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

SummaryBackground 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.

Systemic Therapy for Soft Tissue Sarcoma: Proposals for the Optimal Use of Pazopanib, Trabectedin, and Eribulin

“…The approved dose in Japan is based on the results of a phase I study in Japanese advanced STS patients who had received treatment with at least one anthracycline-based regimen [21]. Dose-limiting toxicity was experienced by two of three patients who received trabectedin at a dose of 1.5 mg/m 2 ; one had grade 3 increased creatine phosphokinase and grade 3 anorexia, and the other had grade 4 decreased platelet count.…”

Time lapse analysis of tumor response in patients with soft tissue sarcoma treated with trabectedin: A pooled analysis of two phase II clinical trials

“…Patients with histologically proven translocation‐related sarcoma and who previously received standard therapy were included 6 . In all patients, trabectedin was administered at a dosage of 1.2 mg/m 2 every 3 weeks according to the results of the preceding phase I study conducted in Japan 7 . Trabectedin treatment was delayed until the following criteria were met; neutrophil count more than 1500 cells per μL, platelet count more than 10 × 10 4 cells per μL, blood albumin more than 2.5 g/dL, total bilirubin less than 1.5 mg/dL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine phosphokinase (CPK) less than 2.5 times of upper limit of normal, and creatinine clearance more than 30 mL per minutes.…”

Efficacy and safety of trabectedin for patients with unresectable and relapsed soft‐tissue sarcoma in Japan: A Japanese Musculoskeletal Oncology Group study

“…13 In Japan, a phase 1 pharmacokinetic study of trabectedin administered to patients with advanced STS resulted in a recommended dose of 1.2 mg/m 2 as a 24-hour continuous infusion, which differs from the recommended dose of 1.5 mg/m 2 as a 24-hour continuous infusion in the United States and Europe. 14 In this dose setting, a phase 2, randomized, open-label study revealed the efficacy of trabectedin in comparison with best supportive care in patients with advanced TRS after standard chemotherapy. 6 In 2015, on the basis of this result, trabectedin was approved in Japan for the treatment of all histological types of STS.…”