title: A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours.
abstract: BACKGROUND
  The objectives of this phase I study were to assess the safety and tolerability of E7080 in patients with advanced, refractory solid tumours; to determine the maximum tolerated dose (MTD) and pharmacokinetics profile of E7080; and to explore preliminary evidence of its anti-tumour efficacy.
  
  
  METHODS
  E7080 was administered orally in escalating doses on a once-daily continuous schedule in 28-day cycles to eligible patients. Samples for pharmacokinetic analyses were collected on days 1, 8, 15 and 22 of cycle 1 and day 1 of cycle 2. Anti-tumour efficacy was assessed every two cycles.
  
  
  RESULTS
  Eighty-two patients received E7080 in dose cohorts from 0.2 to 32 mg. Dose-limiting toxicities were grade 3 proteinuria (two patients) at 32 mg, and the MTD was defined as 25 mg. The most frequently observed cumulative toxicities (all grades) were hypertension (40% of patients), diarrhoea (45%), nausea (37%), stomatitis (32%) and vomiting (23%). Seven patients (9%) had a partial response and 38 patients (46%) had stable disease as best response. E7080 has dose-linear kinetics with no drug accumulation after 4 weeks' administration.
  
  
  CONCLUSIONS
  E7080 is well tolerated at doses up to 25 mg per day. Encouraging anti-tumour efficacy was observed in patients with melanoma and renal cell carcinoma.
authors.affiliation: Division of Medical Oncology, Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands.
authors.forename: D S
authors.initials: DS
authors.lastname: Boss
authors.forename: H
authors.initials: H
authors.lastname: Glen
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: M
authors.initials: M
authors.lastname: Keesen
authors.forename: R
authors.initials: R
authors.lastname: Morrison
authors.forename: B
authors.initials: B
authors.lastname: Tait
authors.forename: W
authors.initials: W
authors.lastname: Copalu
authors.forename: A
authors.initials: A
authors.lastname: Mazur
authors.forename: J
authors.initials: J
authors.lastname: Wanders
authors.forename: J P
authors.initials: JP
authors.lastname: O'Brien
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: T R J
authors.initials: TR
authors.lastname: Evans
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D011505:Protein-Tyrosine Kinases; C531958:lenvatinib