Phase I study of oral CP-4126, a gemcitabine analog, in patients with advanced solid tumors.

Abstract

e13078 Background: CP-4126 (gemcitabine-5′-elaidic acid ester) is a novel nucleoside analogue with preclinical antitumor activity. CP-4126 has been solubilized in a lipid-based formulation and encapsulated in nongelatine hard shell capsules. This dose- escalating study assesses the pharmacokinetics (PK), safety and preliminary antitumor activity of the oral formulation and determines the recommended dose (RD) for phases II. Methods: Patients with advanced refractory solid tumors, performance status ECOG ≤ 2, adequate hematologic, renal, and hepatic function are enrolling. The study has a two- step design; a nonrandomized dose-escalating step I with oral CP-4126 alone, followed by a randomized, cross-over step II comparing oral CP-4126 with IV gemcitabine (gem). In step I CP-4126 is given on days (d) 1, 8, 15 q4w in increasing doses until MTD and RD are established. Step II involves a cross-over design with oral CP-4126 at RD on d1 or d8 and IV gemcitabine (1000 mg/m2) on d1 or d8. Further in step II, from day 15 and all subsequent cycles, all patients will receive oral CP-4126. Serial blood samples are collected for PK analysis on d1 in step I and on d1 and 8 in step II. Results: The study is ongoing. 25 (m=8; f=17) patients (45-80 years age range) have been enrolled in step I at 7 dose levels (100–3000 mg), and have received 1 to 5 treatment cycles. Most had pancreatic, colon, breast, or ovarian carcinoma. Most frequent AEs are fatigue and AST/ALT increases, the majority being grade 1-2. One DLT was reported at 1300 mg: γGT grade 4, and ALT/AST and fatigue grade 3. Two patients showed disease stabilisation according to RECIST evaluation (23-25% reduction from baseline). RD has not yet been established. No CP-4126 was detected in plasma up to 1300 mg and only trace amounts appeared at higher dose levels. dFdC concentrations (Cmax) and exposure (AUC) increased linearly with CP-4126 dose, indicating that oral CP-4126 acts as a prodrug for gemcitabine. Conclusions: Oral CP-4126 is a prodrug for gemcitabine in humans. It is well tolerated at doses up to 3000 mg in a d1, 8, 15 q4w schedule and shows a good safety profile and an early efficacy signal compared with gemcitabine historical data. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Clavis Pharma Clavis Pharma