Cancer Chemotherapy and Pharmacology

, Volume 60, Issue 2, pp 285–293

Phase I study of TZT-1027, a novel synthetic dolastatin 10 derivative and inhibitor of tubulin polymerization, which was administered to patients with advanced solid tumors on days 1 and 8 in 3-week courses

Authors

    • Department of Medical OncologyKinki University School of Medicine
    • Department of Medical OncologyKinki University School of Medicine, Nara Hospital
  • Kazuhiko Nakagawa
    • Department of Medical OncologyKinki University School of Medicine
  • Takayasu Kurata
    • Department of Medical OncologyKinki University School of Medicine
  • Taroh Satoh
    • Department of Medical OncologyKinki University School of Medicine
  • Toshiji Nogami
    • Department of Medical OncologyKinki University School of Medicine
  • Koji Takeda
    • Department of Clinical OncologyOsaka City General Hospital
  • Shigeki Mitsuoka
    • Department of Respiratory MedicineOsaka City University Medical School
  • Naruo Yoshimura
    • Department of Respiratory MedicineOsaka City University Medical School
  • Shinzoh Kudoh
    • Department of Respiratory MedicineOsaka City University Medical School
  • Shunichi Negoro
    • Department of Clinical OncologyOsaka City General Hospital
  • Masahiro Fukuoka
    • Department of Medical OncologyKinki University School of Medicine
Original Article

DOI: 10.1007/s00280-006-0382-7

Cite this article as:
Tamura, K., Nakagawa, K., Kurata, T. et al. Cancer Chemother Pharmacol (2007) 60: 285. doi:10.1007/s00280-006-0382-7

Abstract

Purpose

To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of TZT-1027 (soblidotin), a dolastatin 10 analogue, in Japanese patients with advanced solid tumors when administered on days 1 and 8 in 3-week courses.

Methods

Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, and also met the following criteria: prior chemotherapy ≤2 regimens, Eastern Cooperative Oncology Group (ECOG) performance status ≤1, and acceptable organ function. The MTD was defined as the highest dose at which no more than one of six patients experienced a DLT during course 1. Pharmacokinetic samples were collected in courses 1 and 2.

Results

Eighteen patients were enrolled in the present study. Three doses (1.5, 1.65, and 1.8 mg/m2) were evaluated. Neutropenia was the principal DLT at doses of 1.65 and 1.8 mg/m2. In addition, one patient also experienced grade 3 pneumonia with neutropenia, and another patient experienced grade 3 constipation, neuropathy, grade 4 neutropenia, and hyponatremia as DLTs at 1.65 mg/m2. Phlebitis, the most frequent nonhematological toxicity, was improved by administration of additional saline after TZT-1027 administration. The MTD was 1.5 mg/m2, at which DLT was not observed in a total of nine patients. The pharmacokinetic profile did not differ from that for the European population. One patient with metastatic esophageal cancer achieved partial response, and each of two patients with non-small cell lung cancer had a minor response.

Conclusions

When TZT-1027 was administered on days 1 and 8 in 3-week courses to Japanese patients, the MTD was 1.5 mg/m2 and was lower than the value of 2.4 mg/m2 in European patients. However, antitumor activity was observed at low doses. TZT-1027 was tolerated well at the MTD, without grade 3 nonhematological toxicities or neutropenia up to grade 2. TZT-1027 is a promising new tubulin polymerization inhibitor that requires further investigation in phase II studies.

Keywords

DolastatinTZT-1027Phase IAntitubulinSolid tumors

Copyright information

© Springer-Verlag 2006