Phase I study of intravenous (IV) milataxel in adult patients with advanced malignant tumors

Abstract

2037 Background: M (TL139, MAC-321) is a novel taxane with activity in human xenograft models against tumors resistant to paclitaxel. The maximum tolerated dose (MTD) when given IV every 3 weeks was 35 mg/m2. The current study was designed to determine if the dose intensity of M could be increased by a weekly IV schedule. Methods: The primary objective of the study was to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT) and the recommended dose (RD) for phase II. Secondary objectives were pharmacokinetic (PK)/pharmacodynamic (PD) parameters of M given IV weekly and a preliminary estimate of efficacy in an expanded cohort at the RD. Key pt eligibility criteria included in adult pts with refractory malignant tumors, ECOG PS <3 and adequate hematologic, hepatic and renal function. Patients were not allowed concurrent strong inhibitors of cytochrome p450 3A4. Dose escalation was based on Fibonacci method. At the RD, additional pts with tumors that typically respond to taxane treatment were added. PK data were obtained on day 1 and 15. Results: A total of 32 pts were treated, 15 (6 females, 9 males) in the dose escalation part and 17 (15 females, 2 males) in the MTD confirmation part. The median number of doses was 11 (range 1–18). In the dose escalation phase, 3, 4, and 3 pts were treated at 8, 12, and 16 mg/m2 IV weekly without DLT. At 20 mg/m2, 2 of 5 pts developed DLT (1 pt - myalgia and neuropathy, 1 pt grade 4 neutropenia > 5 days in duration). The RD was 16 mg/m2 weekly. 17 more pts were treated at the RD. The most frequent grade 3 or 4 adverse events were asthenia (19%), nausea (9%), parethesia (9%) and neuropathy (9%). Of the 10 pts with breast cancer who were evaluable for response, one had a PR. Another breast cancer pt with a PR was a protocol violation and was not evaluable. In 20 pts at the MTD, the Tmax was 4 hr, the Cmax was 51.97 ng/mL, AUC 2711 ng*hr/mL, and the Vss was 1496 L/m2. Conclusions: Milataxel had an RD of 16 mg/m2 IV per week. Objective responses were observed in pts with metastatic breast cancer. No significant financial relationships to disclose.