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

TY - JOUR

T1 - 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

AU - Greystoke, A.

AU - Blagden, S.

AU - Thomas, A. L.

AU - Scott, E.

AU - Attard, G.

AU - Molife, R.

AU - Vidal, L.

AU - Pacey, S.

AU - Sarker, Debashis

AU - Jenner, A.

AU - De-Bono, J. S.

AU - Steward, W.

PY - 2006/8

Y1 - 2006/8

N2 - 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.

AB - 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.

KW - carboplatin

KW - dolastatin 10 analogue

KW - phase I

KW - solid tumours

KW - TZT-1027

KW - ANTITUMOR-ACTIVITY

KW - ANTIMICROTUBULE AGENT

KW - CANCER

KW - CARCINOMA

KW - CELLS

KW - LUNG

U2 - 10.1093/annonc/mdl097

DO - 10.1093/annonc/mdl097

M3 - Article

SN - 0923-7534

VL - 17

SP - 1313

EP - 1319

JO - Annals of Oncology

JF - Annals of Oncology

IS - 8

ER -