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WO2025085591A1 - Schémas posologiques à faible dose de floxuridine et méthodes de traitement du cancer à l'aide de floxuridine - Google Patents

Schémas posologiques à faible dose de floxuridine et méthodes de traitement du cancer à l'aide de floxuridine Download PDF

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Publication number
WO2025085591A1
WO2025085591A1 PCT/US2024/051708 US2024051708W WO2025085591A1 WO 2025085591 A1 WO2025085591 A1 WO 2025085591A1 US 2024051708 W US2024051708 W US 2024051708W WO 2025085591 A1 WO2025085591 A1 WO 2025085591A1
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day
floxuridine
days
aspects
dose
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David Dove
Jonathan Reis
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Jnd Therapeutics Inc
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Jnd Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • 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.
  • HAI hepatic arterial infusion
  • 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.
  • 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.
  • HAI hepatic arterial infusion
  • Floxuridine is a pyrimidine analog and is described chemically as 5-fluorodeoxyuridine. Its chemical structure is shown below in Formula I.
  • 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.
  • the dose of floxuridine is administered by hepatic arterial infusion via a pump.
  • the dose of floxuridine is an amount from about 0.01 mg/kg/day to about 0.1 mg/kg/day.
  • the dose of floxuridine is an amount from about 0.01 mg/kg/day to about 0.08 mg/kg/day.
  • the dose of floxuridine is an amount from about 0.01 mg/kg/day to about 0.6 mg/kg/day.
  • the dose of floxuridine is administered daily for about 30 days.
  • the dose of floxuridine is administered daily for about 28 days.
  • the dose of floxuridine is administered daily for about 14 days.
  • the dose of floxuridine is administered daily for less than 14 days.
  • the dose of floxuridine is administered daily for more than 14 days.
  • the dose of floxuridine is administered daily for about 7 days.
  • the total dose of floxuridine in a treatment cycle is less than 1.68 mg/kg or less.
  • the total dose of floxuridine in a treatment cycle is about 0.84 mg/kg.
  • the method further comprises administering concurrent systemic therapy.
  • the method further comprises administering concurrent regional liver therapy.
  • the method of treating cancer can further include administering radiotherapy.
  • the method further comprises administering to the subject an effective amount of dexamethasone.
  • the effective amount of dexamethasone is an amount effective to function as an anti-inflammatory agent.
  • the method further comprises administering to the subject an effective amount of heparin.
  • the effective amount of heparin is an amount effective to prevent clotting of the device, artery, and/or vein.
  • the method of treating cancer can further include administering an additional therapeutic agent.
  • the additional therapeutic agent can be a chemotherapeutic agent.
  • the additional therapeutic agent can be an immunotherapeutic agent.
  • 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.
  • HAI hepatic arterial infusion
  • 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.
  • 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.
  • 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%.
  • a composition including about 10 weight percent of a given ingredient could have from 9 to 11 weight percent of the compound.
  • 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.
  • treat refers 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 the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease or enhancing overall survival.
  • terapéuticaally 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.
  • 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.
  • 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.
  • the subject can be a subject with any cancer that affects the liver.
  • the subject can be a subject with primary liver cancer.
  • the subject can be a subject with secondary liver cancer.
  • the subject can be a subject with colon cancer that has spread to the liver.
  • the subject can be a subject with cancer that started in the bile duct within the liver (intrahepatic cholangiocarcinoma).
  • the subject can be a subject with hepatocellular carcinoma.
  • the subject can be a subject with resectable cancer.
  • the subject can be a subject with unresectable cancer.
  • 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.
  • the subject to be treated can be a subject with macroscopic disease.
  • 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.
  • 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/
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • floxuridine is administered for a treatment cycle.
  • 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.
  • 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.
  • floxuridine can be administered in more than one treatment.
  • 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.
  • floxuridine can be administered in two or three treatments with an interval between each treatment of about two to about eight weeks.
  • 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.
  • 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.
  • 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, about
  • 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.
  • one or several further treatment cycles as described above are given during an indefinite period of time.
  • one or several further treatment cycles as described above are given over the course of about 3 years.
  • one or several further treatment cycles as described above are given over the course of about 2 years.
  • one or several further treatment cycles as described above are given over the course of about 1 year.
  • one or several further treatment cycles as described above are given until the cancer is treated or the desired therapeutic effect is achieved.
  • 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.
  • 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.
  • 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.
  • 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 about
  • 1.4 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.
  • 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 about
  • 1.4 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.
  • 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 about
  • 1.4 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, about 0.3 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.
  • 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 about
  • 1.4 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.
  • 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 about
  • 1.4 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.
  • 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 about
  • 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 about
  • 1.4 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.
  • 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 about
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the dose of floxuridine is continuously administered by the infusion techniques described herein via a pump.
  • the pump can be refilled about every 2 to 4 weeks to maintain continuous administration.
  • the pump can be refilled about every 2 to 3 weeks.
  • the pump can be refilled about every week.
  • the pump can be refilled about every 2 weeks.
  • the pump can be refilled about every 3 weeks.
  • the pump can be refilled about every 4 weeks.
  • the method of treating cancer can further include administering systemic therapy or regional liver therapy, such as chemotherapy, immunotherapy, and radiotherapy.
  • systemic therapy or regional liver therapy such as chemotherapy, immunotherapy, and radiotherapy.
  • the method of treating cancer can further comprise administering concurrent systemic therapy.
  • the method of treating cancer can further comprise administering concurrent regional liver therapy.
  • the method of treating cancer can further comprise administering radiotherapy.
  • the cancer is liver cancer.
  • the method of treating cancer can further include administering at least one additional therapeutic agent.
  • the at least one additional therapeutic agent can be a chemotherapeutic agent.
  • 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, exemestan
  • 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,
  • the cancer is liver cancer.
  • the method of treating cancer can further include administering an effective amount of dexamethasone.
  • the effective amount of dexamethasone is an amount effective to function as an anti-inflammatory agent.
  • the method of treating cancer can further include administering an effective amount of heparin.
  • the effective amount of heparin is an amount effective to prevent clotting of the device, artery, and/or vein.
  • the cancer is liver cancer.
  • At least one additional therapeutic agent can be an immunotherapeutic agent.
  • immunotherapeutic agent refers in general to any agent that produces a therapeutic effect by targeting the immune system or a component thereof.
  • 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.
  • the cancer is liver cancer.

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Abstract

La présente invention concerne des schémas posologiques à faible dose de floxuridine et des méthodes de traitement du cancer à l'aide des schémas posologiques à faible dose de floxuridine.
PCT/US2024/051708 2023-10-17 2024-10-17 Schémas posologiques à faible dose de floxuridine et méthodes de traitement du cancer à l'aide de floxuridine Pending WO2025085591A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090023680A1 (en) * 2005-10-25 2009-01-22 Andrew Janoff Fixed ratio drug combination treatments for solid tumors
US20140328919A1 (en) * 2009-03-30 2014-11-06 Cerulean Pharma Inc. Polymer-agent conjugates, particles, compositions, and related methods of use
US20170000737A1 (en) * 2014-05-09 2017-01-05 Yale University Hyperbranched polyglycerol-coated particles and methods of making and using thereof
US20170071976A1 (en) * 2014-05-26 2017-03-16 Songyuan Chen Pharmaceutical solution having anti-tumor effect-enhancing and toxicity-reducing effect, and pharmaceutical composition comprising same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090023680A1 (en) * 2005-10-25 2009-01-22 Andrew Janoff Fixed ratio drug combination treatments for solid tumors
US20140328919A1 (en) * 2009-03-30 2014-11-06 Cerulean Pharma Inc. Polymer-agent conjugates, particles, compositions, and related methods of use
US20170000737A1 (en) * 2014-05-09 2017-01-05 Yale University Hyperbranched polyglycerol-coated particles and methods of making and using thereof
US20170071976A1 (en) * 2014-05-26 2017-03-16 Songyuan Chen Pharmaceutical solution having anti-tumor effect-enhancing and toxicity-reducing effect, and pharmaceutical composition comprising same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SCOTT DAVIDSON B., IZZO FRANCESCO, CHASE JUDY L, DUBROW RONELLE A., PATT YEHUDA, HOHN DAVID C., CURLEY STEVEN A.: "Alternating floxuridine and 5-fluorouracil hepatic arterial chemotherapy for colorectal liver metastases minimizes biliary toxicity", AMERICAN JOURNAL OF SURGERY, PAUL HOEBER, NEW YORK, NY, US, vol. 172, no. 3, 1 September 1996 (1996-09-01), US , pages 244 - 247, XP093307915, ISSN: 0002-9610, DOI: 10.1016/S0002-9610(96)00159-6 *

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