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

A. Greystoke, S. Blagden, A. L. Thomas, E. Scott, G. Attard, R. Molife, L. Vidal, S. Pacey, Debashis Sarker, A. Jenner, J. S. De-Bono, W. Steward*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

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/m(2) 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 1.6mg/m(2) 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/m(2) 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 1.6mg/m(2) and carboplatin AUC 5. No evidence of a PK interaction between these agents was observed.

Original languageEnglish
Pages (from-to)1313-1319
Number of pages7
JournalAnnals of Oncology
Volume17
Issue number8
DOIs
Publication statusPublished - Aug 2006

Keywords

  • carboplatin
  • dolastatin 10 analogue
  • phase I
  • solid tumours
  • TZT-1027
  • ANTITUMOR-ACTIVITY
  • ANTIMICROTUBULE AGENT
  • CANCER
  • CARCINOMA
  • CELLS
  • LUNG

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