title: Vascular effects, efficacy and safety of nintedanib in patients with advanced, refractory colorectal cancer: a prospective phase I subanalysis.
abstract: 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.
authors.affiliation: Tumor Biology Center, Department of Medical Oncology, Breisacherstrasse 117, D-79106 Freiburg in Breisgau, Germany. mross@tumorbio.uni-freiburg.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Mross
authors.forename: Martin
authors.initials: M
authors.lastname: Büchert
authors.forename: Annette
authors.initials: A
authors.lastname: Frost
authors.forename: Michael
authors.initials: M
authors.lastname: Medinger
authors.forename: Peter
authors.initials: P
authors.lastname: Stopfer
authors.forename: Matus
authors.initials: M
authors.lastname: Studeny
authors.forename: Rolf
authors.initials: R
authors.lastname: Kaiser
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C530716:nintedanib