Phase I study of TZT-1027, a novel synthetic dolastatin 10 derivative, for the treatment of patients with non-small cell lung cancer.
OBJECTIVE
The purpose of this phase I study was to evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), the recommended dose for phase II study, pharmacokinetics, and antitumor activity of TZT-1,027 (soblidotin) in patients with non-small cell lung cancer (NSCLC) when administered every 3-4 weeks.


METHODS
Eligible patients had the following characteristics: stage III/b or IV NSCLC that was refractory to conventional therapy or for which no standard therapy was available; Eastern Cooperative Oncology Group (ECOG) performance status (PS) <or=2; adequate organ function; and age >or=20 and <75 years. The patients were administered TZT-1,027 in escalating doses from 0.5 to 5.6 mg/m(2). Pharmacokinetic samples were collected during each treatment course.


RESULTS
Forty-nine patients were enrolled. Three patients had DLTs, including neutropenia, neutropenia complicated by fever, myalgia, and neuropathic pain. The common toxicities included constipation, anorexia, alopecia, nausea, leukopenia, and neutropenia. One complete response and three partial responses were observed. The pharmacokinetic parameters (AUC and C (max)) of TZT-1,027 tended to increase linearly with dose.


CONCLUSIONS
DLTs included neutropenia, neutropenia complicated by fever, myalgia, and neuropathic pain. The MTD was 4.8 mg/m(2). The recommended phase II study dose of TZT-1027 is 4.8 mg/m(2) administered every 3-4 weeks.
Horti
J
J
National Institute of Oncology, 1122 Ráth Gy. u. 7-9, Budapest, Hungary. hortij@oncol.hu
Juhasz
E
E
Monostori
Z
Z
Maeda
K
K
Eckhardt
S
S
Bodrogi
I
I
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006402:Hematologic Diseases / Q000097:blood / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009842:Oligopeptides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D009842:Oligopeptides; C105791:soblidotin