Phase I and Pharmacokinetic Study of Trabectedin as a 1- or 3-hour Infusion Weekly in Patients with Advanced Solid Malignancies

Abstract

Purpose: This study was designed to determine the safety, tolerability, and pharmacokinetics, and to seek preliminary evidence of anticancer activity of trabectedin, a novel marine-derived DNA minor grove binder, when administered as a 1-hour or 3-hour i.v. infusion for 3 consecutive weeks every 4 weeks in patients with advanced solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) levels of trabectedin on these schedules, as well as to recommend doses for disease-directed studies. Experimental Design: A total of 32 and 31 patients were treated in sequential cohorts with trabectedin on the 1-hour schedule (doses ranging from 0.46 to 0.80 mg/m 2 ) and on the 3-hour schedule (doses ranging from 0.30 to 0.65 mg/m 2 ). Results: Neutropenia, transient elevations in hepatic transaminases and creatine phosphokinase, and fatigue precluded dose escalation above 0.70 mg/m 2 (1-hour schedule) and 0.65 mg/m 2 (3-hour schedule), which were determined to be the MTD levels, respectively. The pharmacokinetics of trabectedin on both schedules were characterized by a high clearance rate, a long terminal half-life, and a large volume of distribution. A patient with soft tissue sarcoma had partial response, and several soft tissue sarcoma patients had prolonged (≥6 months) stable disease. Conclusions: The MTD levels of trabectedin given weekly for 3 weeks every 4 weeks is 0.61 mg/m 2 as a 1-hour infusion and 0.58 mg/m 2 as a 3-hour infusion. The manageable toxicities at the MTDs, preliminary evidence of antitumor activity, pharmacokinetic profile, and the unique mechanistic aspects of trabectedin warrant further disease-directed evaluations on weekly schedules.

Phase I and Pharmacokinetic Study of Sequential Paclitaxel and Trabectedin Every 2 Weeks in Patients with Advanced Solid Tumors

“…PK studies of both paclitaxel and trabectedin revealed high clearance rates, long half-lives, and large volumes of distribution, and PK parameters were within the range of those reported in prior single-agent studies (14,36,37). Both paclitaxel and trabectedin are substrates of cytochrome P450 metabolism (CYP3A4 and CYP2C8 for paclitaxel; CYP3A4 for trabectedin) that may be induced or inhibited by other drugs.…”

“…Effects on WBC and neutrophils were generally reversible and rarely resulted in treatment delay. At the MTD level, grade 3 to 4 neutropenia was generally noted on day 14 (range, [7][8][9][10][11][12][13][14][15][16][17][18][19] and usually resolved to grade ≤2 on day 21 (range, 9-26). One patient each had grade 4 anemia and leukopenia, whereas four patients developed grade 4 neutropenia.…”

“…Based on experimental data indicating that the magnitude of cytotoxicity produced by paclitaxel and trabectedin was maximal when paclitaxel treatment preceded trabectedin treatment, and the overlapping antitumor spectra of these agents, particularly in ovarian and breast cancer (10,11,14,22,23), this phase I study evaluated the feasibility of administering paclitaxel and trabectedin in a sequential manner, simulating optimal preclinical conditions. The principal hematologic toxicity of both trabectedin (24,25) and paclitaxel (26)(27)(28) , the paclitaxel/ trabectedin regimen lacked relevant cumulative toxicity and was well tolerated when administered repeatedly.…”

“…The starting dose of trabectedin was 0.525 mg/m 2 , which is 9% lower than that recommended for trabectedin on a weekly 3-hour schedule (14). The planned dose escalation scheme (designated as paclitaxel/trabectedin in mg/m 2 ) based on the incidence of DLT at each proceeding dose level, as discussed below, was as follows: 9 /L for longer than 5 days; ANC of <1.0 × 10 9 /L with fever (≥38.5°C); platelets of <25 × 10 9 /L; grade 3 transaminitis for >7 days resulting in cycle delay or grade 4 transaminitis; any other grade 3/4 nonhematologic toxicity, except for nausea and/ or vomiting (in the absence of optimal prophylaxis and/or management), and treatment delay exceeding 1 week due to treatment-induced toxicity.…”

“…Based on the results of the aforementioned preclinical studies suggesting favorable antitumor interactions with the combination of trabectedin and paclitaxel, as well as their overlapping antitumor spectra, particularly with regard to breast and ovarian cancer (14), this phase I study sought to evaluate the feasibility, safety, pharmacokinetics (PK), drug-drug PK interactions, and preliminary antitumor activity of paclitaxel and trabectedin administered on an every-2-week schedule in patients with advanced solid malignancies. It was elected to administer trabectedin 24 hours after the paclitaxel treatment based on the superior antitumor activity shown with this sequence in preclinical studies, particularly when treatment with trabectedin occurred 24 hours after paclitaxel (9,10).…”