Delivery of chemotherapy drug via an implantable iontophoresis drug delivery device

Abstract

A method delivers a drug to a target site of internal body tissue for treating cancer. The method provides a chemotherapy drug having a concentration of from about 10 mg / mL to about 40 mg / mL. Also provided is a surgically implantable iontophoresis device including a source electrode and a counter electrode. The iontophoresis device comprises a housing secured to the target tissue and defining a reservoir having an opening. The chemotherapy drug flows through the reservoir at a flow rate of from about 50 μL / min to about 7 mL / min. A localized electrical field is generated by applying a current of between about 1 mA to about 10 mA at the tissue of the target site inducing the chemotherapy drug to permeate the membrane. The method thus delivers by iontophoresis the chemotherapy drug, including gemcitabine hydrochloride and carboplatin, into the tissue of the target site.

Description

[0001] DELIVERY OF CHEMOTHERAPY DRUG VIA AN

[0002] IMPLANTABLE IONTOPHORESIS DRUG DELIVERY DEVICE

[0003] Cross-References

[0004] This application claims the benefit of U.S. Provisional patent application no. 63 / 698,954, filed September 25, 2024, entitled Implantable Reservoir for Use with a Medical Device and System for Interventional Drug Delivery; U.S. Provisional patent application no. 63 / 557,303, filed February 23, 2024, entitled Delivery of Gemcitabine Hydrochloride Via an Implantable Iontophoresis Drug Delivery Device; and U.S. Provisional patent application no. 63 / 749,361, filed January 24, 2025, entitled Delivery of mRNA by Iontophoresis, the contents of all three of which are incorporated herein in their entirety.

[0005] Background

[0006] The present application relates to treatment of cancer with chemotherapeutic drugs and, more particularly, the treatment of pancreatic cancer and oral cavity cancer using an implantable iontophoresis drug delivery device to deliver, for example, gemcitabine hydrochloride and carboplatin.

[0007] Pancreatic cancer is a devastating disease characterized by early and aggressive metastasis with a 5 -year survival rate of 13%. Surgical resection remains the only opportunity for cure. However, only 15- 20% of patients present with resectable disease at the time of diagnosis. Another approximately 45% of patients will have no evidence of distant metastases but will be considered unresectable due to involvement of surrounding vasculature. For these patients, several treatment paradigms have emerged including both chemotherapy and chemoradiotherapy.

[0008] Gemcitabine hydrochloride (FIG. 1A) is a chemotherapeutic drug comprising a nucleoside metabolic inhibitor indicated (1) in combination with carboplatin for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy; (2) in combination with paclitaxel for first-line treatment of metastatic breast cancer after failure of prior anthracycline- containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated; (3) in combination with cisplatin for the treatment of non-small cell lung cancer; and (4) as a first line treatment for patients with locally advanced or metastatic adenocarcinoma of the pancreas. However, with single agents such as gemcitabine hydrochloride, the one-year survival rate remains dismal at less than 20%. Over the past decade, cytotoxic combinations have shown improved survival over gemcitabine hydrochloride alone in patients with advanced or metastatic pancreatic cancer, leading to the use of cytotoxic combinations in patients with locally advanced disease. However, due to cumulative toxicity, most patients eventually require dose reductions or discontinuation all together. Given that surgery represents the only potential curative strategy, more effective therapies for patients with locally advanced pancreatic cancer that can convert them to surgically resectable candidates are urgently needed.

[0009] Moreover, current chemotherapies indicated for the treatment of pancreatic cancer are hampered by poor efficacy, development of refraction to therapy, and systemic toxicity. Development of a targeted delivery system of marketed chemotherapeutics could enhance efficacy at the site of the tumor, as well as improve tolerability by limiting systemic exposure. Local drug delivery technologies offer a promising adjunct to systemic delivery by facilitating the delivery of drug directly to the tumor site in a controlled manner. A key challenge of local drug delivery technologies, particularly polymeric -drug eluting technologies has been diffusion limitations. The lack of spatial distribution of drugs and elevated interstitial fluid pressures in solid tumors have relegated the use of many local drug delivery technologies to post-surgical therapy. Only a small number of local drug delivery technologies have demonstrated potentially curative preclimcal results for cancer applications, and far fewer have progressed toward clinical practice.

[0010] Recurrent oral cavity cancer also presents significant treatment challenges and is associated with a notably reduced prognosis. While the overall 5-year survival rate for oral cancer is approximately 68%, this rate diminishes substantially in cases of recurrence. Salvage surgery is a common approach for managing recurrent tumors; however, patients undergoing this procedure face a high risk of further recurrence, with studies indicating that 50-60% of these patients experience additional tumor recurrence. Moreover, the likelihood of distant metastasis in this population is less than 20%. These statistics underscore the aggressive nature of recunent oral cavity cancer and highlight the critical need for early detection and comprehensive treatment strategies to improve patient outcomes.

[0011] Carboplatin (FIG. IB) is a platinum-based chemotherapy drug used to treat various cancers, including oral cavity cancer. It functions by binding to DNA and interfering with cell division, leading to cancer cell death. Carboplatin is often used in combination with other treatments like radiation or other chemotherapy agents for head and neck cancers, including recunent or advanced oral cavity cancer. While it is generally less toxic to the kidneys and nerves than its predecessor, cisplatin, carboplatin still has significant toxicities. The most common side effects include bone marrow suppression, which can cause low blood cell counts, increasing the risk of infections, anemia, and bleeding complications. Other side effects include nausea, vomiting, fatigue, and, in some cases, hearing loss or neuropathy. Many patients have to stop using carboplatin due to severe myelosuppression, which can lead to life-threatening infections or bleeding, or because of hypersensitivity reactions that develop after multiple cycles. Its doselimiting toxicity often requires careful monitoring to balance efficacy with patient safety.

[0012] Iontophoresis is a minimally invasive method of drug delivery that involves the application of a mild electric current to propel high concentrations of charged or polarizable drug molecules into tissues. Iontophoresis is better known for transcutaneous drug delivery in which cunent is applied to the skin to enhance transport of small or large polar or hydrophilic molecules and peptides. Iontophoresis overcomes many of the diffusion limitations associated with chemotherapy and other drugs by adding electromotive and electroosmotic forces to the drug delivery process. Using iontophoresis to drive chemotherapy agents directly into the tumor has been successfully employed to treat bladder cancers via delivery ofmitomycin-C.

[0013] For the foregoing reasons, there is a need for delivery of chemotherapeutic drugs, such as gemcitabine hydrochloride and carboplatin, to the pancreas and the oral cavity. A preferred approach would include using iontophoresis to deliver the drugs into tumor tissue while minimizing systemic toxicity. The iontophoretic approach should demonstrate electrical safety and meet a target local tissue concentration.

[0014] Summary

[0015] A method is provided for delivering a drug to a target site of internal body tissue for treating cancer. The method comprises the steps of providing gemcitabine hydrochloride having a concentration of from about 10 mg / mL to about 40 mg / mL. Also provided is a surgically implantable iontophoresis device including a source electrode and a counter electrode. The iontophoresis device comprises a housing adapted to be secured to the target tissue and defining a reservoir having an opening covered by a membrane and an inlet and an outlet for fluid flow into and out of the reservoir. The chemotherapy drug flows through the reservoir at a flow rate of from about 50 μL / min to about 7 mL / min. A localized electrical field is generated by applying a current of between about 1 mA to about 10 mA between the source electrode and the counter electrode at the tissue of the target site for inducing the chemotherapy drug to permeate the membrane, lire chemotherapy drug is thus delivered by iontophoresis into the tissue of the target site. Gemcitabine hydrochloride and carboplatin are two non-limiting examples of the chemotherapy drug that may be delivered by the method.

[0016] In one aspect, the step of providing the chemotherapy drug comprises providing the chemotherapy drug having a concentration of about 19 mg / mL to about 30 mg / mL and, in another aspect, the step of providing the chemotherapy drug comprises providing the chemotherapy drug having a concentration of about 28.5 mg / mL.

[0017] The step of flowing the chemotherapy drug may comprise flowing the chemotherapy drug through the reservoir at a flow rate of from about 1 mL / min to about 4 mL / min. The step of flowing the chemotherapy drug may also comprise flowing the chemotherapy drug through the reservoir at a flow rate of about 4 mL / min.

[0018] In one aspect, the step of generating a localized electrical field comprises applying a cunent of between about 5 mA to about 10 mA. In another aspect, the step of generating a localized electrical field comprises applying a current of between about 7.5 mA to about 10 mA. The step of generating a localized electrical field can comprise applying a current of up to about 10 mA.

[0019] The chemotherapy drug is delivered by iontophoresis into the tissue of the target site at a treatment frequency of at least once per week. In one aspect, the chemotherapy drug is delivered for two treatments per week. In yet another aspect, the chemotherapy drug treatments are delivered for 4 to 8 consecutive weeks.

[0020] The target site may be the pancreas and the cancer is pancreatic cancer. The target site may also be the oral cavity and the cancer is oral cavity cancer.

[0021] In one aspect, the tissue at the target site is a solid tumor.

[0022] Brief Description of the Drawings

[0023] For a more complete understanding of the present invention, reference should now be had to the embodiments shown in the accompanying drawings and described below. In the drawings:

[0024] FIG. 1A is a chemical diagram for gemcitabine hydrochloride. Fig. IB is a chemical diagram for carboplatin.

[0025] FIG. 2 is a schematic view of an implantable iontophoresis chemotherapy drug delivery device and system during treatment of a pancreas where drug solution flows through a reservoir and excess drug not delivered to the pancreas is flowed to waste.

[0026] FIG. 3 is a schematic view of an implantable iontophoresis chemotherapy drug delivery device and system during treatment of a pancreas as shown in FIG. 2 where the drug solution is recirculated through the reservoir.

[0027] FIG. 4 is a schematic view of a system of iontophoresis for treatment of pancreatic cancer.

[0028] Description

[0029] A method is described for targeted delivery of the chemotherapeutic drug, including for example gemcitabine hydrochloride and carboplatin, via iontophoresis for treatment of pancreatic, oral cavity and other aggressive cancers. A novel implantable iontophoresis chemotherapy drug delivery device is available from Focal Medical, Inc., of Raleigh, North Carolina (hereinafter referred to as “the IOP”, “the IOP device” or “the IOP drug delivery device”). The IOP device is described in U.S. Patent No. 10,532,226, issued January 14, 2020; U.S. Patent No. 10,695,562, issued June 30, 2020; U.S. Patent No. 11,351,399, issued June 7, 2022; and U.S. Patent Application Publication No. 2022 / 0218978, the contents of all four of which are hereby incorporated by reference in their entirety. The IOP device may be used to deliver the chemotherapy drug directly, efficiently, and safely to the target tissue site, targeting drug delivery where drug concentrations are required to locally treat tumors, while at the same time, limiting systemic exposure of a relatively toxic drug product.

[0030] Referring to the FIGs. 2 and 3, the IOP drug delivery device is generally designated at 10. The IOP device 10 comprises an implantable housing 12 and an electrofluidic connector (EFC) 14 in the form of a tubular conduit or umbilical. The implantable housing includes a polysulfone drug reservoir 16. The reservoir 16 is configured to receive an electrode (not shown) for contacting a drug solution within the reservoir. The reservoir 16 is connected to a distal end of a multi -lumen tube 18 that terminates with a hybrid connector 20 at the proximal end. The multilumen tube 18 includes an inlet conduit for flow into the reservoir, an outlet conduit for flow out of the reservoir, and an electrical wire connected to the electrode. The hybrid connector 20 is externalized after implantation of the housing 12 and is configured to mate for fluid and electrical communication with the EFC 14.

[0031] The EFC 14 is a part of an external disposable subsystem that is connected to the implantable device 10 for delivery of therapeutic treatment. The EFC 14 comprises a bundle of tubes for passing fluid and an electrical wire. The inlet and outlet conduits from the reservoir 16 terminate at their proximal ends with the EFC 14 in fluidic connectors on the inlet and outlet conduits. An electrical connector is connected at the proximal end of the electrode wire. An intravenous set 22 is connected via the EFC 14 to the inlet conduit via the fluidic connector. A waste bag (FIG. 2) may be connected to the fluidic connector of the outlet conduit. An IV infusion pump moves fluid into the inlet conduit and through the implant reservoir 16 and out through the outlet conduit to the waste bag when flushing and priming the implanted drug delivery device. During treatment of the target tissue, a drug solution is pumped through the EFC 14 and the IOP drug delivery device 10. The drug solution may pass through the outlet conduit and the EFC 14 and is recirculated back into the drug solution bag (FIG. 3). A return, or counter, electrode (not shown) is placed on the subject’s body directly adjacent the source electrode. There may be a plurality of counter electrodes as needed, for example, up to five or more at selected locations. The counter electrodes are electrically connected to direct a current (DC) power supply and controller, completing the circuit. The power supply provides a specified voltage limited constant current during treatment application. A BK Precision PN 1739 or similar is suitable. A schematic view of a system of iontophoresis treating pancreatic cancer is shown in FIG. 4.

[0032] Nonclinical testing was conducted to assess the effect of local iontophoretic delivery of chemotherapeutic drugs, including gemcitabine hydrochloride and carboplatin, which is designed to maximize delivery to the target tissue (pancreatic and oral cavity tumors ) while minimizing systemic exposure to a toxic chemotherapeutic drug. The pharmacology, pharmacokinetics / toxicokinetics, and local toxicity of iontophoresis delivery of the chemotherapy drugs using the IOP device was initially investigated in mice and dogs. Single and repeat dose studies were conducted in mice and pigs, and single dose studies were conducted in dogs and pigs. The pharmacokinetic distribution, toxicology, and safety of iontophoresis delivery of the chemotherapy drugs via the IOP device was subsequently investigated in pigs.

[0033] Data from the nonclinical studies provided supportive information for both pharmacokinetics and toxicity assessment, therefore the terms pharmacokinetics and toxicokinetics are used interchangeably throughout this document. Biocompatibility studies using the IOP device were also conducted in accordance with ISO 10993-1 and FDA Guidance. Once development of the IOP device was complete, the total body of pharmacology, toxicology and pharmacokinetics / toxicokinetics evidence was reviewed, informing a pivotal toxicity study that was performed in pigs, which was conducted in accordance with Good Laboratory Practice (GLP) regulations.

[0034] Gemcitabine was initially made available as the marketed injectable product Gemzar® (NDA No. 020509) but has since been discontinued. Multiple generic injectable products; however, are available. Within this specification the trade name Gemzar and the generic name gemcitabine may be used interchangeably to refer to the same drug, while attempting to use the trade name when specifically referencing studies that were part of the original Gemzar package insert. The Agency's prior findings of safety and efficacy are relied on for the reference product Gemzar and generic products.

[0035] Example 1.

[0036] A pharmacology assessment of the IOP device delivering gemcitabine hydrochloride was investigated in a xenograft pancreatic cancer model in mice. The efficacy of gemcitabine hydrochloride delivered with the IOP device with gemcitabine hydrochloride was evaluated in a pharmacology study of an orthotopic patient-derived xenograft pancreatic cancer model in mice. lontophoretic delivery of saline only, and iontophoretic delivery of gemcitabine hydrochloride at a cunent of 2 mA, a gemcitabine hydrochloride drug concentration of 20 mg / mL at a flow rate of 50 uL / min for a treatment time of 10 minutes were both well tolerated, with no adverse test article-related effect on body weight, clinical pathology, or local histopathology. Delivery of 80 mg / kg gemcitabine hydrochloride via intravenous (IV) infusion was less well tolerated, as indicated by decreased body weight gain, but there was no treatment- related effect on clinical pathology parameters. Local iontophoretic delivery of gemcitabine hydrochloride significantly reduced cell proliferation and significant tumor regression was observed in 7 out of 7 (100%) of the animals that received gemcitabine hydrochloride via iontophoretic device delivery. Tumor regression was not observed in any other treatment group, including IV gemcitabine hydrochloride. These data indicated that local delivery of chemotherapeutic agents by iontophoresis may be a viable future treatment option for solid tumors.

[0037] Studies of the absorption and local distribution of gemcitabine hydrochloride following iontophoretic delivery using the IOP device were conducted in mice and dogs. Studies of the distribution of gemcitabine hydrochloride following iontophoretic delivery using the IOP device were conducted in pigs. The formulations used in these studies were marketed gemcitabine hydrochloride, either Gemzar or a generic equivalent, which was formulated with saline to achieve the desired concentrations. Bioanalytical methods were developed for analysis of gemcitabine hydrochloride in mouse, dog, and pig plasma and / or whole blood as well as pancreas tissue, and methods in dog plasma and pancreas underwent a rigorous qualification.

[0038] The absorption and distribution of the clinical route of administration of gemcitabine hydrochloride via the IOP device were simulated in studies of iontophoretic delivery of gemcitabine hydrochloride to the pancreas for up to 10 minutes in mice and up to 90 minutes in dogs and pigs. The local and systemic distribution of the clinical route of administration of IOP were established in studies of iontophoretic delivery of gemcitabine hydrochloride to the pancreas for 30, 60 or 90 minutes, and differing gemcitabine hydrochloride concentrations in 60-minute administration in pigs.

[0039] Example 2.

[0040] A study in the murme pancreatic derived xenograft tumor model was conducted with 3 animals per group. Animals received a single administration of either 40, 20 or lOmg / mL gemcitabine hydrochloride delivered by iontophoresis for 10 minutes at 1 mA or 2 mA with a flow rate of 50uL / min, or 80 mg / kg gemcitabine hydrochloride delivered via intravenous (IV) infusion over 10 minutes. Plasma, tumors, and organs were collected at 0-, 3-, and 6-hours post-dose for the device group, while the tissue from the IV group was collected starting at ten minutes post-infusion. Gemcitabine hydrochloride blood plasma exposure as measured by the area under the curve (AUG) for IV delivery was 52.0 hr*pg / ml, with no detectable gemcitabine hydrochloride in the blood plasma of the animals receiving gemcitabine hydrochloride via iontophoretic device. Gemcitabine hydrochloride tumor concentration AUC for iontophoretic delivery was an order of magnitude greaterthan IV delivery (344.4 versus 30.8 hr*pg / g, respectively).

[0041] Example 3.

[0042] Drug delivery of 10 and 40 mg / mL gemcitabine hydrochloride using an IOP of 10 mA at a flow rate of 1.5 mL / min over 60 minutes was performed successfully in dogs, with no local or systemic tolerability findings observed. A comparator group received 1000 mg / m2as an intravenous infusion over 30 minutes. There was a higher concentration of gemcitabine hydrochloride in the pancreas after IOP device delivery of gemcitabine hydrochloride compared with IV administration. The distance of gemcitabine hydrochloride transport in the pancreas after device treatment using high and low gemcitabine hydrochloride concentrations were statistically different at 9.6 mm and 6.4 mm away from the electrode, respectively. Minimal to no gemcitabine hydrochloride concentration in plasma was observed in the device groups, demonstrating decreased systemic exposure following device deliver}' of gemcitabine hydrochloride directly to the target organ when compared with IV administration.

[0043] Example 4.

[0044] A pilot study was conducted in two dogs. Using a low dose and a high dose of gemcitabine hydrochloride (10 mg / mL versus 40 mg / mL), iontophoresis with a flow rate of 1 mL / min and a current of 10 mA for both dogs, local exposure in the pancreas increased as the dose increased. Measured gemcitabine hydrochloride concentrations in pancreas tissue from a high dose animal demonstrated exposure trends related to both depth and distance, demonstrating a concentration gradient across the tissue. Gemcitabine hydrochloride delivery using the IOP device was well tolerated, and the device performed as expected, delivering gemcitabine hydrochloride directly to the target tissue in the pancreas.

[0045] Example 5.

[0046] Local tissue and plasma pharmacokinetics following IOP administration of gemcitabine hydrochloride was explored in mongrel dogs (1-3 per group). Treatment conditions were 10 mA of current, a flow rate of 1.0 mL / min and a gemcitabine hydrochloride concentration of 40 mg / mL Treatment times were 60 minutes, 90 minutes, and 180 minutes respectively for each group. Pre-treatment baseline blood plasma PK measurements were taken, followed by approximately every 15 minutes during treatment. Overall, gemcitabine hydrochloride concentration in plasma following iontophoresis administration of gemcitabine hydrochloride using the IOP device was low, indicating that localized administration of gemcitabine hydrochloride results in minimal systemic exposure. Increased duration of dosing time did not seem to impact plasma gemcitabine hydrochloride concentration. Most of the plasma samples from all groups ranged from 32.8 to 210 ng / mL gemcitabine hydrochloride and were generally consistent during the dosing period. Gemcitabine hydrochloride concentration in pancreas samples was variable. Gemcitabine hydrochloride concentration in the pancreas was highest at the location of dose administration and decreased as the distance from the site of dose administration increased.

[0047] Example 6. Local and systemic effects of multiple drug procedures and comparison of administration of gemcitabine hydrochloride via systemic intravenous delivery versus iontophoresis delivery was conducted using the IOP device in an acute and chronic model of domestic Yorkshire Cross pigs (1-4 / group). Seven (7) animals received IOP treatments with 38 mg / mL gemcitabine hydrochloride, 10mA current, 1 mL / min flow rate for 60 minutes. Three (3) animals were either terminated acutely, survived to 3 days, or for 7 days receiving one treatment. Six (6) animals were survived for 21 days, receiving 4 total treatments. In addition to the gemcitabine hydrochloride IOP animals, one animal was treated with IOP saline through the Test Article system within the same parameters, and one animal was administered 38 mg / mL gemcitabine hydrochloride via IV at a dose of 1000 mg / m2. In pancreatic tissue PK, gemcitabine hydrochloride levels were undetectable in any of the survival animals, and minimal in the acute animal. Overall, the data show the IOP device was able to focally deliver gemcitabine hydrochloride to the pancreas with little to no regional / systemic spread of the drug to the rest of the pancreas or systemic circulation. In contrast, the animal that received treatment via peripheral IV showed up to 25x higher levels of gemcitabine hydrochloride in the systemic plasma than any animal that received treatment via the IOP device.

[0048] Example 7.

[0049] An IOP device was surgically implanted in domestic Yorkshire pigs (2-3 per group) to test varying treatment conditions for the purpose of identifying a clinically relevant dose of gemcitabine hydrochloride in pancreatic tissue using the shortest treatment duration and lowest applied current. Treatment conditions of 30-, 60- or 90-minute duration with 5, 7.5 or 10 mA current were completed in 11 acute swine. Pancreatic tissue PK showed a trend of increase in total drug delivered as a function of increasing treatment duration and current. Overall, the IOP implant and treatment procedures were performed successfully. The device was able to focally deliver gemcitabine hydrochloride to the pancreas with little to no regional / systemic spread to the rest of the pancreas or systemic circulation.

[0050] Example 8.

[0051] The IOP device was utilized in eleven (11) purpose-bred domestic swine to assess the effects of the implanted device without treatments and twice weekly 10 mA, 60- or 90-min iontophoresis treatments with 38mg / mL gemcitabine hydrochloride in 16 treatments over an 8-week survival period. While surgical procedure related early death / termination prevented collection of PK data for three animals, plasma PK results in the remaining animals and foreshortened survival timepoint animals showed very little gemcitabine hydrochloride found systemically immediately post-treatment and was undetectable at 3 days post-treatment. Results indicated no obvious relationship between increased treatment duration and systemic gemcitabine hydrochloride levels post-treatment. Pancreatic tissue samples collected for PK analysis in one 60-min animal averaged 69080 ng / sample, comparable to levels observed in animals treated with 90min, 10mA, 38mg / mL treatment conditions in the previous acute study.

[0052] Example 9.

[0053] Following the chronic study that utilized high gemcitabine hydrochloride concentrations (38 mg / mL) and current (10mA) described above, an acute swine study (2 / group) was performed with a reduced current of 7.5mA and two gemcitabine hydrochloride concentrations, 19mg / mL and 38mg / mL, to assess post-treatment systemic and local levels of gemcitabine hydrochloride. Gemcitabine hydrochloride was delivered via a non-tunneled IOP device for a duration of 60 minutes. Overall, the IOP gemcitabine hydrochloride treatment procedures were performed without complications. Upon tissue analysis, local gemcitabine hydrochloride levels in the pancreas exhibited a positive correlation with the gemcitabine hydrochloride concentration administered. Systemic plasma gemcitabine hydrochloride levels approximately doubled between the 19mg / mL and 38mg / mL groups but were still low compared to IV gemcitabine hydrochloride administration results from a previous study.

[0054] Example 10.

[0055] Dose responses to twice weekly trans-pancreatic iontophoresis treatments with gemcitabine hydrochloride following 5, 10 and 16 treatments were assessed in ten (10) purpose-bred swine. Three (3) treatment applications were applied, 7.5 mA with 38 mg / mL gemcitabine hydrochloride at 4 mL / min, 7.5 mA with 19 mg / mL at 4 mL / min and 5.0 mA with 19 mg / mL for 1 mL / min to determine recommended treatment conditions for a pivotal nonclinical animal study. Very little gemcitabine hydrochloride was found to be present systemically in the IOP gemcitabine hydrochloride animals immediately posttreatment and was undetectable at 3 days post-treatment. Plasma PK result averages within groups show a positive correlation between post-treatment gemcitabine hydrochloride levels in the systemic plasma and the treatment variables of current and gemcitabine hydrochloride concentration. Pancreatic tissue PK results showed a strong positive correlation between tissue gemcitabine hydrochloride levels and treatment variables, current and gemcitabine hydrochloride concentration, between groups. Table 1. Summary of the ADME Studies Conducted with IOP Device

[0056] Overall, the pharmacokinetic profile of ACT-IOP-003 / 003.2 supports clinical evaluation of iontophoretic delivery of gemcitabine hydrochloride in patients with pancreatic cancer. Purpose-bred mongrel hound dogs and domestic Yorkshire cross swine were utilized to assess the performance, tolerability, and pharmacokinetics of gemcitabine hydrochloride administered using the IOP device as compared with intravenous (IV) administration.

[0057] Example 11.

[0058] One study assessed local tolerability during the dosing procedure, and to measure systemic exposure and drug distribution within the pancreas. Drug delivery of 10 and 40 mg / mL gemcitabine hydrochloride using the IOP drug delivery device was performed successfully in dogs, with no tolerability findings observed in the limited endpoints included in this study.

[0059] Example 12.

[0060] Drug delivery of 10 and 40 mg / mL gemcitabine hydrochloride using the IOP drug delivery device was performed in two dogs (1 / group). The device performed as expected, with no mechanical or electrical issues noted during testing or dose administration. Vital signs were collected, with findings limited to mild respiratory distress in the high dose animal which was mitigated by altering the anesthesia parameters. There were no gross pathology findings in the low dose animal, while an impression of the device was observed on the pancreas of the high dose animal at the dose site. Gemcitabine hydrochloride delivery using the IOP device was well tolerated, and the device performed as expected, delivering gemcitabine hydrochloride directly to the target tissue in the pancreas.

[0061] Example 13.

[0062] The tolerability of the IOP device delivering 40 mg / mL gemcitabine hydrochloride for up to 90 minutes was assessed in mongrel dogs (1-3 / group). There were no device-related complications such as death during the procedure, or gross abnormalities noted in the pancreas, liver, spleen, stomach, and duodenum of the animals treated. There were no acute systemic effects observed in the study animals based on the monitoring of vitals (body temperature, blood pressure, heart rate, and peripheral oxygen saturation) during and post-sham / gemcitabine hydrochloride administration. All animals survived through the planned termination at the end of the treatment procedure. Histopathology assessment indicated that treatment with the IOP device used to administer gemcitabine hydrochloride and / or saline in canines resulted in areas of pancreatic necrosis, mostly confined along the pancreatic surface, that were judged to be secondary to the device treatment, with no findings that were considered to be related to treatment with gemcitabine hydrochloride. Based on the data obtained in this study, IOP administration of gemcitabine hydrochloride and saline using the IOP device was well tolerated in dogs.

[0063] Example 14.

[0064] A pilot study of local tolerance of single and multi-IOP treatment via the IOP device, and IV administration of 38mg / mL gemcitabine hydrochloride for 60 minutes was assessed in domestic Yorkshire cross swine. IOP delivery methods were utilized in a single treatment acute, 3-day and 7-day pigs (1 / group) to demonstrate the drug delivery method previously performed in the canine model was tolerable in the pig model. Six animals were survived for three (3) weeks receiving four (4) IOP gemcitabine hydrochloride (n=4), IOP saline (n= 1) or IV gemcitabine hydrochloride (n=l) treatments. The purpose of the study was to evaluate in the pig model (1) the ability to implant the device, (2) local tolerability of multiple drug procedures, (3) compare tolerability of gemcitabine hydrochloride via systemic (IV) delivery versus iontophoresis delivery, and (4) tolerability of gemcitabine hydrochloride iontophoresis delivery versus saline iontophoresis delivery.

[0065] All treatment procedures (with gemcitabine hydrochloride or saline) were performed without complications involving animal health or safety. Survival animals remained relatively healthy throughout the in-life duration, and clinical pathology excursions did not present any clinical symptoms. Gross necropsy showed all implant sites had an expected healing response to the implant, including fibrotic capsular formations which varied by survival duration.

[0066] Example 15.

[0067] An acute study was conducted to evaluate the effect of differing treatment conditions for gemcitabine hydrochloride delivery with the IOP device. A total of 11 Yorkshire Cross swine were enrolled in this acute study with the objective of identifying a treatment time and treatment current (mA) pair, via a statistically designed experimental approach, that came closest to delivering a clinically relevant dose of gemcitabine hydrochloride into the pancreatic tissue using the shortest treatment duration and lowest applied current. Overall, the data showed that the device implant onto the pancreas and the gemcitabine hydrochloride treatment procedures via iontophoresis with the IOP device were well tolerated by the animals.

[0068] Example 16.

[0069] A chronic tolerability study was then conducted to evaluate the effects of the treatment conditions tested in the previous acute study in an extended duration chronic model of healthy swine over an ~8-week treatment period. For chronic tolerability study, eleven (11) domestic Yorkshire Cross swine underwent surgical implant of the IOP device on the surface of the pancreas. The original study design included three (3) implant-only control animals, and four (4) animals to receive either 60 or 90 min IOP treatments of 38 mg / mL gemcitabine hydrochloride at a current of 10mA and infusion rate of ImL / min. The resulting study design was (n=2) Control, (n=3) 60min IOP treatments, and (n=3) 90min IOP treatments.

[0070] During treatment procedures for three (3) animals, it was not possible to complete treatment within delivery specifications (maintaining constant current and voltage under 12V), and the pigs were terminated early in order to determine an assignable root cause. Issues were concluded to be unrelated to functionality of the IOP device. Despite voltage variations during treatments, all treatment procedures were performed without complications involving animal health or safety. Control (implant only) animals were generally healthy and experienced no major complications during the study duration. No clinically relevant trends in body weight changes or clinical pathology excursions were observed in any animal. At gross necropsy, most animals had an expected healing response to the implanted device. Abnormalities were limited to adhesions in the abdomen, enlarged lymph nodes and a discolored spleen. Histopathology showed animals terminated early due to the inability to complete treatment within the device delivery specifications had moderate to severe necrosis and mineralization, and a zone of autolysis in one animal at the device treatment site. Higher voltage excursions that were observed in earlier IOP treatments were attributed to the accumulation of air bubbles in the reservoir between treatments, that were shown to be displaced and removed by adjustments to animal position and saline flushes of the device. Higher voltages were seen at later treatments that could not be mitigated with air bubble displacement. Histopathological results indicated a cumulative fibrotic tissue response at the treatment site that correlated with a hypothesized increase in electrical resistance of the treated tissue during subsequent treatments.

[0071] With one study cohort representing implant only, no treatment, and two study cohorts representing the clinical treatment maximums in current (10mA), drug concentration (38 mg / mL), treatment time (either 60 or 90 minutes), as well as treatment frequency (16 treatments) and duration (twice a week for 8 weeks), this study achieved some very important endpoints in (1) reproducibly eliciting a typical and acceptable foreign body response from the non-treatment cohort (implant only), and (2) eliciting a local tissue response from the treatment cohorts that required steadily increasing voltages to complete the treatment (ultimately exceeding the specified 12V limit). With treatment ceiling conditions established, these study data recommend conducting additional pilot studies with milder treatment conditions (lower current, lower starting drug concentration, reduced time, and treatment frequencies) to identify the clinically acceptable ranges in treatment conditions where the target drug concentration can be delivered within the functional specifications of the IOP drug device and system.

[0072] Example 17.

[0073] An acute study was subsequently conducted using a reduced current of 7.5 mA and gemcitabine hydrochloride concentrations of 19 mg / mL and 38 mg / mL to evaluate the effects of different gemcitabine hydrochloride concentrations under identical treatment conditions of current, flow rate (4 mL / min) and duration (60 min) on local and systemic drug delivery. These milder conditions demonstrated the ability to continue to deliver a potentially therapeutic dose to the tissue while maintaining low systemic spillover.

[0074] Example 18.

[0075] A final pilot chronic study in pigs was conducted to evaluate the local tolerance and physiological response to three (3) clinically relevant treatment applications to identify optimal treatment conditions that would be used in a nonclinical safety study. Ten (10) domestic (Yorkshire Cross) swine underwent surgical implantation of the IOP device and were subjected to twice weekly trans-pancreatic IOP treatments with gemcitabine hydrochloride via the IOP device and system. Three (3) clinically relevant treatment conditions were applied within three study groups over a 60 minute treatment period: Group A animals received treatments with a reconstituted gemcitabine hydrochloride concentration of 38 mg / mL, 7.5 mA cunent, and 4 mL / min flow rate, Group B animals received 19 mg / mL, 7.5 mA current, and 4 mL / min flow rate, and Group C animals received 19 mg / mL, 5 mA current, 1 mL / min flow rate. All treatments were applied twice weekly for a duration of 60 minutes. Animals within each group were subjected to 5, 10, or 16 treatments prior to terminal sacrifice.

[0076] Study animals survived to scheduled sacrifice with no clinical health concerns. All animals gained weight appropriately for their respected survival duration and remained in ideal body condition. There were no clinically relevant excursions within hematology or serum chemistry results at any time point. There was no appreciable implant- or treatment-mediated trend in amylase or lipase levels suggestive of pancreatic injury or dysfunction. Grossly, all implant sites appeared to be within expected healing response stages for the respected survival durations. Other gross abnormalities were unremarkable. Consistent with gross findings, no findings of concern for safety of implant or treatment were identified during histopathological evaluation.

[0077] Overall, the data collected on this study demonstrated that implantation and gemcitabine hydrochloride treatment with the IOP device and system was well tolerated by all study animals under all treatment conditions evaluated. Furthermore, these data were appropriate to inform the optimal treatment conditions for future safety studies.

[0078] Example 19.

[0079] Six (6) domestic swine were utilized in a pivotal nonclimcal GLP safety study to characterize the safety and physiologic response to treatment with the IOP device when employed under clinically relevant implant methods and treatment conditions formulated from the previous studies. Animals were laparoscopically implanted with the IOP device and subjected to twice weekly trans-pancreatic iontophoresis treatment with gemcitabine hydrochloride using the IOP device and system over the course of eight (8) weeks, beginning post-operative Week 1. All animals received gemcitabine hy drochloride at a concentration of 28.5 mg / mL (flowing into the device at a rate of 4 mL / min over 60 minutes of treatment infusion) using an iontophoresis current of 7.5 milliampere (mA). Five (5) animals successfully completed the sixteen (16) prescribed treatments and survived to scheduled termination. The animals remained in good clinical health, and no adverse events were encountered in these animals throughout the in-life duration. Assessments of overall animal health inclusive of daily clinical observations, weekly veterinary physical examinations, weekly body weights, and weekly body condition scores suggested that all full -term animals remained in excellent clinical health and ideal body condition throughout the study. No implant- or treatment-mediated trends in abnormal clinical pathology parameters were identified, and no changes in amylase and lipase levels were observed. Together, these results indicate no pancreatic injury or impairment of pancreatic function. The gross findings at necropsy in the five (5) full term animals were representative of typical and expected changes for the device type, implantation procedure, implant location, and survival time point; there were no gross findings suggestive of a safety concern for the chronic implantation and use of the IOP device and system. The implantable drug reservoir of the IOP device was considered to have minimal to no histological reaction. There were no histological indicators of systemic toxicity in all non-target and downstream organ systems and tissues as evaluated in line with ISO 10993-11. Based on the data obtained in this study, the physiological response to twice weekly trans-pancreatic iontophoresis treatment with gemcitabine hydrochloride utilizing the implantable iontophoresis chemotherapy delivery device demonstrated no concern for safety when employed under clinically relevant conditions.

[0080] Example 20.

[0081] An in-vitro test was conducted to determine the amount of drug delivered into tissue-mimicking agarose gels by the IOP delivery device. This in-vitro study used the same IOP devices used in prior in- vivo study examples in order to generate correlative, predictive results between the in-vitro tossue- mimicking model and the in-vivo testing. Fifteen agarose gels were prepared. The IOP delivery device was used to deliver gemcitabine hydrochloride into the gels under the following varied conditions of drug concentration (19, 28.5 and 38 mg / mL), current (5, 7.5 and 10 mA), and flow rate (1, 4 and 7 mL / min) for 60 minutes.

[0082] Fifteen gel tests (13 tests plus 2 replicates) were completed in five testing sessions using three IOP delivery devices. A stainless-steel counter electrode was placed in a base under the gel and the IOP delivery device was placed on top of the gel. The amount of drug delivered to each gel as a function of the variables was evaluated. Data analysis shows that the drug concentration has the greatest influence on the total amount of drug delivered while the current and flow rate are evenly matched. A linear model fits the data well and provided insight for planning iontophoretic drug delivery conditions for the IOP delivery device.

[0083] Table 2. Summary of the Toxicology Studies Conducted with Implantable Iontophoresis Chemotherapy Delivery Device with Gemcitabine Hydrochloride

[0084] TOXICOLOGY OVERVIEW

[0085] The toxicology profile of the IOP device supports the clinical use of iontophoretic delivery of gemcitabine hydrochloride in patients with pancreatic cancer.

[0086] Example 21.

[0087] An in-vitro test was conducted to determine the amount of carboplatin delivered into tissuemimicking agarose gels by the IOP delivery device to generate correlative, predictive results between the in-vitro tissue-mimicking model and future in-vivo testing. The IOP delivery device was used to deliver carboplatin into the gels under the following varied conditions of drug concentration (5 mg / mL and 10 mg / mL), current (2.5, 5 and 10 mA), flow rate (1 and 3 mL / min), treatment time (60 minutes), diluent (saline, dextrose and water), and semi-permeable membrane pore size (5 and 20 kDa).

[0088] Sixteen gel tests (8 tests, 2 replicates each) were completed in three testing sessions using two IOP delivery devices. A stainless-steel counter electrode was placed in a base under the gel and the IOP delivery device was placed on top of the gel. The amount of drug delivered to each gel as a function of the variables was evaluated. Data analysis shows that the drug concentration has the greatest influence on the total amount of drug delivered, followed by current and flow rate. Modeling the data provided insight for planning in-vivo iontophoretic drug delivery conditions for the IOP delivery device. Example 22.

[0089] Three (3) companion canines (33 lbs or greater, with diagnosis of oral cavity cancer, with a tumor that is at least 1.5 cm in all directions), one female border collie (age = 11 years), one male mutt (age = 11 years), and one male coonhound (age = 8 years) were utilized in a pilot nonclinical, non-GLP safety study to characterize the safety and physiologic response to treatment with the IOP device when employed under clinically relevant placement methods and treatment conditions formulated from the previous studies. Animals were put under general anesthesia and placed on a treatment table with their body stabilized using a radiation pillow shaped to the specific canine patient. The device reservoir was inserted into the oral cavity and a device stand was used to ensure there was proper and consistent pressure of the device on the tumor for the treatment. Canines were subjected to one treatment of trans-tumor iontophoresis treatment with carboplatin using the IOP device and system, were recovered, and then were evaluated for 3 weeks post treatment. All animals received carboplatin at a concentration of 10 mg / mL (flowing into the device at a rate of 1 mL / min over 60 minutes of treatment infusion) using an iontophoresis current of 2.5 milliampere (mA). Three (3) animals successfully completed the prescribed treatment and survived. The animals remained in good clinical health, and no adverse events were encountered in these animals throughout the study duration. Assessments of overall animal health inclusive of weekly clinical observations, weekly veterinary physical examinations, weekly body weights, and weekly body condition scores suggested that all animals remained in excellent clinical health and ideal body condition throughout the study. No device- or treatment-mediated trends in abnormal clinical pathology parameters were identified. Together, these results indicate no oral cavity injury or impairment of oral cavity function. The gross findings at recovery in the three (3) animals were representative of typical and expected changes for the device type, treatment procedure and treatment location; there were no gross findings suggestive of a safety concern for the acute treatment and use of the IOP device and system. The drug reservoir of the IOP device was considered to have minimal to no histological reaction. In addition to the acceptable safety results, all dogs experienced tumor volume reductions ranging from 13% to 33% after 3 weeks following the single treatment, as measured by computed tomography scans. Based on the data obtained in this study, the physiological response to a single dose of trans-tumor iontophoresis treatment with carboplatin utilizing the iontophoresis chemotherapy delivery device demonstrated no concern for safety and showed evidence of efficacy when employed under clinically relevant conditions.

[0090] IOP device parameters such as cunent, delivery time, drug concentration, drug flow rate and treatment frequency have been investigated in in-vitro and in-vivo nonclinical studies in order to maximize the concentration of gemcitabine hydrochloride in the tumor while minimizing the concentration of gemcitabine hydrochloride in blood plasma. Results from these studies demonstrated that doses of gemcitabine hydrochloride that resulted in therapeutically relevant tumor gemcitabine hydrochloride concentrations could be delivered while keeping blood plasma gemcitabine hydrochloride concentrations low. This is true even with treatment frequency of more than once per week, which is the current recommended dosage frequency for IV delivery of gemcitabine.

Claims

We claim:

1. A method of delivering a drug to a target site of internal body tissue for treating cancer, the method comprising the steps of: providing a chemotherapy drug having a concentration of from about 10 mg / mL to about 40 mg / mL; providing a surgically implantable iontophoresis device including a source electrode and a counter electrode, the iontophoresis device comprising a housing adapted to be secured to the target tissue and defining a reservoir having an opening covered by a membrane and inlet and an outlet for fluid flow into and out of the reservoir: flowing the chemotherapy drug through the reservoir at a flow rate of from about 50 μL / min to about 7 mL / min; and generating a localized electrical field by applying a current of between about 1 mA to about 10 mA between the source electrode and the counter electrode at the tissue of the target site for inducing the chemotherapy drug to permeate the membrane, wherein the chemotherapy drug is delivered by iontophoresis into the tissue of the target site at a treatment frequency of greater than once per week.

2. The method as recited in claim 1, wherein the step of providing chemotherapy drug comprises providing gemcitabine hydrochloride.

3. The method as recited in claim 1, wherein the step of providing chemotherapy drug comprises providing carboplatin.

4. The method as recited in claim 1, wherein the step of providing chemotherapy drug comprises providing chemotherapy drug having a concentration of about 19 mg / mL to about 30 mg / mL;5. The method as recited in claim 1, wherein the step of providing chemotherapy drug comprises providing chemotherapy drug having a concentration of about 28.5 mg / mL.

6. The method as recited in claim 1, wherein the step of flowing the chemotherapy drug through the reservoir at a flow rate of from about 1 mL / min to about 4 mL / min.

7. The method as recited in claim 1, wherein the step of flowing the chemotherapy drug comprises flowing chemotherapy drug through the reservoir at a flow rate of about 4 mL / min.

8. The method as recited in claim 1, wherein the step of generating a localized electrical field comprises applying a current of between about 5 mA to about 10 mA.

9. The method as recited in claim 1, wherein the step of generating a localized electrical field comprises applying a current of between about 7.5 mA to about 10 mA.

10. The method as recited in claim 9, wherein the step of generating a localized electrical field comprises applying a current up to about 10 mA.

11. The method as recited in claim 1, wherein the chemotherapy drug is delivered for 10 to 180 minutes per treatment.

12. The method as recited in claim 11, wherein the chemotherapy drug is delivered for 30 to 90 minutes per treatment.

13. The method as recited in claim 1, wherein chemotherapy drug is delivered for two treatments per week.

14. The method as recited in claim 13, wherein the chemotherapy drug treatments are delivered for 4 to 8 consecutive weeks.

15. The method as recited in claim 1, wherein the target site is the pancreas, and the cancer is pancreatic cancer.

16. The method as recited in claim 1, wherein the target site is the oral cavity, and tire cancer is in tire oral cavity.

17. The method as recited in claim 1, wherein the tissue at the target site is a solid tumor

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