Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to an antitumor agent administered to cancer patients by intravenous infusion, and in some preferred embodiments, by continuous intravenous infusion.
• CNDAC 4-amino-l-(2-cyano-2-deoxy- ⁇ -D-arabinofuranosyl)-2(lH)-pyrimidinone
• CNDAC is a deoxycytidine analog, which at the time of filing of this application, is synthesized in Japan. Unlike deoxycytidine derivatives (gemcitabine) which are widely clinically used, CNDAC primarily causes DNA strand breaks. Specifically, it is considered that CNDAC is phosphorylated by intracellular deoxycytidine kinase, and thereby a triphosphorylated form (CNDACTP) is provided; that CNDACTP is incorporated into a DNA strand, thus inducing hydrolysis and breaking the DNA strand; and that the cell cycle is thus arrested at the G2/M phase and the cell is killed.
• CNDACTP triphosphorylated form
• CNDAC can be differentiated from DNA synthesis inhibitors in wide clinical use, and that CNDAC is a clinically effective antitumor agent (Molecular
• the present invention solves the aforementioned problems by using CNDAC in a way that achieves a high antitumor effect and a low risk of causing toxicity that leads to interruption of continuous administration.
• JP2009/058725 JP2009/058725
• an antitumor treatment regimen comprising: administering, to a patient diagnosed with cancer, an antitumor agent comprising 4- amino-l-(2-cyano-2-deoxy- ⁇ -D-arabinofuranosyl)-2(lH)-pyrimidinone, or a salt thereof, by way of continuous intravenous infusion, in an amount of 2.0 to 4.0 mg per m 2 total body surface area of the patient, of 4-amino-l-(2-cyano-2-deoxy- ⁇ -D-arabinofuranosyl)-2(lH)-pyrimidinone equivalent, per day, for a duration of 168 to 336 hours.
• the antitumor agent is administered in an amount of 2.0 mg per m 2 total body surface area of the patient, of 4-amino-l-(2-cyano-2-deoxy- ⁇ -D-arabinofuranosyl)-2(lH)-pyrimidinone equivalent, per day, for a duration of 336 hours. In some preferred embodiments, the antitumor agent is administered in an amount of 3.0 mg per m 2 total body surface area of the patient, of 4-amino-l- (2-cyano-2-deoxy- ⁇ -D-arabinofuranosyl)-2(lH)-pyrimidinone equivalent, per day, for a duration of 168 hours.
• a treatment course is performed at least twice, wherein the course comprises administering the antitumor agent by continuous intravenous infusion in an amount of 2.0 mg per m 2 total body surface area of the patient, of 4-amino-l-(2-cyano-2-deoxy- ⁇ -D-arabinofuranosyl)-2(lH)-pyrimidinone equivalent, per day, for a duration of 336 hours once every three weeks.
• a treatment course is performed at least twice, wherein the course comprises administering the antitumor agent by continuous intravenous P2009/058725
• the invention also provides a composition for continuous intravenous administration of an antitumor agent to a patient comprising a container comprising 4-amino- l-(2-cyano-2-deoxy- ⁇ -D-arabinofuranosyl)-2(lH)-pyrimidinone, or a salt thereof, diluted in a physiologically acceptable fluid medium for delivering intravenous antitumor agents, to a concentration sufficient to provide an amount of 2.0 to 4.0 mg per m 2 total body surface area of the patient, of 4-amino-l-(2-cyano-2-deoxy- ⁇ -D-arabinofuranosyl)-2(lH)-pyrimidinone equivalent, per day, for a duration of 168 to 336 hours.
• the concentration of the antitumor agent is sufficient to provide an amount of 2.0 mg per m total body surface area of the patient, of 4-amino- 1 -(2-cyano-2-deoxy- ⁇ -D-arabinofuranosyl)-2(l H)-pyrimidinone equivalent, per day, for a duration of 336 hours. In some preferred embodiments, the concentration of the antitumor agent is sufficient to provide an amount of 3.0 mg per m 2 total body surface area of the patient, of 4-amino-l-(2-cyano-2-deoxy- ⁇ -D-arabinofuranosyl)-2(lH)-pyrimidinone equivalent, per day, for a duration of 168 hours.
• the invention also provides a composition for continuous intravenous administration of an antitumor agent to a patient, comprising a container comprising 4-amino- l-(2-cyano-2-deoxy- ⁇ -D-arabinofuranosyl)-2(lH)-pyrimidinone, or a salt thereof, diluted in a physiologically acceptable fluid medium for delivering infavenous antitumor agents, to a concentration sufficient to provide an amount of 2.0 to 4.0 mg per m 2 total body surface area of the patient, of 4-amino-l-(2-cyano-2-deoxy- ⁇ -D-arabinofuranosyl)-2(lH)-pyrimidinone equivalent, per day, for a duration of 168 to 336 hours.
• the invention also provides use of 4-amino-l-(2-cyano-2-deoxy- ⁇ -D-arabinofuranosyl)- 2(lH)-pyrimidinone or a salt thereof for the production of an antitumor agent, wherein the antitumor agent is administered to a patient, by way of continuous intravenous infusion, in an amount of 2.0 to 4.0 mg per m 2 total body surface area of the patient, of 4-amino-l-(2-cyano-2- deoxy- ⁇ -D-arabinofuranosyl)-2(lH)-pyrimidinone equivalent, per day, for a duration of 168 to 336 hours.
• the antitumor agent according to the present invention is capable of achieving a high antitumor effect while reducing risk of side effects, mainly including body weight suppression and leucopenia. hi other words, the antitumor agent has a low risk of interrupting treatment due to side effects and provides a high treatment effect so as to surely prolong patient survival.
• FIGURE 1 shows the antitumor effect in rapid intravenous infusion and continuous intravenous infusion of CNDAC administered to tumor-bearing rats having the human lung cancer line LX-I. 009/058725
• FIGURE 2 shows the antitumor effect in continuous intravenous infusion of CNDAC and gemcitabine administered to tumor-bearing rats having the human colon cancer line KM20C.
• FIGURE 3 shows the antitumor effect in continuous intravenous infusion of CNDAC administered to tumor-bearing rats having the human pancreatic cancer line PAN-4.
• FIGURE 4 shows side effect (body weight suppression) in continuous intravenous infusion of CNDAC administered to tumor-bearing rats having the human pancreatic cancer line PAN-4.
• a reference to a compound or component includes the compound or component by itself, as well as in combination with other compounds or components, such as mixtures of compounds.
• CNDAC exhibits a strong antitumor effect against a wide range of tumor lines. It was found in antitumor tests using animal models that CNDAC demonstrated strong antitumor and antiproliferative effects on a majority of human- derived tumor lines when administered by rapid intravenous infusion for 10 consecutive days, five times a week for two weeks, and once a week for two weeks. However, the regrowth of tumors was observed after completion of the administration, and the cytoreductive effect was not necessarily shown. Further, increasing the dosage so as to increase the antitumor effect causes toxicity, including body weight suppression and leucopenia.
• CNDAC which is an active ingredient of the antitumor agent according to the present invention, is a known compound indicated as 4-amino-l-(2-cyano-2-deoxy- ⁇ -D- arabinofuranosyl)-2(lH)-pyrimidinone. It is known that the compound has an antitumor effect on many cancer types by its DNA strand break effect. It is described in Biochemical 058725
• any pharmaceutically acceptable salts can be used, such as, for example, inorganic and organic acid salts.
• Inorganic acid salts include hydrochloride, hydrobromate, sulfate, nitrate, phosphate, and the like.
• Organic acid salts include acetate, propionate, tartrate, fumarate, maleate, malate, citrate, methanesulfonate, p-toluenesulfonate, trifluoroacetate, and the like.
• hydrochloride or acetate is preferable.
• CNDAC according to the present invention and the salt thereof can be manufactured by any method, examples of which are known, such as, for example, a method described in Japanese Patent Publication No. 2559917.
• the antitumor agent according to the present invention is administered intravenously.
• the agent is administered in form of injections.
• Injections may be liquid injections or solid injections, such as, lyophilized injections, which are dissolved when used, powder injections, and the like.
• the antitumor agent according to the present invention can be prepared in any procedure, examples of which are known, in which pharmacologically acceptable carriers are added to CNDAC or the salt thereof.
• pharmacologically acceptable carriers are added to CNDAC or the salt thereof.
• a variety of organic and inorganic carrier materials commonly used as pharmaceutical materials can be used as the carriers.
• excipients, lubricants, binders, disintegrants, and the like can be added.
• agents and the like can be added.
• pharmaceutical additives such as antiseptics, antioxidants, colorants, and the like, can be used when necessary.
• Excipients may include, for example, lactose, sucrose, sodium chloride, glucose, maltose, mannitol, erythritol, xylitol, maltitol, inositol, dextran, sorbitol, albumin, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin, alginate sodium, gum arabic, and mixtures of the above-listed ingredients.
• Lubricants may include, for example, purified talc, stearate, borax, polyethyleneglycol, and mixtures of the above-listed ingredients.
• Binders may include, for example, simple syrups, dextrose solutions, starch solutions, gelatin solutions, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, water, ethanol, potassium phosphate, and mixtures of the above-listed ingredients.
• Disintegrants may include, for example, dry starch, alginate sodium, powdered agar, powdered laminaran, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose, and mixtures of the above-listed ingredients.
• Diluents may include, for example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxidized isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and mixtures of the above-listed ingredients.
• Stabilizers may include, for example, sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid, and mixtures of the above-listed ingredients.
• Tonicity agents may include, for example, sodium chloride, boric acid, glucose, glycerin, and mixtures of the above-listed ingredients.
• PH adjusters and buffers may include, for example, sodium citrate, citric acids, sodium acetate, sodium phosphate, and mixtures of the above-listed ingredients.
• Soothing agents may include, for example, procaine hydrochloride, lidocaine hydrochloride, and mixtures of the above-listed ingredients.
• a preferable dosage of the antitumor agent according to the present invention is 2.0 to 3.0 mg per m 2 total body surface area of the patient (also presented herein as mg/m 2 ) of CNDAC equivalent per day, in terms of a relation between the risk of side-effects development and antitumor effect.
• the antitumor agent of the present invention In view of effective cancer treatment with inhibition of side-effects development, including body weight suppression and leucopenia, it is preferable to administer the antitumor agent of the present invention for a duration of 168 to 336 hours when the dosage per day is 2.0 mg/m 2 of CNDAC equivalent. It is more preferable to administer the antitumor agent for a duration of 336 hours. When the dosage per day is 3.0 mg/m 2 of CNDAC equivalent, it is preferable to administer the antitumor agent for a duration of 168 hours. [0033] La order to reduce toxicity and achieve a better antitumor effect, it is preferable to administer the antitumor agent of the present invention intravenously in a repeated manner in a course of a series of administration schedule.
• a preferable administration schedule is that a course is performed, one time or a plurality of repeated times, in which the antitumor agent is administered by continuous intravenous infusion in an amount of 2.0 to 4.0 mg/m of CNDAC equivalent per day for a duration of 336 hours once every three weeks; and that a course is performed, one time or a plurality of repeated times, in which the antitumor agent is administered by continuous intravenous infusion in an amount of 3.0 to 4.0 mg/m 2 of CNDAC equivalent per day for a duration of 168 hours once every two weeks. It is more preferable that a course is performed, one time or a plurality of repeated times, in which the antitumor agent is P2009/058725
• the antitumor agent of the present invention can be applied to non-limiting cancer types, including head and neck cancer, esophagus cancer, stomach cancer, colorectal cancer, liver cancer, gallbladder and bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, bladder cancer, prostate cancer, testis tumor, bone and soft-tissue sarcoma, malignant lymphoma, leukemia, cervical cancer, skin cancer, brain tumor, and the like. It is particularly preferable to apply the antitumor agent to head and neck cancer, breast cancer, lung cancer, stomach cancer, colorectal cancer, pancreatic cancer, and bladder cancer.
• the antitumor agent of the present invention may be administered to patients who have never undergone cancer treatment, currently treated patients, and previously treated patients. [0036] The antitumor agent of the present invention can be administered concurrently with other antitumor agents and/or radiation.
• Antitumor agents that can be administered concurrently may include, for example, 5-FU, tegafur/uracil preparations, tegafur/gimeracil/oteracil potassium preparations, doxorubicin, epirubicin, irinotecan hydrochloride, etoposide, docetaxel, paclitaxel, cisplatin, carboplatin, oxaliplatin, krestin, lentinan, picibanil, and the like. Examples
• the present test was conducted on patients having a variety of solid cancers for which standard treatment was ineffective or no treatment was available (e.g., digestive system cancer, head and neck cancer, breast cancer, and the like).
• the test is equivalent to the Clinical Phase I Test, which primarily evaluates safety so as to determine a recommended dose (RD) that can be safely administered with no side effect concerns in the Clinical Phase II Test implemented per cancer type. Treatment effect on tumors was also evaluated in the test when possible.
• RD recommended dose
• the cytoreductive effect was determined based on comprehensive evaluation of target lesions (lesions having a size measurable at a slice width on CT and a larger size) and non-target lesions (all lesions not included in the target lesions), with reference to the RECIST evaluation method (Journal of the National Cancer Institute, 2000, Vol. 92, No. 3, 205 - 216).
• PR partial response indicates a case where a reduction of 30% or more in the sum of the longest diameter of target lesions was demonstrated, compared with the sum of the 009/058725
• PD progression disease
• SD stable disease
• Example 2 the continuous intravenous infusion being administered to patients having a variety of solid cancers (e.g., digestive system cancer, lung cancer, bladder cancer, and the like) for which standard treatment was ineffective or no treatment was available.
• solid cancers e.g., digestive system cancer, lung cancer, bladder cancer, and the like
• continuous intravenous infusion was an administration method that achieved a high efficacy while inhibiting toxicity development, the continuous intravenous infusion being administered to patients having a variety of solid cancers (e.g., digestive system cancer, and head and neck cancer) for which standard treatment was ineffective or no treatment was available.
• solid cancers e.g., digestive system cancer, and head and neck cancer
• CNDAC free base
• CNDAC was administered by rapid intravenous infusion (rapidly injected into a caudal vein using a syringe) in an amount of 800 mg/kg/day on Days 1 to 5 and 8 to 12, or 20 mg/kg/day on Days 1 and 8.
• CNDAC was administered by continuous intravenous infusion (continuously injected under the skin for 24 hours using a subcutaneous implantation constant-speed pump) in an amount of 4.5 mg/kg/day for two weeks.
• Relative tumor volume (a ratio of tumor volume on Day 1 of administration and that on Day 14 of administration) was obtained in a CNDAC administered group and a non-administered group (control group) of each administration method, and the obtained relative tumor volume was compared.
• a high antitumor effect was demonstrated in the continuous intravenous infusion, compared with the rapid intravenous infusion. The effect was exhibited not only in the human lung cancer line, but also in human breast cancer and colon cancer lines.
• CNDAC was administered by continuous intravenous infusion (continuously injected under the skin for 24 hours using a subcutaneous implantation constant-speed pump) in an amount of 36 mg/kg/day on Days 1 and 8, or 4.5 mg/kg/day on Days 1 to 14.
• gemcitabine was administered by rapid intravenous infusion in an amount of 300 mg/kg/day once a week for two weeks (Days 1 and 8), or by continuous intravenous infusion in an amount of 1.0 mg/kg/day for two weeks.
• Relative tumor volume was obtained and compared in a drug administered group and a non-administered group (control group) of each administration method.
• the tumor volume was significantly reduced even after the administration was completed.
• gemcitabine which is a deoxycytidine derivative having a similar structure as CNDAC
• the tumor volume was not reduced after the administration was completed. The results indicate that administering CNDAC at low doses for a long period of time enhanced the antitumor effect extremely strongly beyond expectation, compared with the enhancement by gemcitabine.
• CNDAC was administered by continuous intravenous infusion (continuously injected under the skin for 24 hours using a subcutaneous implantation constant-speed pump) in an amount of 36 mg/kg/day on Day 1, or 4.5 mg/kg/day on Days 1 to 14. Relative tumor volume was obtained and compared in a CNDAC administered group and a non-administered group (control group) of each administration method. A significantly high antitumor effect was demonstrated in the two-week continuous intravenous infusion, compared with the 24-hour continuous intravenous infusion.

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