title: Phase I study of nintedanib incorporating dynamic contrast-enhanced magnetic resonance imaging in patients with advanced solid tumors.
abstract: BACKGROUND
  This open-label phase I dose-escalation study investigated the safety, efficacy, pharmacokinetics (PK), and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) effects of the oral angiokinase inhibitor nintedanib in patients with advanced solid tumors.
  
  
  METHODS
  Nintedanib was administered once daily continuously, starting at 100 mg and later amended to allow evaluation of 250 mg b.i.d. The primary endpoint was maximum tolerated dose (MTD). DCE-MRI studies were performed at baseline and on days 2 and 28.
  
  
  RESULTS
  Fifty-one patients received nintedanib 100-450 mg once daily (n = 40) or 250 mg b.i.d. (n = 11). Asymptomatic reversible liver enzyme elevations (grade 3) were dose limiting in 2 of 5 patients at 450 mg once daily. At 250 mg b.i.d., 2 of 11 patients experienced dose-limiting toxicity (grade 3 liver enzyme elevation and gastrointestinal symptoms). Common toxicities included fatigue, diarrhea, nausea, vomiting, and abdominal pain (mainly grade ≤2). Among 45 patients, 22 (49%) achieved stable disease; 7 remained on treatment for >6 months. DCE-MRI of target lesions revealed effects in some patients at 200 and ≥400 mg once daily.
  
  
  CONCLUSIONS
  Nintedanib is well tolerated by patients with advanced solid malignancies, with MTD defined as 250 mg b.i.d., and can induce changes in DCE-MRI. Disease stabilization >6 months was observed in 7 of 51 patients.
authors: Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom; chooi.lee@boehringer-ingelheim.com.
authors: Chooi Peng
authors: CP
authors: Lee
authors: Mount Vernon Cancer Centre, Northwood, United Kingdom;
authors: N Jane
authors: NJ
authors: Taylor
authors: Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom;
authors: Gerhardt
authors: G
authors: Attard
authors: Department of Oncology, The University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom;
authors: Simon
authors: S
authors: Pacey
authors: Mount Vernon Cancer Centre, Northwood, United Kingdom;
authors: Paul D
authors: PD
authors: Nathan
authors: Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom;
authors: Johann S
authors: JS
authors: de Bono
authors: Boehringer Ingelheim Ltd, Bracknell, United Kingdom;
authors: Graham
authors: G
authors: Temple
authors: Boehringer Ingelheim Ltd, Bracknell, United Kingdom;
authors: Susan
authors: S
authors: Bell
authors: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany;
authors: Martin
authors: M
authors: Stefanic
authors: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany;
authors: Peter
authors: P
authors: Stopfer
authors: Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom;
authors: Adrian
authors: A
authors: Tang
authors: Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom;
authors: Dow-Mu
authors: DM
authors: Koh
authors: Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom; Cancer Research UK and Engineering and Physical Sciences Research Council Cancer Imaging Centre, Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom.
authors: David J
authors: DJ
authors: Collins
authors: Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom; Cancer Research UK and Engineering and Physical Sciences Research Council Cancer Imaging Centre, Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom.
authors: James
authors: J
authors: d'Arcy
authors: Mount Vernon Cancer Centre, Northwood, United Kingdom;
authors: Anwar R
authors: AR
authors: Padhani
authors: Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom; Cancer Research UK and Engineering and Physical Sciences Research Council Cancer Imaging Centre, Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom.
authors: Martin O
authors: MO
authors: Leach
authors: Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom;
authors: Ian R
authors: IR
authors: Judson
authors: Mount Vernon Cancer Centre, Northwood, United Kingdom;
authors: Gordon J
authors: GJ
authors: Rustin
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003287:Contrast Media; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D004791:Enzyme Inhibitors; D007211:Indoles; C530716:nintedanib