Low dosing regimens of floxuridine and methods of treatment of cancer using floxuridine

Abstract

The present disclosure provides low dose regimens of floxuridine and methods of treating cancer using the low dose regimens of floxuridine.

Description

LOW DOSING REGIMENS OF FLOXURIDINE AND METHODS OF TREATMENT OF CANCER USING FLOXURIDINEBACKGROUND

[0001] Primary liver cancer is one of the most common forms of cancer in the world and the third leading cause of cancer deaths worldwide. Secondary liver cancer, or metastasis in the liver, is a cancer that starts somewhere else in the body and then spreads to the liver. Examples of secondary liver cancer includes many common types of cancer, such as colon, rectum, lung, and breast cancer. One of the potentially effective treatments for liver cancer include hepatic arterial infusion (HAI) of floxuridine. However, one of the most common adverse events in subjects associated with hepatic arterial infusion of floxuridine is the development of biliary sclerosis in subjects, which results in the discontinuation of treatment with HAI floxuridine. Accordingly, there is a need for a new dosing regimen for effective treatments of liver disease, such as liver cancer, both primary and metastatic, to reduce the development of biliary sclerosis.BRIEF SUMMARY

[0002] The present disclosure is directed to low dosing regimens of floxuridine that demonstrate a similar clinical efficacy as higher dosing regimens of floxuridine by hepatic arterial infusion and reduce the development of biliary sclerosis and other toxic effects in subjects. The present disclosure also discloses methods of treatment of cancer by administration of floxuridine by hepatic arterial infusion (HAI) based on the low dosing regimens disclosed herein. Floxuridine is a pyrimidine analog and is described chemically as 5-fluorodeoxyuridine. Its chemical structure is shown below in Formula I.Formula I

[0003] In some aspects, the method comprises administering to the subject a dose of floxuridine in an amount less than 0.12 mg / kg / day by hepatic arterial infusion.

[0004] In some aspects, the dose of floxuridine is administered by hepatic arterial infusion via a pump.

[0005] In some aspects, the dose of floxuridine is an amount from about 0.01 mg / kg / day to about 0.1 mg / kg / day.

[0006] In some aspects, the dose of floxuridine is an amount from about 0.01 mg / kg / day to about 0.08 mg / kg / day.

[0007] In some aspects, the dose of floxuridine is an amount from about 0.01 mg / kg / day to about 0.6 mg / kg / day.

[0008] In some aspects, the dose of floxuridine is administered daily for about 30 days.

[0009] In some aspects, the dose of floxuridine is administered daily for about 28 days.

[0010] In some aspects, the dose of floxuridine is administered daily for about 14 days.

[0011] In some aspects, the dose of floxuridine is administered daily for less than 14 days.

[0012] In some aspects, the dose of floxuridine is administered daily for more than 14 days.

[0013] In some aspects, the dose of floxuridine is administered daily for about 7 days.

[0014] In some aspects, the total dose of floxuridine in a treatment cycle is less than 1.68 mg / kg or less.

[0015] In some aspects, the total dose of floxuridine in a treatment cycle is about 0.84 mg / kg.

[0016] In some aspects, the method further comprises administering concurrent systemic therapy.

[0017] In some aspects, the method further comprises administering concurrent regional liver therapy.

[0018] In some aspects, the method of treating cancer can further include administering radiotherapy.

[0019] In some aspects, the method further comprises administering to the subject an effective amount of dexamethasone. In some aspects, the effective amount of dexamethasone is an amount effective to function as an anti-inflammatory agent.

[0020] In some aspects, the method further comprises administering to the subject an effective amount of heparin. In some aspects, the effective amount of heparin is an amount effective to prevent clotting of the device, artery, and / or vein.

[0021] In some aspects, the method of treating cancer can further include administering an additional therapeutic agent. In some aspects, the additional therapeutic agent can be a chemotherapeutic agent. In some aspects, the additional therapeutic agent can be an immunotherapeutic agent.DETAILED DESCRIPTION

[0022] The present disclosure is directed to low dosing regimens of floxuridine and methods of treatment of cancer by administration of floxuridine by hepatic arterial infusion (HAI) based on the low dosing regimens. Without being bound to any particular theory, the low dosing regimens of floxuridine disclosed herein reduce the development of biliary sclerosis in subjects while preserving or nearly preserving the clinical efficacy of floxuridine treatment as compared to HAI floxuridine treatment with higher dosing.Definitions

[0023] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0024] As used herein, the term “or” is a logical disjunction (z.e., and / or) and does not indicate an exclusive disjunction unless expressly indicated as such with the terms “either,” “unless,” “alternatively,” and words of similar effect.

[0025] As used herein, the term “about” refers to ±10% of the noted value, unless otherwise specified, and unless the upper bound of the range would exceed 100% of the composition, in which case the upper limit of the range is limited to 99.9%. Thus, and by way of example only, a composition including about 10 weight percent of a given ingredient could have from 9 to 11 weight percent of the compound. Similarly, a composition including about 95 weight percent of a given ingredient could have from 85.5 to 99.9 weight percent of the ingredient in the composition.

[0026] The terms "treat," "treating," and "treatment," as used herein, refer to any type of intervention or process performed on, or administering an active agent to, a subject with the objective of reversing, alleviating, ameliorating, inhibiting, or slowing down theprogression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease or enhancing overall survival.

[0027] The term "therapeutically effective amount" refers to an amount of a compound that is effective in reducing, eliminating, treating or controlling the herein-described diseases and conditions or the symptoms of the herein-described diseases and conditions.Methods of Treatment

[0028] The disclosure provides low dosing regimens of floxuridine and methods of treatment of cancer by administration of floxuridine by hepatic arterial infusion (HAI) based on the low dosing regimens. Without being bound to any particular theory, the low dosing regimens of floxuridine disclosed herein reduce the development of biliary sclerosis and other toxic effects in subjects while preserving or nearly preserving the efficacy of HAI floxuridine treatment as compared to HAI floxuridine treatment with higher dosing. In some aspects, the subject can be a subject with any cancer that affects the liver. In some aspects, the subject can be a subject with primary liver cancer. In some aspects, the subject can be a subject with secondary liver cancer. In some aspects, the subject can be a subject with colon cancer that has spread to the liver. In some aspects, the subject can be a subject with cancer that started in the bile duct within the liver (intrahepatic cholangiocarcinoma). In some aspects, the subject can be a subject with hepatocellular carcinoma. In some aspects, the subject can be a subject with resectable cancer. In some aspects, the subject can be a subject with unresectable cancer.

[0029] In some aspects, the subject can be a subject with microscopic disease or one that is more prone to liver metastases such that the administration of of floxuridine treats microscopic disease (e.g., eliminates microscopic disease) and / or inhibits or slows down the progression from microscopic to macroscopic disease. In some aspects, the subject to be treated can be a subject with macroscopic disease.

[0030] In some aspects, the method comprises administering to the subject a dose of floxuridine in an amount less than 0.12 mg / kg / day by hepatic arterial infusion. In some aspects, the method comprises administering to the subject a dose of floxuridine in an amount from about 0.01 mg / kg / day to less than 0.12 mg / kg / day by hepatic arterial infusion. In some aspects, the dose of floxuridine is in an amount from about 0.01 mg / kg / day to about 0.11 mg / kg / day, about 0.01 mg / kg / day to about 0.1 mg / kg / day, about 0.01 mg / kg / day to about 0.09 mg / kg / day, about 0.01 mg / kg / day to about 0.08 mg / kg / day,about 0.01 mg / kg / day to about 0.07 mg / kg / day, about 0.01 mg / kg / day to about 0.06 mg / kg / day, about 0.01 mg / kg / day to about 0.05 mg / kg / day, about 0.01 mg / kg / day to about 0.04 mg / kg / day, about 0.01 mg / kg / day to about 0.03 mg / kg / day, about 0.01 mg / kg / day to about 0.02 mg / kg / day, about 0.02 mg / kg / day to less than 0.12 mg / kg / day, about 0.02 mg / kg / day to about 0.11 mg / kg / day, about 0.02 mg / kg / day to about 0.10 mg / kg / day, about 0.02 mg / kg / day to about 0.09 mg / kg / day, about 0.02 mg / kg / day to about 0.08 mg / kg / day, about 0.02 mg / kg / day to about 0.07 mg / kg / day, about 0.02 mg / kg / day to about 0.06 mg / kg / day, about 0.02 mg / kg / day to about 0.05 mg / kg / day, about 0.02 mg / kg / day to about 0.04 mg / kg / day, about 0.02 mg / kg / day to about 0.03 mg / kg / day, about 0.03 mg / kg / day to less than 0.12 mg / kg / day, about 0.03 mg / kg / day to about 0.11 mg / kg / day, about 0.03 mg / kg / day to about 0.10 mg / kg / day, about 0.03 mg / kg / day to about 0.09 mg / kg / day, about 0.03 mg / kg / day to about 0.08 mg / kg / day, about 0.03 mg / kg / day to about 0.07 mg / kg / day, about 0.03 mg / kg / day to about 0.06 mg / kg / day, about 0.03 mg / kg / day to about 0.05 mg / kg / day, about 0.03 mg / kg / day to about 0.04 mg / kg / day, about 0.04 mg / kg / day to less than 0.12 mg / kg / day, about 0.04 mg / kg / day to about 0.11 mg / kg / day, about 0.04 mg / kg / day to about 0.10 mg / kg / day, about 0.04 mg / kg / day to about 0.09 mg / kg / day, about 0.04 mg / kg / day to about 0.08 mg / kg / day, about 0.04 mg / kg / day to about 0.07 mg / kg / day, about 0.04 mg / kg / day to about 0.06 mg / kg / day, about 0.04 mg / kg / day to about 0.05 mg / kg / day, about 0.05 mg / kg / day to less than 0.12 mg / kg / day, about 0.05 mg / kg / day to about 0.11 mg / kg / day, about 0.05 mg / kg / day to about 0.10 mg / kg / day, about 0.05 mg / kg / day to about 0.09 mg / kg / day, about 0.05 mg / kg / day to about 0.08 mg / kg / day, about 0.05 mg / kg / day to about 0.07 mg / kg / day, about 0.05 mg / kg / day to about 0.06 mg / kg / day, about 0.06 mg / kg / day to less than 0.12 mg / kg / day, about 0.06 mg / kg / day to about 0.11 mg / kg / day, about 0.06 mg / kg / day to about 0.10 mg / kg / day, about 0.06 mg / kg / day to about 0.09 mg / kg / day, about 0.06 mg / kg / day to about 0.08 mg / kg / day, about 0.06 mg / kg / day to about 0.07 mg / kg / day, about 0.07 mg / kg / day to less than 0.12 mg / kg / day, about 0.07 mg / kg / day to about 0.11 mg / kg / day, about 0.07 mg / kg / day to about 0.10 mg / kg / day, about 0.07 mg / kg / day to about 0.09 mg / kg / day, about 0.07 mg / kg / day to about 0.08 mg / kg / day, about 0.08 mg / kg / day to less than 0.12 mg / kg / day, about 0.08 mg / kg / day to about 0.11 mg / kg / day, about 0.08 mg / kg / day to about 0.10 mg / kg / day, about 0.08 mg / kg / day to about 0.09 mg / kg / day, about 0.09 mg / kg / day to less than 0.12 mg / kg / day,about 0.09 mg / kg / day to about 0.11 mg / kg / day, about 0.09 mg / kg / day to about 0.10 mg / kg / day, about 0.1 mg / kg / day to less than 0.12 mg / kg / day, about 0.1 mg / kg / day to about 0.11 mg / kg / day, or about 0.11 mg / kg / day to less than 0.12 mg / kg / day, by hepatic arterial infusion.

[0031] In some aspects, the method comprises administering to the subject a dose of floxuridine about 0.01 mg / kg / day, about 0.02 mg / kg / day, about 0.03 mg / kg / day, about 0.04 mg / kg / day, about 0.05 mg / kg / day, about 0.06 mg / kg / day, about 0.07 mg / kg / day, about 0.08 mg / kg / day, about 0.09 mg / kg / day, about 0.1 mg / kg / day, about 0.11 mg / kg / day, or less than 0.12 mg / kg / day by hepatic arterial infusion. For example, for a 65 kg human, the method comprises administering to the subject a dose of floxuridine about 0.65 mg / day, about 1.3 mg / day, about 1.95 mg / day, about 2.6 mg / day, about 3.25 mg / day, about 3.9 mg / day, about 4.55 mg / day, about 5.2 mg / day, about 5.85 mg / day, about 6.5 mg / day, about 7.15 mg / day, or less than 7.8 mg / day by hepatic arterial infusion. By way of another example, for a 70 kg human, the method comprises administering to the subject a dose of floxuridine about 0.7 mg / day, about 1.4 mg / day, about 2.1 mg / day, about 2.8 mg / day, about 3.5 mg / day, about 4.2 mg / day, about 4.9 mg / day, about 5.6 mg / day, about 6.3 mg / day, about 7 mg / day, about 7.7 mg / day, or less than 8.4 mg / day by hepatic arterial infusion, and, for a 75 kg human, the method comprises administering to the subject a dose of floxuridine about 0.75 mg / day, about 1.5 mg / day, about 2.25 mg / day, about 3 mg / day, about 3.75 mg / day, about 4.5 mg / day, about 5.25 mg / day, about 6 mg / day, about 6.75 mg / day, about 7.5 mg / day, about 8.25 mg / day, or less than 9 mg / day by hepatic arterial infusion.

[0032] In some aspects, the dose of floxuridine can be administered by hepatic arterial infusion via a pump. Hepatic artery infusion pumps known by and available to one of ordinary skill in the art can be used to administer floxuridine, including, but not limited to, implantable pumps, external pumps, continuous flow pumps, and programmable pumps.

[0033] In some aspects, the dose of floxuridine is continuously administered for an indefinite period of time. In some aspects, the dose of floxuridine is continuously administered for about 3 years, about 2 years, about a year, about 9 months, about 6 months, about 3 months, about 2 months, about 1 month, about 30 days, about 29 days, about 28 days, about 27 days, about 26 days, about 25 days, about 24 days, about 23 days,about 22 days, about 21 days, about 20 days, about 19 days, about 18 days, about 17 days, about 16 days, about 15 days, about 14 days, about 13 days, about 12 days, about 11 days, about 10 days, about 9 days, about 8 days, about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day. In some aspects, the dose of floxuridine is continuously administered for less than 14 days. In some aspects, the dose of floxuridine is continuously administered for more than 14 days. In some aspects, the dose of floxuridine is administered until the cancer is treated or the desired therapeutic effect is achieved. In some aspects, the dose of floxuridine is administered up to the lifetime of the subject.

[0034] The concentration and volume of floxuridine to be administered and the flow rate can be determined by those of ordinary skill in the art in order to infuse the daily dose of floxuridine (e.g., about 0.01 mg / kg / day to less than 0.12 mg / kg / day).

[0035] In some aspects, floxuridine is administered for a treatment cycle. In some aspects, the treatment cycle is about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about a month, about 2 months, about 3 months, about 6 months, about 9 months, about a year, about 2 years, or about 3 years. In some aspects, the treatment cycle comprises 7 days on and 7 days off floxuridine. In some aspects, the treatment cycle comprises 14 days on and 7 days off floxuridine. In some aspects, the treatment cycle comprises 14 days on and 14 days off floxuridine. In some aspects, the treatment cycle comprises 14 days on and 1-14 days off floxuridine. In some aspects, the treatment cycle comprises 21 days on and 1-14 days off floxuridine. In some aspects, the treatment cycle comprises 21 days on and 7 days off floxuridine. In some aspects, the treatment cycle comprises 21 days on and 14 days off floxuridine. In some aspects, the treatment cycle comprises 28 days on and 1-14 days off floxuridine. In some aspects, the treatment cycle comprises 28 days on and 7 days off floxuridine. In some aspects, the treatment cycle comprises 28 days on and 14 days off floxuridine.

[0036] In some aspects, floxuridine can be administered in more than one treatment. In some aspects, floxuridine can be administered in one or several further treatment cycles(after initial treatment, e.g., the first infusion) with an interval of about 1 week to about 8 weeks between treatments. In some aspects, floxuridine can be administered in two or three treatments with an interval between each treatment of about two to about eight weeks. In some aspects, the interval between treatments is about 1 week to about 8 weeks, about 2 weeks to about 8 weeks, about 3 weeks to about 8 weeks, about 4 weeks to about 8 weeks, about 6 weeks to about 8 weeks, about 1 week to about 6 weeks, about 2 weeks to about 6 weeks, about 3 weeks to about 6 weeks, about 4 weeks to about 6 weeks, about 1 week to about 4 weeks, about 2 weeks to about 4 weeks, or about 3 weeks to about 4 weeks. In some aspects, the interval between treatments is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks. In some aspects, the interval between treatments is 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about28 days, about 29 days, about 30 days, about a month, about 2 months, or about 3 months.

[0037] Doses administered in each treatment cycle may be identical or different. The number of treatment cycles and the doses to be administered may be determined by the physician according to the physiological state of the patient, rising liver function tests, hepatic toxicity tests, biliary sclerosis, and the evolution of the disease. In some aspects, one or several further treatment cycles as described above are given during an indefinite period of time. In some aspects, one or several further treatment cycles as described above are given over the course of about 3 years. In some aspects, one or several further treatment cycles as described above are given over the course of about 2 years. In some aspects, one or several further treatment cycles as described above are given over the course of about 1 year. In some aspects, one or several further treatment cycles as described above are given until the cancer is treated or the desired therapeutic effect is achieved. In some aspects, one or several further treatment cycles as described above are given as long as the subject does not develop biliary sclerosis. In some aspects, one or several further treatment cycles as described above are given up to the lifetime of the subject.

[0038] In some aspects, the total dose of floxuridine in a treatment cycle is less than 1.68 mg / kg. In some aspects, the total dose of floxuridine in a treatment cycle is about 1.6 mg / kg or less, about 1.5 mg / kg or less, about 1.4 mg / kg or less, about 1.3 mg / kg or less, about 1.2 mg / kg or less, about 1.1 mg / kg or less, about 1.0 mg / kg or less, about 0.9 mg / kg or less, about 0.8 mg / kg or less, about 0.7 mg / kg or less, about 0.6 mg / kg or less, about 0.5 mg / kg or less, about 0.4 mg / kg or less, about 0.3 mg / kg or less, about 0.2 mg / kg or less, or about 0.1 mg / kg or less. In some aspects, the total dose of floxuridine in a treatment cycle is about 0.84 mg / kg. In some aspects, the total dose of floxuridine in a treatment cycle is about 0.42 mg / kg.

[0039] In some aspects, the total dose of floxuridine in a treatment cycle is about 0.1 mg / kg to about 1.6 mg / kg, about 0.1 mg / kg to about 1.5 mg / kg, about 0.1 mg / kg to about1.4 mg / kg, about 0.1 mg / kg to about 1.3 mg / kg, about 0.1 mg / kg to about 1.2 mg / kg, about 0.1 mg / kg to about 1.1 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 0.1 mg / kg to about 0.9 mg / kg, about 0.1 mg / kg to about 0.8 mg / kg, about 0.1 mg / kg to about 0.9 mg / kg, about 0.1 mg / kg to about 0.8 mg / kg, about 0.1 mg / kg to about 0.7 mg / kg, about 0.1 mg / kg to about 0.6 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.1 mg / kg to about 0.4 mg / kg, about 0.1 mg / kg to about 0.3 mg / kg, or about 0.1 mg / kg to about 0.2 mg / kg.

[0040] In some aspects, the total dose of floxuridine in a treatment cycle is about 0.2 mg / kg to about 1.6 mg / kg, about 0.2 mg / kg to about 1.5 mg / kg, about 0.2 mg / kg to about1.4 mg / kg, about 0.2 mg / kg to about 1.3 mg / kg, about 0.2 mg / kg to about 1.2 mg / kg, about 0.2 mg / kg to about 1.1 mg / kg, about 0.2 mg / kg to about 1 mg / kg, about 0.2 mg / kg to about 0.9 mg / kg, about 0.2 mg / kg to about 0.8 mg / kg, about 0.2 mg / kg to about 0.9 mg / kg, about 0.2 mg / kg to about 0.8 mg / kg, about 0.2 mg / kg to about 0.7 mg / kg, about 0.2 mg / kg to about 0.6 mg / kg, about 0.2 mg / kg to about 0.5 mg / kg, about 0.2 mg / kg to about 0.4 mg / kg, or about 0.2 mg / kg to about 0.3 mg / kg.

[0041] In some aspects, the total dose of floxuridine in a treatment cycle is about 0.3 mg / kg to about 1.6 mg / kg, about 0.3 mg / kg to about 1.5 mg / kg, about 0.3 mg / kg to about1.4 mg / kg, about 0.3 mg / kg to about 1.3 mg / kg, about 0.3 mg / kg to about 1.2 mg / kg, about 0.3 mg / kg to about 1.1 mg / kg, about 0.3 mg / kg to about 1 mg / kg, about 0.3 mg / kg to about 0.9 mg / kg, about 0.3 mg / kg to about 0.8 mg / kg, about 0.3 mg / kg to about 0.9 mg / kg, about 0.3 mg / kg to about 0.8 mg / kg, about 0.3 mg / kg to about 0.7 mg / kg, about0.3 mg / kg to about 0.6 mg / kg, about 0.3 mg / kg to about 0.5 mg / kg, or about 0.3 mg / kg to about 0.4 mg / kg.

[0042] In some aspects, the total dose of floxuridine in a treatment cycle is about 0.4 mg / kg to about 1.6 mg / kg, about 0.4 mg / kg to about 1.5 mg / kg, about 0.4 mg / kg to about1.4 mg / kg, about 0.4 mg / kg to about 1.3 mg / kg, about 0.4 mg / kg to about 1.2 mg / kg, about 0.4 mg / kg to about 1.1 mg / kg, about 0.4 mg / kg to about 1 mg / kg, about 0.4 mg / kg to about 0.9 mg / kg, about 0.4 mg / kg to about 0.8 mg / kg, about 0.4 mg / kg to about 0.9 mg / kg, about 0.4 mg / kg to about 0.8 mg / kg, about 0.4 mg / kg to about 0.7 mg / kg, about 0.4 mg / kg to about 0.6 mg / kg, or about 0.4 mg / kg to about 0.5 mg / kg.

[0043] In some aspects, the total dose of floxuridine in a treatment cycle is about 0.5 mg / kg to about 1.6 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 0.5 mg / kg to about1.4 mg / kg, about 0.5 mg / kg to about 1.3 mg / kg, about 0.5 mg / kg to about 1.2 mg / kg, about 0.5 mg / kg to about 1.1 mg / kg, about 0.5 mg / kg to about 1 mg / kg, about 0.5 mg / kg to about 0.9 mg / kg, about 0.5 mg / kg to about 0.8 mg / kg, about 0.5 mg / kg to about 0.9 mg / kg, about 0.5 mg / kg to about 0.8 mg / kg, about 0.5 mg / kg to about 0.7 mg / kg, or about 0.5 mg / kg to about 0.6 mg / kg.

[0044] In some aspects, the total dose of floxuridine in a treatment cycle is about 0.6 mg / kg to about 1.6 mg / kg, about 0.6 mg / kg to about 1.5 mg / kg, about 0.6 mg / kg to about1.4 mg / kg, about 0.6 mg / kg to about 1.3 mg / kg, about 0.6 mg / kg to about 1.2 mg / kg, about 0.6 mg / kg to about 1.1 mg / kg, about 0.6 mg / kg to about 1 mg / kg, about 0.6 mg / kg to about 0.9 mg / kg, about 0.6 mg / kg to about 0.8 mg / kg, or about 0.6 mg / kg to about 0.7 mg / kg.

[0045] In some aspects, the total dose of floxuridine in a treatment cycle is about 0.7 mg / kg to about 1.6 mg / kg, about 0.7 mg / kg to about 1.5 mg / kg, about 0.7 mg / kg to about1.4 mg / kg, about 0.7 mg / kg to about 1.3 mg / kg, about 0.7 mg / kg to about 1.2 mg / kg, about 0.7 mg / kg to about 1.1 mg / kg, about 0.7 mg / kg to about 1 mg / kg, about 0.7 mg / kg to about 0.9 mg / kg, or about 0.6 mg / kg to about 0.7 mg / kg.

[0046] In some aspects, the total dose of floxuridine in a treatment cycle is about 0.8 mg / kg to about 1.6 mg / kg, about 0.8 mg / kg to about 1.5 mg / kg, about 0.8 mg / kg to about1.4 mg / kg, about 0.8 mg / kg to about 1.3 mg / kg, about 0.8 mg / kg to about 1.2 mg / kg, about 0.8 mg / kg to about 1.1 mg / kg, about 0.8 mg / kg to about 1 mg / kg, or about 0.8 mg / kg to about 0.9 mg / kg.

[0047] In some aspects, the total dose of floxuridine in a treatment cycle is about 0.9 mg / kg to about 1.6 mg / kg, about 0.9 mg / kg to about 1.5 mg / kg, about 0.9 mg / kg to about 1.4 mg / kg, about 0.9 mg / kg to about 1.3 mg / kg, about 0.9 mg / kg to about 1.2 mg / kg, about 0.9 mg / kg to about 1.1 mg / kg, or about 0.9 mg / kg to about 1 mg / kg. In some aspects, the total dose of floxuridine in a treatment cycle is about 1 mg / kg to about 1.6 mg / kg, about 1 mg / kg to about 1.5 mg / kg, about 1 mg / kg to about 1.4 mg / kg, about 1 mg / kg to about 1.3 mg / kg, about 1 mg / kg to about 1.2 mg / kg, or about 1 mg / kg to about 1.1 mg / kg. In some aspects, the total dose of floxuridine in a treatment cycle is about 1.1 mg / kg to about 1.6 mg / kg, about 1.1 mg / kg to about 1.5 mg / kg, about 1.1 mg / kg to about 1.4 mg / kg, about 1.1 mg / kg to about 1.3 mg / kg, or about 1.1 mg / kg to about 1.2 mg / kg. In some aspects, the total dose of floxuridine in a treatment cycle is about 1.2 mg / kg to about 1.6 mg / kg, about 1.2 mg / kg to about 1.5 mg / kg, about 1.2 mg / kg to about 1.4 mg / kg, or about 1.2 mg / kg to about 1.3 mg / kg. In some aspects, the total dose of floxuridine in a treatment cycle is about 1.2 mg / kg to about 1.6 mg / kg, about 1.2 mg / kg to about 1.5 mg / kg, about 1.2 mg / kg to about 1.4 mg / kg, or about 1.2 mg / kg to about 1.3 mg / kg.

[0048] In some aspects, the total dose of floxuridine in a treatment cycle is about 1.3 mg / kg to about 1.6 mg / kg, about 1.3 mg / kg to about 1.5 mg / kg, or about 1.3 mg / kg to about 1.4 mg / kg. In some aspects, the total dose of floxuridine in a treatment cycle is about 1.4 mg / kg to about 1.6 mg / kg, about 1.4 mg / kg to about 1.5 mg / kg, or about 1.5 mg / kg to about 1.6 mg / kg.

[0049] In some aspects, the dose of floxuridine is continuously administered by the infusion techniques described herein via a pump. In some aspects, the pump can be refilled about every 2 to 4 weeks to maintain continuous administration. In some aspects, the pump can be refilled about every 2 to 3 weeks. In some aspects, the pump can be refilled about every week. In some aspects, the pump can be refilled about every 2 weeks. In some aspects, the pump can be refilled about every 3 weeks. In some aspects, the pump can be refilled about every 4 weeks.

[0050] In some aspects, the method of treating cancer can further include administering systemic therapy or regional liver therapy, such as chemotherapy, immunotherapy, and radiotherapy. In some aspects, the method of treating cancer can further comprise administering concurrent systemic therapy. In some aspects, the method of treating cancercan further comprise administering concurrent regional liver therapy. In some aspects, the method of treating cancer can further comprise administering radiotherapy. In some aspects, the cancer is liver cancer.

[0051] In some aspects, the method of treating cancer can further include administering at least one additional therapeutic agent. In some aspects, the at least one additional therapeutic agent can be a chemotherapeutic agent. In some aspects, the chemotherapeutic agent includes, but is not limited to: aminoglutethimide, amsacrine, anastrozole, asparaginase, beg, bicalutamide, bleomycin, buserelin, busulfan, campothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ironotecan, letrozole, leucovorin, leuprolide, levamisole, lomustine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, suramin, tamoxifen, temozolomide, teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, and vinorelbine. In some aspects, the cancer is liver cancer.

[0052] In some aspects, the chemotherapeutic agent can include: anti-metabolites / anti- cancer agents, such as pyrimidine analogs (5-fluorouracil, capecitabine, gemcitabine and cytarabine) and purine analogs, folate antagonists and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine)); antiproliferative / antimitotic agents including natural products such as vinca alkaloids (vinblastine, vincristine, and vinorelbine), microtubule disruptors such as taxane (paclitaxel, docetaxel), vincristin, vinblastin, nocodazole, epothilones and navelbine, epidipodophyllotoxins (teniposide), DNA damaging agents (actinomycin, amsacrine, anthracyclines, bleomycin, busulfan, camptothecin, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cytoxan, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, melphalan,merchlorethamine, mitomycin, mitoxantrone, nitrosourea, paclitaxel, plicamycin, procarbazine, teniposide, tri ethylenethiophosphoramide and etoposide (VP 16)); antibiotics such as dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin; enzymes (L-asparaginase); antiplatelet agents; antiproliferative / antimitotic alkylating agents such as nitrogen mustards (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan, nitrosoureas (carmustine (BCNU) and analogs, streptozocin), trazenes-dacarbazinine (DTIC); antiproliferative / antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, COX-2 inhibitors, dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory agents; antisecretory agents (breveldin); immunosuppressives (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); anti -angiogenic compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor (VEGF) inhibitors, fibroblast growth factor (FGF) inhibitors, epidermal growth factor (EGF) inhibitors); angiotensin receptor blocker; nitric oxide donors; anti-sense oligonucleotides; antibodies (trastuzumab); cell cycle inhibitors and differentiation inducers (tretinoin); mTOR inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), amsacrine, camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan (CPT-11) and mitoxantrone, topotecan, irinotecan), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, and prenisolone); growth factor signal transduction kinase inhibitors; mitochondrial dysfunction inducers and caspase activators; chromatin disruptors. In some aspects, the cancer is liver cancer.

[0053] In some aspects, the method of treating cancer can further include administering an effective amount of dexamethasone. In some aspects, the effective amount of dexamethasone is an amount effective to function as an anti-inflammatory agent. In someaspects, the method of treating cancer can further include administering an effective amount of heparin. In some aspects, the effective amount of heparin is an amount effective to prevent clotting of the device, artery, and / or vein. In some aspects, the cancer is liver cancer.

[0054] In some aspects, at least one additional therapeutic agent can be an immunotherapeutic agent. The term “immunotherapeutic agent” refers in general to any agent that produces a therapeutic effect by targeting the immune system or a component thereof. As used herein, the immunotherapeutic agent typically promotes an immune response, e.g. the agent may be an immunostimulatory agent or an inhibitor of an immunosuppressive agent (i.e. an anti-immunosuppressive agent). Immunotherapeutic agents can also include checkpoint blockers or inhibitors, chimeric antigen receptors (CARs), and adoptive T-cell therapy. In some aspects, the cancer is liver cancer.

[0055] It is to be appreciated that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections may set forth one or more but not all exemplary aspects of the present disclosure as contemplated by the inventor(s), and thus, are not intended to limit the present disclosure and the appended claims in any way.

Claims

WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a dose of floxuridine in an amount less than 0.12 mg / kg / day by hepatic arterial infusion.

2. The method of claim 1, wherein the dose of floxuridine is administered by hepatic arterial infusion via a pump.

3. The method of claim 1 or claim 2, wherein the dose of floxuridine is an amount from about 0.01 mg / kg / day to about 0.1 mg / kg / day.

4. The method of any one of claims 1-3, wherein the dose of floxuridine is an amount from about 0.01 mg / kg / day to about 0.08 mg / kg / day.

5. The method of any one of claims 1-4, wherein the dose of floxuridine is an amount from about 0.01 mg / kg / day to about 0.06 mg / kg / day.The method of any one of claims 1 to 5, wherein the dose of floxuridine is administered daily for about 30 days.The method of any one of claims 1 to 5, wherein the dose of floxuridine is administered daily for about 28 days.The method of any one of claims 1 to 5, wherein the dose of floxuridine is administered daily for about 14 days.

9. The method of any one of claims 1 to 5, wherein the dose of floxuridine is administered daily for less than 14 days.The method of any one of claims 1 to 5, wherein the dose of floxuridine is administered daily for more than 14 days.

11. The method of any one of claims 1 to 5, wherein the dose of floxuridine is administered daily for about 7 days.

12. The method of any one of claims 1 to 11, wherein the total dose of floxuridine in a treatment cycle is less than 1.68 mg / kg.

13. The method of any one of claims 1 to 12, wherein the total dose of floxuridine in a treatment cycle is about 0.84 mg / kg.

14. The method of any one of claims 1 to 13, further comprising administering concurrent systemic therapy.

15. The method of any one of claims 1 to 14, further comprising administering concurrent regional liver therapy.

16. The method of any one of claims 1 to 15, further comprising administering to the subject an effective amount of dexamethasone.

17. The method of any one of claims 1 to 16, further comprising administering to the subject an effective amount of heparin.

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