Abstract A95: Local iontophoretic delivery of FOLFIRINOX minimizes systemic toxicity for the treatment of pancreatic cancer
Authors: Byrne James D. , Jajja Mohammed R. , Schorzman Allison N. , Keeler Amanda W. , O'Neill Adrian T. , Luft James C. , Zamboni William C. , DeSimone Joseph M. , Yeh Jen Jen 
Published: October 2015

Systemic toxicity and poor delivery of many cytotoxic agents restrict their utility in the treatment of pancreatic cancer. Newer drug regimens, such as FOLFIRINOX, are limited to patients with the best performance status due to substantial toxicity. In an attempt to mitigate systemic toxicity, improve delivery and thus the efficacy of cytotoxic agents, we have developed modalities for the localized iontophoretic delivery of cytotoxic agents to primary pancreatic tumors. Iontophoretic delivery of mitomycin C, dexamethasone, and lidocaine have been successfully implemented for bladder cancer, anterior uveitis, and regional anesthesia.

We initially evaluated the local iontophoretic device delivery of gemcitabine (GEM) to orthotopic patient-derived xenograft (PDX) models of pancreatic cancer. Devices were surgically implanted when tumors reached a median volume of 200 mm3, as determined by high-resolution 3D ultrasound. High-performance liquid chromatography (LC) analysis of the tumors directly after a single treatment showed a mean concentration of 229.4±233.0 µg/g for device delivery compared to 19.4±15.9 µg/g for intravenous (IV) delivery. Tumor pharmacokinetics (PK) as measured by area under the curve (AUC) was 384.1 hr*µg/g for device and 30.8 hr*µg/g for IV delivery; plasma GEM AUC was undetectable for device and 65.2 hr*µg/mL for IV delivery. To evaluate the tumor response to device delivery of GEM (DEVGEM), twice weekly treatments were administered for 7 weeks. DEVGEM resulted in significant tumor regression in 7 of 7 mice, outperforming IVGEM and the control arms of IV and device saline. Mice treated with DEVGEM had a mean log2-fold change in tumor volume of -0.8 compared to a mean log2-fold change in tumor volume of 1.1 for IVGEM, 3.0 for IV saline, and 2.6 for device saline groups (p &lt; 0.01). DEVGEM was better tolerated based on greater body weight gain compared to IVGEM with minimal changes in alanine transaminase and lipase. Overall, DEVGEM resulted in tumor regression in 7/7 mice compared to no regression (0/7) in the IVGEM group while maintaining low systemic exposure of GEM. The safe and effective delivery of GEM in the PDX models supported the extension of this delivery modality to the more effective, but highly toxic regimen of FOLFIRINOX.

Dose toxicity studies in mice were performed and IV dosing of FOLFIRINOX was determined. A doublet regimen (oxaliplatin (OX)/leucovorin (LV) followed by fluorouracil (FU)/irinotecan(IRI)), which leverages the potentiation of FU activity by LV and possible enhancement of IRI activity by OX, was used for both device and IV delivery. To evaluate the PK of device delivery of FOLFIRINOX, devices were implanted in PDX mice and a single treatment was administered. LC- and inductively coupled plasma-mass spectrometry analysis of the tumors directly after the treatment revealed a 33-fold greater concentration of FU (261.1±321.5 vs 8.0±2.1 µg/g), 31-fold greater concentration of OX (15.6±7.6 vs 0.5±0.3 µg/g), and 3-fold greater concentration of IRI (21.7±9.3 vs 7.2±1.9 µg/g) for device delivery compared to IV FOLFIRINOX. Analysis of plasma, pancreas, liver, and kidney showed significantly lower concentrations of drugs after device delivery compared to IV delivery, suggesting that device delivery of FOLFIRINOX will have minimal systemic toxicity. Long-term therapeutic studies in orthotopic PDX models of pancreatic cancer are ongoing. The local iontophoretic delivery of chemotherapeutics, especially FOLFIRINOX, has the potential to surpass conventional techniques of treatment by driving cytotoxic therapies directly into the tissue. This has potential paradigm shifting implications for the treatment of pancreatic cancer for patients with unresectable non-metastatic disease, palliation of local symptoms, and may be considered as a neoadjuvant modality prior to surgery.

Citation Format: James D. Byrne, Mohammed R. Jajja, Allison N. Schorzman, Amanda W. Keeler, Adrian T. O'Neill, James C. Luft, William C. Zamboni, Joseph M. DeSimone, Jen Jen Yeh. Local iontophoretic delivery of FOLFIRINOX minimizes systemic toxicity for the treatment of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A95.