Phase I and pharmacokinetic study of trabectedin, a DNA minor groove binder, administered as a 24-h continuous infusion in Japanese patients with soft tissue sarcoma.

Abstract

BACKGROUND:

Trabectedin is a novel anticancer agent used to treat soft tissue sarcoma (STS). This phase I study of trabectedin was performed to determine the recommended dose for phase II studies in Japanese patients with STS.

METHODS:

Patients who had STS refractory to, or who could not tolerate, anthracycline-based chemotherapy were enrolled. The starting dose of trabectedin was 0.9 mg/m(2), given as a 24-h continuous infusion every 21 days. The dose was escalated to 1.2 mg/m(2) and then to 1.5 mg/m(2), using a "3 + 3" cohort expansion design. Plasma samples were collected for pharmacokinetic analysis.

RESULTS:

Fifteen patients received 1 of 3 dose levels of trabectedin. Dose-limiting toxicity occurred in two of three patients at 1.5 mg/m(2): 1 had a grade 3 increase in creatine phosphokinase and grade 3 anorexia, and the other had grade 4 platelet count decreased. Frequent grade 3 or 4 adverse events (AEs) included elevations of alanine aminotransferase and aspartate aminotransferase and decrease in neutrophil count. The frequency and severity of AEs were clearly greater at 1.5 mg/m(2) than at the lower doses. Pharmacokinetic analysis showed that the area under the concentration-time curve at a dose of 1.2 mg/m(2) was adequate to produce antitumor activity. A partial response was obtained in three patients with translocation-related sarcomas (1 each with myxoid liposarcoma, synovial sarcoma, and extraskeletal Ewing sarcoma).

CONCLUSIONS:

The recommended dose of trabectedin for phase II studies is 1.2 mg/m(2) in Japanese patients with STS. Trabectedin may be especially effective against translocation-related sarcomas.

• Authors: Takafumi Ueda, Shigeki Kakunaga, Masashi Ando, Kan Yonemori, Hideshi Sugiura, Kenji Yamada, Akira Kawai
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 4 Pg. 691-9 (Aug 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24696229 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Dioxoles
• Tetrahydroisoquinolines
• DNA
• Trabectedin

Topics

• Adult
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Area Under Curve
• DNA (drug effects)
• Dioxoles (administration & dosage, adverse effects, pharmacokinetics)
• Drug Administration Schedule
• Female
• Humans
• Male
• Middle Aged
• Sarcoma (drug therapy)
• Tetrahydroisoquinolines (administration & dosage, adverse effects, pharmacokinetics)
• Trabectedin
• Young Adult