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

Takafumi Ueda,Kan Yonemori,Masashi Ando,Shigeki Kakunaga,Kenji Yamada,Akira Kawai,Hideshi Sugiura

doi:10.1007/s10637-014-0094-5

Abstract

Summary 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/m2, given as a 24-h continuous infusion every 21 days. The dose was escalated to 1.2 mg/m2 and then to 1.5 mg/m2, 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/m2: 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/m2 than at the lower doses. Pharmacokinetic analysis showed that the area under the concentration-time curve at a dose of 1.2 mg/m2 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/m2 in Japanese patients with STS. Trabectedin may be especially effective against translocation-related sarcomas.

Highlights

Soft tissue sarcomas (STS) are a heterogeneous group of rare malignant tumors of mesenchymal origin that account for less than 1 % of all adult malignancies
The protocol was approved by an independent review board at each investigational site, and written informed consent was obtained from all patients before enrollment
As for histological type of sarcoma, fusion gene was confirmed in five patients, The median number of treatment cycles was 4, 4, and 2 at dose level 1, 2, and 3, respectively

Summary

Introduction

Soft tissue sarcomas (STS) are a heterogeneous group of rare malignant tumors of mesenchymal origin that account for less than 1 % of all adult malignancies. Sarcoma translocations and the associated chimeric oncoproteins provide attractive targets for therapeutic intervention, given that these fusion proteins are critical for disease pathogenesis and tumor-cell survival, and no alternative pathways exist to avoid their blockade [2,3,4,5]. As for chemotherapy, doxorubicin and ifosfamide, given sequentially as single agents or in combination, have been used as standard treatment for most histologic subtypes of advanced STS to date [7], the outcomes of patients with advanced or metastatic sarcoma remain poor over the past two decades, with an estimated median survival of approximately 1 year from the start of first-line therapy [8,9,10,11]. Pazopanib, a multitargeted tyrosine kinase inhibitor has demonstrated single-agent activity in patients

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Conclusion