A phase I study of a novel taxane, TL310, orally administered every week in patients (pts) with advanced solid tumors

Abstract

2544 Background: TL310 is a novel, oral taxane with potent pre-clinical activity in taxane-resistant model systems. This is the first study to evaluate the safety, tolerability and pharmacokinetics (PK) of TL310 in pts with advanced refractory solid tumors. Methods: Pts with adequate hematologic, renal, and liver function received TL310 administered orally on days 1, 8 and 15 of a 28-day cycle. Pts were continuously assessed for safety and dose-limiting toxicity (DLT) was based on first cycle toxicity only. A rapid dose escalation schedule was used (1 pt per dose level until ≥ grade 2 toxicity then 3–6 patients per cohort). The maximum tolerated dose (MTD) was defined as the dose level below that at which ≥ 2 of 3–6 pts experienced DLT. PK sampling was performed on days 1, 2, 3–4, 8, 15, 16, 17–18, 22 of cycle one. Serial imaging with CT was performed every 8 weeks to assess response. Results: 18 patients [M=11, F=7], ECOG PS ≤ 2 were treated with doses of 5 (1 pt), 10 (1pt), 20 (1pt), 40(2pts), 80 (5pts), 120 (3pts) and 160 mg/m2 (5pts). 1 pt had grade 2 vomiting at 80mg/m2. This, and subsequent, dose levels were expanded to include 3 pts. 3 pts (2 at 80 and 1 at 160 mg/m2) vomited immediately after drug administration during cycle 1 and were replaced. 1/5 patients experienced a DLT at 160 mg/m2 with G5 neutropenic sepsis, G4 neutropenia and G4 thrombocytopenia. No other grade 3/4 toxicities attributed to study drug have occurred. Of 18 patients assessable for response, 1 had a partial response (gastric cancer) at 80 mg/m2 and 6 had stable disease for > 2 cycles (esophageal 3, melanoma 1, ovary 1, cervix 1). The maximum concentration (Cmax) increased with dose up to 120 mg/m2, but appeared to plateau (86±6 ng/ml) in 4 of 5 patients at 160 mg/m2. TL310 has a half-life of up to 80 hours, but PK were very similar on successive courses of treatment. Conclusions: TL310 can be administered orally up to 160 mg/m2 on day 1, 8, 15 of a 28 day cycle and shows promising activity at doses below the MTD. The MTD has not yet been defined and dose escalation continues. No significant financial relationships to disclose.