First-in-human study of a novel nucleoside analogue, CP-4126, in patients with advanced solid tumors

Abstract

2577 Background: CP-4126 (gemcitabine 5'-elaidic acid ester) is a novel nucleoside analogue with proven preclinical antitumor activity. Unlike gemcitabine, the intracellular uptake of CP-4126 is independent of nucleoside transporters. The aims of this study were to determine the safety, toxicity, MTD and the RD of CP-4126, to describe its pharmacokinetic (PK) characteristics, and to assess its preliminary antitumor activity. Methods: Patients (pts) with refractory solid tumors, performance status ECOG < 2, with adequate haematologic, renal and hepatic function were enrolled in this dose escalation study (1–6 pts per dose level (DL)). CP-4126 was administered on days (d) 1, 8 and 15 every 4 week by a 30 min IV infusion. Start dose was 30 mg/m2/d and the dose was increased by 100% until toxicity > CTCAE grade 2 occurred. Standard DLT definitions were used. Activity was assessed at the end of every 2nd cycle (cy). Plasma and urine PK were determined during d1 (24 hrs) of cy1; plasma at all DLs and urine at DL= 1400 mg/m2/d. Results: 39 pts have been included, (m =24; f =15 ), median age 60 (range 19–78), receiving 96 cycles (range 1–9) of treatment, with 1 pt/DL from 30 to 240 mg/m2/d. The first grade 2 AE (neutropenia) was reported at 480 mg/m2/d. Most frequent toxicities include nausea, vomiting, fatigue and anorexia, the majority of mild severity (grade 1–2). 5 DLTs have been reported; 800 mg/m2/d (1 pt - d8 dose delay >2 weeks due to grade 3 thrombocytopenia and anaemia); 1000 mg/m2/d (1 pt died 48 hrs after treatment start due to acute lung damage); 1400 mg/m2/d (1 pt - fatigue grade 3); 2 pts at 1600 mg/m2/d (grade 3 ALT/AST elevation [1 pt]; 1 pt grade 4 neutropenia and grade 3 fatigue). Stabilisation of disease (≥ 3 months) reported in 5 pts (pancreas, colon and ovarian cancer) lasting between 3.5 to 8 months. One ovarian pt had a 28.3% reduction in tumor mass. CP-4126 was detected in plasma up to 24 hrs post-dosing. AUC for dFdC exposure was significantly higher than reported with gemcitabine at comparable dose levels. Urinary excretion of the main metabolite dFdU during the first 24 hrs was approximately 60% of dose. Conclusions: CP-4126 is well tolerated and accrual is ongoing at 1400 mg/m2/d to establish RD for phase II studies. Updated results including plasma and urine PK will be presented. [Table: see text]