title: A phase I study of intravenous TZT-1027 administered on day 1 and day 8 of a three-weekly cycle in combination with carboplatin given on day 1 alone in patients with advanced solid tumours.
abstract: BACKGROUND
  TZT-1027 is a tubulin-binding drug and synthetic derivative of dolastatin-10 with cytotoxic and antivascular activity in vitro and in vivo. Studies have demonstrated anti-tumour activity in several tumour types.
  
  
  METHODS
  Patients were treated with escalating doses of TZT-1027 and carboplatin at doses from 1.6 to 2.0 mg/m2 and AUC 4 and 5 respectively. For pharmacokinetic analysis, plasma sampling was done during the first course using a high-performance liquid chromatographic assay.
  
  
  RESULTS
  14 patients received a total of 55 cycles at three dose levels. Dose limiting toxicities (DLTs) were first observed with 1.6 mg/m2 TZT-1027 and carboplatin AUC 5; 1 patient had grade 4 neutropenia and a delay in day 8 treatment occurred in two patients (gr 2 fatigue, gr 3 diarrhoea). At TZT-1027 2 mg/m2 and carboplatin AUC 5, one patient experienced grade 3 paralytic ileus. The most frequent toxicities were neutropenia, anaemia, fatigue, constipation, infection and vomiting. Peripheral neuropathy was reported in 36% of patients. One patient (pancreatic adenocarcinoma) achieved a partial response lasting 181 days. Pharmacokinetic analysis did not demonstrate any interaction between TZT-1027 and carboplatin.
  
  
  CONCLUSIONS
  The recommended phase II dose is TZT-1027 1.6 mg/m2 and carboplatin AUC 5. No evidence of a PK interaction between these agents was observed.
authors.affiliation: Drug Development Unit, Royal Marsden Hospital, Sutton, UK.
authors.forename: A
authors.initials: A
authors.lastname: Greystoke
authors.forename: S
authors.initials: S
authors.lastname: Blagden
authors.forename: A L
authors.initials: AL
authors.lastname: Thomas
authors.forename: E
authors.initials: E
authors.lastname: Scott
authors.forename: G
authors.initials: G
authors.lastname: Attard
authors.forename: R
authors.initials: R
authors.lastname: Molife
authors.forename: L
authors.initials: L
authors.lastname: Vidal
authors.forename: S
authors.initials: S
authors.lastname: Pacey
authors.forename: D
authors.initials: D
authors.lastname: Sarkar
authors.forename: A
authors.initials: A
authors.lastname: Jenner
authors.forename: J S
authors.initials: JS
authors.lastname: De-Bono
authors.forename: W
authors.initials: W
authors.lastname: Steward
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009842:Oligopeptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D016190:Carboplatin; C105791:soblidotin