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.
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.
Greystoke
A
A
Drug Development Unit, Royal Marsden Hospital, Sutton, UK.
Blagden
S
S
Thomas
A L
AL
Scott
E
E
Attard
G
G
Molife
R
R
Vidal
L
L
Pacey
S
S
Sarkar
D
D
Jenner
A
A
De-Bono
J S
JS
Steward
W
W
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
D000970:Antineoplastic Agents; D009842:Oligopeptides; D016190:Carboplatin; C105791:soblidotin