title: Phase I safety and pharmacokinetic study of SU-014813 in combination with docetaxel in patients with advanced solid tumours.
abstract: BACKGROUND
  In pre-clinical models enhanced anti-tumour activity was observed when SU-014813, an oral multi-targeted tyrosine kinase inhibitor was combined with docetaxel. This synergy might be explained by improvement of the penetration of cytotoxic agents into tumours as a result of both VEGFR and PDGFR inhibition. We assessed the maximal tolerated dose (MTD), evaluated the pharmacokinetics and preliminary anti-tumour efficacy of oral SU-014813 administered continuously in combination with docetaxel to patients with advanced solid tumours.
  
  
  METHODS
  In this phase I study successive patient cohorts received docetaxel 60 or 75mg/m(2) every 3weeks in combination with chronic daily dosing of SU-014813. Dose limiting toxicity was assessed both in the first and second treatment cycle.
  
  
  RESULTS
  Twenty-five patients were entered on study of which 24 started treatment. Dose limiting toxicities were prolonged neutropenia, neutropenic fever, fatigue and diarrhoea. Other toxicities included fatigue, alopecia, nausea, vomiting, anorexia, rash, hypertension and hair discolouration. The recommended phase II dose was determined to be docetaxel 75mg/m(2) in combination with SU-014813 50mg/day. There was no clinically relevant pharmacokinetic drug-drug interaction. Two patients (8%) achieved a partial response (PR) and 7 patients (29%) had stabilisation of their disease (SD) >6months, for a clinical benefit rate of 37.5%. The activity observed in patients with melanoma and sunitinib refractory gastrointestinal stromal tumours (GIST) was particularly noteworthy.
  
  
  CONCLUSIONS
  Oral SU-014813 50mg/day with docetaxel 75mg/m(2) is a clinically feasible regimen with a manageable safety profile and anti-tumour activity. Further development is warranted in patients with melanoma and GIST.
authors: Dept. of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands. m.dejonge@erasmusmc.nl
authors: M J A
authors: MJ
authors: de Jonge
authors: H
authors: H
authors: Dumez
authors: J J E M
authors: JJ
authors: Kitzen
authors: B
authors: B
authors: Beuselinck
authors: J
authors: J
authors: Verweij
authors: R
authors: R
authors: Courtney
authors: A
authors: A
authors: Battista
authors: N
authors: N
authors: Brega
authors: P
authors: P
authors: Schöffski
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015331:Cohort Studies; D000077143:Docetaxel; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy; D006801:Humans; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012107:Research Design; D012449:Safety; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor