Intra-arterial gemcitabine versus intravenous gemcitabine: Pharmacokinetic and pharmacodynamic sub-study of the TIGeR-PaC phase 3 clinical trial.

Abstract

732 Background: Localized, dual balloon catheter-mediated, intra-arterial delivery of gemcitabine (IAG) targeted to tumors/tissue can provide higher local drug potency. 1 Furthermore, IAG may result in decreased systemic drug concentration and associated side effects with superior tumor response due to intra-cellular delivery prior to conversion to its inactive metabolite, diflourodeoxyuridine (dF/dU). The ongoing TIGeR-PaC phase 3 trial is testing this approach in patients with locally advanced pancreatic cancer. Here we report the results of an 11-patient pharmacokinetics (PK) sub-study analysis within TIGeR-PaC. An association between systemic drug levels and a reduction in CA19-9 markers was also assessed. 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 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. Plasma from each sample was frozen and shipped to a reference lab for gemcitabine and dF/dU assays. Maximum plasma drug concentration (C max ) and the area under the drug plasma concentration curve (AUC) based on the terminal phase were compared between the two groups. CA19-9 levels were also measured prior to treatment and 2 weeks post-procedure. Results: As previously shown, IAG results in lower gemcitabine C max and AUC compared to IVG. 2 Additional analyses showed the dF/dU C max and AUC were higher for IAG compared to IVG, consistent with a more rapid conversion of gemcitabine to dF/dU with targeted IAG compared to systemic IVG. With IAG administration, there was a direct correlation between increased dF/dU levels and reduced CA19-9 levels ( r = 0.66). These results suggest the conversion of gemcitabine to dF/dU at the tissue level may provide a surrogate marker for drug response with IAG administration. Conclusions: In this analysis, localized, dual-balloon catheter-mediated IAG resulted in decreased systemic levels of gemcitabine compared to IVG, along with increased levels of its inactive metabolite dF/dU. Thus, in addition to providing increased local potency, the IAG approach, in which gemcitabine is rapidly converted to its inactive metabolite, may also be beneficial in decreasing gemcitabine-related systemic side effects. 1. Farsad K, et al. 2024. JVIR 35:1043-48 e3. 2. 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 (SD) IAG Group(N=11) IVG Group(N=5) Gemcitabine:  C max (mcg/mL) 12.9 (8.03) 14.6 (2.66)  AUC (hr ⋅ mcg/mL) 4.9 (3.10) 8.8 (2.22) dF/dU:  C max (mcg/mL) 48.3 (18.6) 30.6 (4.93)  AUC (hr ⋅ mcg/mL) 46.3 (15.2) 37.1 (5.21)