Phase I and pharmacokinetics (PK) study of sequential paclitaxel and trabectedin every 2 weeks in patients with advanced solid tumors

Abstract

2029 Background: Trabectedin (ET-743) is a DNA minor-groove intercalating agent that blocks transcription factor activity, elicits G2/M cell cycle arrest, and induces apoptosis. Single agent activity has been demonstrated in soft tissue sarcoma (STS), breast, prostate and ovarian cancer. In preclinical studies sequential exposure of paclitaxel (P) followed by trabectedin (T) 24 hrs later resulted in synergy. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RD) of sequential P and T administered every 2 weeks in patients with advanced solid tumors. Methods: Escalating doses of P (80–120 mg/m2) over 1hr iv on day 1 and T ( 525–775 μg/m2) as 3 hrs iv day 2 every 2 weeks were administered. To evaluate drug:drug interactions, P was administered alone on day -7 in course 1 and PK studies performed courses 1 & 2. MTD was defined as ≥ 2/3 pts with dose limiting toxicity (DLT) in the 1st 2 courses. Results: 29 pts were enrolled and 27 were evaluable: median age was 48 yrs (19–82). M/F 16/13. Pts were treated over 5 dose levels: I 80/525 (n = 3), II 80/580 (n = 3), III 120/580 (n = 6), IV 120/650 (n = 11), V 120/775 (n = 4). A total of 213 courses of therapy were given, median number of course was 4 (range 1–28). There were 4 DLTs due to neutropenia delaying therapy > 1 week; one each at 120/580 (Grade 2) and 120/650 (Grade 4) and 2 at the MTD of 120/775 (Grade 4). Most common toxicities observed for P+T were neutropenia (24%), nausea (51%), vomiting (24%), transaminitis (23%), myalgia (24%) and alopecia (20%). One pt with PNET has an ongoing CR 16 months, one breast cancer pt (prior P failure) has PR 12 mo+ and 8 pts (6 STS) had SD > 3 mo (range 4–15 mo). There appear to be no marked drug:drug interactions for P and T. Preliminary non-compartmental PK results [geometric mean (CV%)] for T include t1/2 52.4 hr (43.6%); Cl l/hr/m2 31.6 (57.3%); Vss l/m2 1382 (69%) and for P are t1/2, 29.2 hr (39.1%); Cl l/hr/m2 15.3 (44.1%); Vss 213 l/m2 (72%). Conclusions: The recommended dose for this combination is paclitaxel 120 mg/m2 day 1 and trabectedin 650 μg/m2 day 2 administered every 2 weeks. Antitumor activity in STS and breast cancer, predictable PK parameters, and tolerable toxicity warrants further study of this combination. [Table: see text]