      initial area under the DCE-MRI contrast agent concentration-time curve after 60 
      seconds (iAUC60) or the volume transfer constant between blood plasma and 
      extravascular extracellular space (Ktrans). RESULTS: Patients received a median 
      of 4.0 courses (range: 1-13). Among 21 evaluable patients, 14 (67%) had a >/=40% 
      reduction from baseline in Ktrans and 13 (62%) had a >/=40% decrease from baseline 
      in iAUC60, representing clinically relevant effects on tumour blood flow and 
      permeability, respectively. A >/=40% reduction from baseline in Ktrans was 
      positively associated with non-progressive tumour status (Fisher's exact: p = 
      0.0032). One patient achieved a partial response at 250 mg twice-daily and 24 
      (80%) achieved stable disease lasting >/=8 weeks. Time to tumour progression (TTP) 
      at 4 months was 26% and median TTP was 72.5 days (95% confidence interval: 
      65-114). Common drug-related adverse events (AEs) included nausea (67%), vomiting 
      (53%) and diarrhoea (40%); three patients experienced drug-related AEs >/= grade 3. 
      Four patients treated with nintedanib once-daily had an alanine aminotransferase 
      and/or aspartate aminotransferase increase >/= grade 3. No increases > grade 2 were 
      seen in the twice-daily group. CONCLUSIONS: Nintedanib modulates tumour blood 
      flow and permeability in patients with advanced, refractory CRC, while achieving 
      antitumour activity and maintaining an acceptable safety profile.
FAU - Mross, Klaus
AU  - Mross K
AD  - Tumor Biology Center, Department of Medical Oncology, Breisacherstrasse 117, 
      D-79106 Freiburg in Breisgau, Germany. mross@tumorbio.uni-freiburg.de.
FAU - Buchert, Martin
AU  - Buchert M
FAU - Frost, Annette
AU  - Frost A
FAU - Medinger, Michael
AU  - Medinger M
FAU - Stopfer, Peter
AU  - Stopfer P
FAU - Studeny, Matus
AU  - Studeny M
FAU - Kaiser, Rolf
AU  - Kaiser R
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140711
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Indoles)
RN  - G6HRD2P839 (nintedanib)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Agents/*administration & dosage/*adverse effects
MH  - Colorectal Neoplasms/*blood supply/*drug therapy
MH  - Dose-Response Relationship, Drug
MH  - Drug Administration Schedule
MH  - Female
MH  - Humans
MH  - Indoles/*administration & dosage/*adverse effects
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Prospective Studies
MH  - Treatment Outcome
PMC - PMC4105047
EDAT- 2014/07/12 06:00
MHDA- 2015/02/28 06:00
PMCR- 2014/07/11
CRDT- 2014/07/12 06:00
PHST- 2013/10/02 00:00 [received]
PHST- 2014/07/04 00:00 [accepted]
PHST- 2014/07/12 06:00 [entrez]
PHST- 2014/07/12 06:00 [pubmed]
PHST- 2015/02/28 06:00 [medline]
PHST- 2014/07/11 00:00 [pmc-release]
AID - 1471-2407-14-510 [pii]
AID - 10.1186/1471-2407-14-510 [doi]
PST - epublish
SO  - BMC Cancer. 2014 Jul 11;14:510. doi: 10.1186/1471-2407-14-510.