title: Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours.
abstract: BACKGROUND
  As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel.
  
  
  METHODS
  Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mg m(-2) q3w, paclitaxel 80 mg m(-2) every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175 mg m(-2) q3w. The primary endpoint was safety/tolerability.
  
  
  RESULTS
  A total of 116 patients received saracatinib 125 (N=20), 175 (N=44), 225 (N=40), 250 (N=9), or 300 mg (N=3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade ≥3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; ≥225 mg, 33%), and grade ≥3 neutropenia occurred more commonly at doses ≥225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w.
  
  
  CONCLUSIONS
  Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials.
authors.affiliation: Drug Development Unit, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. stan.kaye@rmh.nhs.uk
authors.forename: S
authors.initials: S
authors.lastname: Kaye
authors.forename: S
authors.initials: S
authors.lastname: Aamdal
authors.forename: R
authors.initials: R
authors.lastname: Jones
authors.forename: G
authors.initials: G
authors.lastname: Freyer
authors.forename: E
authors.initials: E
authors.lastname: Pujade-Lauraine
authors.forename: E G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: J
authors.initials: J
authors.lastname: Barriuso
authors.forename: S
authors.initials: S
authors.lastname: Sandhu
authors.forename: D S-W
authors.initials: DS
authors.lastname: Tan
authors.forename: V
authors.initials: V
authors.lastname: Hartog
authors.forename: B
authors.initials: B
authors.lastname: Kuenen
authors.forename: R
authors.initials: R
authors.lastname: Ruijter
authors.forename: G B
authors.initials: GB
authors.lastname: Kristensen
authors.forename: M
authors.initials: M
authors.lastname: Nyakas
authors.forename: S
authors.initials: S
authors.lastname: Barrett
authors.forename: W
authors.initials: W
authors.lastname: Burke
authors.forename: D
authors.initials: D
authors.lastname: Pietersma
authors.forename: M
authors.initials: M
authors.lastname: Stuart
authors.forename: U
authors.initials: U
authors.lastname: Emeribe
authors.forename: E
authors.initials: E
authors.lastname: Boven
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000008:administration & dosage* / Q000009:adverse effects; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D052117:Benzodioxoles; D011799:Quinazolines; C515233:saracatinib; D016190:Carboplatin; D017239:Paclitaxel