The TIGeR-PaC phase 3 clinical trial examining intra-arterial gemcitabine versus intravenous gemcitabine: Pharmacokinetic and pharmacodynamic sub-study.

Abstract

e16463 Background: Intra-arterial delivery of gemcitabine (IAG) targeted to tumors/tissue may provide higher local drug potency. 1 Furthermore, IAG may result in decreased systemic drug concentration and associated side effects due to intracellular delivery prior to conversion to gemcitabine’s inactive metabolite, difluorodeoxyuridine (dFdU). The ongoing TIGeR-PaC phase 3 trial is testing this approach in patients with locally advanced pancreatic cancer. Here we report the results of a 16-patient pharmacokinetics (PK) and pharmacodynamics sub-study within TIGeR-PaC. Methods: PK analyses were performed for a total of 16 participants across 6 TIGeR-PaC study sites; 11 participants received IAG with the RenovoCath dual balloon catheter at 1000 mg/m 2 over 20 minutes and 5 participants received intravenous gemcitabine (IVG) at 1000 mg/m 2 over 30 minutes. Blood was collected at T = -5, 10, 15, 20, 30, 40, 60, and 90 minutes from the onset of infusion for gemcitabine and dFdU assays. Maximum plasma drug concentration (C max ) and the area under the drug plasma concentration curve from time zero to the last measurable concentration (AUC 0-t ) were compared between the two groups. CA 19-9 tumor marker levels were measured prior to treatment and 2 weeks post-procedure. The relationship between AUC 0-t and the percent change in CA 19-9 levels was assessed; 3 patients with normal CA 19-9 baseline values were excluded from the analysis. Results: As previously shown, IAG results in lower gemcitabine C max and AUC 0-t compared to IVG. 2 Additional analyses showed the dFdU C max and AUC 0-t were higher for IAG compared to IVG, consistent with a more rapid conversion of gemcitabine to dFdU with targeted IAG compared to systemic IVG. With IAG administration, there was a direct correlation between increased dFdU levels and a reduction in CA 19-9 levels (Pearson’s r = 0.75; P = 0.034). These results suggest the conversion of gemcitabine to dFdU at the tissue level may provide a surrogate marker for drug response with IAG administration. Conclusions: In this analysis, localized IAG resulted in decreased systemic levels of gemcitabine compared to IVG, along with increased levels of its inactive metabolite dFdU. Thus, in addition to providing increased local potency, the IAG approach, in which gemcitabine is rapidly converted to its inactive metabolite, may be beneficial in decreasing gemcitabine-related systemic side effects. Clinical trial information: NCT03257033. Farsad K, et al. 2024. JVIR 35:1043-48 e3. Novelli P, et al. 2025. J Clin Oncol 43(4_suppl):719. Clinical trial information: NCT03257033 . Effects of treatment mode on mean pharmacokinetic parameters. PK parameter, mean (SE) IAG Group(N=11) IVG Group(N=5) P -value Gemcitabine: C max (mcg/mL) 12.9 (2.42) 14.6 (1.19) 0.535 AUC (hr ⋅ mcg/mL) 4.9 (0.94) 8.8 (0.99) 0.018 dFdU: C max (mcg/mL) 48.3 (5.61) 30.6 (2.20) 0.012 AUC (hr ⋅ mcg/mL) 46.3 (4.59) 37.1 (2.33) 0.097