Therapy and new therapeutic agent for blood cancer

Abstract

An object of the present invention is to provide a new means for treating or ameliorating a blood cancer patient, wherein the new means has high effect and few side effects. The present invention relates to a combined medicine for use in a method for treating or ameliorating a blood cancer patient, comprising 4-amino-1-(2-cyano-2-deoxy-?-D-arabinofuranosyl)-2(1H)-pyrimidinone or a salt thereof and venetoclax or a salt thereof.

Claims

1. A combined medicine, comprising 4-amino-1-(2-cyano-2-deoxy-(3-D-arabinofuranosyl)-2(1H)-pyrimidinone or a salt thereof in a dosage form for continuous intravenous infusion in an amount sufficient to provide an amount from 1 to 10 mg per 1 m.sup.2 of body surface area of a patient per day over 168 to 336 hours, said patient having a blood cancer, and venetoclax or a salt thereof in a dosage form for oral administration to the patient.

2. The medicine according to claim 1, wherein blood cancer is selected from the group consisting of acute myelogenous leukemia (AML), chronic myelogenous leukemia (CIVIL), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), a myeloproliferative neoplasm (MPN), and lymphoma.

3. The medicine according to claim 1, wherein venetoclax or the salt thereof is in a dosage form for oral administration in an amount sufficient to provide an amount from 20 to 400 mg/day to the patient.

4. The medicine according to claim 1, wherein the patient is a newly diagnosed and/or elderly patient.

5. A method for treating or ameliorating blood cancer, comprising administering to a patient with blood cancer 4-amino-1-(2-cyano-2-deoxy-(3-D-arabinofuranosyl)-2(1H)-pyrimidinone or a salt thereof by way of continuous intravenous infusion, in an amount from 1 to 10 mg per 1 m.sup.2 of body surface area of the patient per day over 168 to 336 hours and venetoclax or a salt thereof orally.

6. The method according to claim 5, wherein the blood cancer is selected from the group consisting of acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), a myeloproliferative neoplasm (MPN), and lymphoma.

7. The method according to claim 5, wherein venetoclax or a salt thereof is orally administered in an amount from 20 to 400 mg/day.

8. The method according to claim 5, wherein the patient is a newly diagnosed and/or elderly patient.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 is a graph showing the results obtained by investigating the cytostatic effects (cell survival rate (%)) of the combined use of DFP-10917 and venetoclax on acute myelogenous leukemia (AML) cells derived from a human. (A) (A) shows the results of the use of DFP-10917 alone and the combined use of DFP-10917 and venetoclax (96.8 pM). (B) (B) shows the results of the use of venetoclax alone and the combined use of venetoclax and DFP-10917 (1.53 ?M).

(2) FIG. 2 is a graph showing the results obtained by investigating the cytostatic effects (tumor volume (mm.sup.3)) of the combined use of DFP-10917 and venetoclax in animal models into which AML cells are transplanted.

(3) FIG. 3 is a graph showing the results obtained by measuring weights(g) after the administration of DFP-10917 and/or venetoclax over time in animal models into which AML cells are transplanted.

DESCRIPTION OF EMBODIMENTS

(4) The present invention relates to a method for treating or ameliorating blood cancer, comprising administering a combination of CNDAC or a salt thereof and venetoclax or a salt thereof to a blood cancer patient, and to pharmaceutical agents or a combined medicine used in the method.

(5) In the present invention, 4-amino-1-(2-cyano-2-deoxy-?-D-arabinofuranosyl)-2(1H)-pyrimidinone or CNDAC is a compound represented by the following structural formula:

(6) ##STR00001##
or a salt thereof. The salt is a pharmaceutically acceptable salt, and examples thereof include acid addition salts and basic addition salts. Examples of the acid addition salts include hydrochloride, sulfate, nitrate, phosphate, hydrobromid, carbonate, acetate, trifluoroacetate, p-toluenesulfonate, propionate, tartrate, fumarate, malate, maleate, citrate, and methanesulfonate (but are not limited thereto). Examples of the basic addition salts include alkali metal salts (sodium salt, potassium salt, and the like), alkaline-earth metal salts (calcium salt, and the like), magnesium salt, and ammonium salt (but are not limited thereto). In the present invention, the hydrochloride or acetate of CNDAC is preferable. More specifically, in the present invention, 4-amino-1-(2-cyano-2-deoxy-?-D-arabinofuranosyl)-2(1H)-pyrimidinone monohydrochloride is particularly preferable. In the present specification, 4-amino-1-(2-cyano-2-deoxy-?-D-arabinofuranosyl)-2(1H)-pyrimidinone monohydrochloride may be described as DFP-10917.

(7) In the present invention, venetoclax is a compound represented by the following structural formula:

(8) ##STR00002##
or a salt thereof. The salt is a pharmaceutically acceptable salt, and examples thereof include acid addition salts and basic addition salts. Examples of the acid addition salts and the basic addition salts include the above addition salts.

(9) CNDAC or the salt thereof and venetoclax or the salt thereof may be industrially synthesized in accordance with conventionally well-known techniques, or CNDAC or the salt thereof and venetoclax or the salt thereof marketed for drugs may be used.

(10) In the present invention, blood cancer means cancer occurred from the hematopoietic organ. Examples of such blood cancer include but are not limited to acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), a myeloproliferative neoplasm (MPN), and lymphoma. In the present invention, blood cancer is preferably acute myelogenous leukemia (AML).

(11) In the present invention, the patient is a blood cancer patient without particular limitation. Although the patient may be a newly diagnosed patient or a recurrent patient, the patient is preferably a newly diagnosed patient; and/or the age of the patient is not particularly limited, and the patient may be an infant patient (5 years old or less), a juvenile patient (6 to 14 years old), a young patient (15 to 34 years old), a patient in the prime of life (35 to 64 years old), or an elderly patient (65 years old or more), but is preferably an elderly patient.

(12) In the present invention, the combined administration of CNDAC or the salt thereof and venetoclax or the salt thereof to a blood cancer patient is performed.

(13) In the present invention, the combined administration includes not only the case where components are administered simultaneously but also the case where components are administered sequentially at predetermined intervals over a therapeutic period, respectively, and the case where only any component is administered before and/or after components are administered simultaneously. The administration route and the administration means of the components administered in combination may be the same or different.

(14) Although the dose and administration route of CNDAC or the salt thereof can vary depending on factors such as the type and severity of blood cancer, and the age, weight and condition of the patient, in combined administration with venetoclax or the salt thereof, CNDAC or the salt thereof can be administered in an amount enough to treat or ameliorate blood cancer through any administration route (oral administration or parenteral administration).

(15) For example, the parenteral administration of CNDAC or the salt thereof can be performed in an amount from 1 to 10 mg/m.sup.2/day, preferably 4 to 6 mg/m.sup.2/day, per 1 m.sup.2 of the body surface area of a patient per day in terms of the amount of CNDAC. Examples of the parenteral administration include intravenous injection, hypodermic injection, intradermal injection, intramuscular injection, and intravenous drip. The parenteral administration is particularly preferably continuous intravenous infusion. The continuous intravenous infusion means continuous drip administration of the above-mentioned amount over 168 to 336 hours. The administration interval is not particularly limited.

(16) Although the dose and administration route of venetoclax or the salt thereof can vary depending on factors such as the type and severity of blood cancer, and the age, weight and condition of the patient, in combined administration with CNDAC or the salt thereof, venetoclax or the salt thereof can be administered in an amount enough to treat or ameliorate blood cancer through any administration route (oral administration or parenteral administration).

(17) For example, venetoclax or the salt thereof can be orally administered in an amount from 20 to 400 mg/day, preferably 200 to 400 mg/day by dividing it into 1 to 5 doses (for example, 2 or 3) per day every day, every other day, every several days, on 1 day every week, on 2 to 3 days every month, on 1 day every 2 weeks, or on 1 day every month. Alternatively, venetoclax or the salt thereof may be parenterally administered in a dose by which an intravenous level of venetoclax or the salt thereof becomes comparable to that in the case of the oral administration. The parenteral administration can be performed by the above-mentioned techniques.

(18) CNDAC or the salt thereof and venetoclax or the salt thereof administered in combination may be provided in the form of separate pharmaceutical agents (or pharmaceutical compositions), or in the form of a combined medicine.

(19) When CNDAC or the salt thereof and venetoclax or the salt thereof are provided as separate pharmaceutical agents (or pharmaceutical compositions), the pharmaceutical agents (or pharmaceutical compositions) are intended to be used in the above-mentioned combined administration, and it can be stated in a column showing efficacy and effect or a column showing use and dose in its attachment that the pharmaceutical agents (or pharmaceutical compositions) are used in the above-mentioned combined administration. For example, if the pharmaceutical agent (or pharmaceutical composition) is a pharmaceutical agent (or pharmaceutical composition) containing CNDAC or the salt thereof, it can be stated in its attachment that the pharmaceutical agent (or pharmaceutical composition) is used in combination with venetoclax or a salt thereof for treating or ameliorating blood cancer. If the pharmaceutical agent (or pharmaceutical composition) is a pharmaceutical agent (or pharmaceutical composition) containing venetoclax or the salt thereof, it can be stated in its attachment that the pharmaceutical agent (or pharmaceutical composition) is used in combination with 4-amino-1-(2-cyano-2-deoxy-?-D-arabinofuranosyl)-2(1H)-pyrimidinone or a salt thereof for treating or ameliorating blood cancer.

(20) The combined medicine may be in the form of a combination drug which contains the components in the same composition, or may be prepared in a form for which the components are provided separately, and produced, packed and distributed as individual packages suitable for combined administration (namely, kit preparations).

(21) In the above-mentioned pharmaceutical agents (or pharmaceutical compositions) and combination medicine, a vehicle, a binder, a disintegrator, a lubricant and the like which are usually used in the production of pharmaceutical agents can be further incorporated besides the above-mentioned components. The above-mentioned pharmaceutical agents (or pharmaceutical compositions) and combination medicine can be produced as dosage forms suitable to designed administration routes.

(22) Examples of the vehicle include sugar (monosaccharides, disaccharides, polysaccharide such as cyclodextrin and alginic acid), metal salts, kaolin, silicic acid, polyethylene glycol, and a mixture thereof.

(23) Examples of the binder include simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, carboxymethyl cellulose, shellac, methyl cellulose, ethyl cellulose, and a mixture thereof.

(24) Examples of the disintegrator include dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, and a mixture thereof.

(25) Examples of the lubricant include purified talc, stearates, borax, polyethylene glycol, and a mixture thereof.

(26) A diluent, a stabilizer, an isotonizing agent, a pH adjuster, a buffer, a solubilizing agent, a suspending agent, a coloring agent, a flavoring agent, a smell correcting agent, a coating agent, a preservative, an antiseptic, an antioxidant, and the like which are usually used in the production of pharmaceutical agents can be further incorporated optionally if needed.

(27) Examples of the dosage form suitable for oral administration include tablets, pills, capsules, granules, powders, syrups, and suspensions. Pharmaceutical agents having a solid dosage form can be coated if needed (for example, sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, and the like).

(28) Examples of the dosage form suitable for parenteral administration include injections and drips. These dosage forms may be provided in a freeze-dried and storable state, and before use, dissolved in water or in a buffer solution or the like containing a physiological saline solution or the like to prepare a solution at a suitable concentration.

(29) The present invention can be used in combination with an anticancer agent and/or radiotherapy which is used to treat or ameliorate blood cancer. Examples of such an anticancer agent include but are not limited to azacytidine, enocitabine, decitabine, cytarabine, cytarabine ocfosfate, fludarabine, pentostatin, nelarabine, aclarubicin, idarubicin, daunorubicin, doxorubicin, cyclophosphamide, 6-mercaptopurine, methotrexate, busulfan, nimustine, ranimustine, vincristine, vindesine, etoposide, prednisolone, dexamethasone, retinoic acid, tamibarotene, imatinib, nilotinib, dasatinib, mitoxantrone, hydroxyurea, asparaginase, arsenious acid, interferon, and lenalidomide. Here, Combined administration is as defined above.

(30) One or more of anticancer agents can be appropriately selected depending on factors such as the type and severity of blood cancer, and the age, weight and condition of the patient.

(31) The present invention can be used for treating or ameliorating blood cancer. More specifically, the present invention relates to a method for treating or ameliorating blood cancer, comprising administering the pharmaceutical agents (or pharmaceutical compositions) or combined medicine of the present invention to a blood cancer patient.

(32) In the present invention, treating or ameliorating blood cancer means not only a condition in which blood cancer disappears completely but also a condition in which blood cancer decreases or disappears temporarily or permanently and a condition in which blood cancer is stable without progression (aggravation). For example, treating or ameliorating cancer in the present invention includes one or more of a decrease in the number of blood cancer cells, a decrease in the blood cancer marker level, an improvement in symptoms accompanying blood cancer, and the prolongation of criteria such as overall survival time, progression-free survival time and median survival time in the patient as compared with those before the administration or ingestion of the composition of the present invention.

(33) According to the present invention, a blood cancer patient can be treated or ameliorated by administering the above-mentioned pharmaceutical agents (or pharmaceutical compositions) or combined medicine of the present invention. Especially if the patient is a newly diagnosed and/or elderly patient, the effect thereof is observed remarkably, and the survival rate (median survival time and the like) can be enhanced greatly.

(34) The present invention will be specifically described by Examples hereinafter, but the present invention is not limited thereto.

EXAMPLES

Example 1

Effect of Combined Use of 4-amino-1-(2-cyano-2-deoxy-?-D-arabinofuranosyl)-2(1H)-pyrimidinone monohydrochloride (DFP-10917) and Venetoclax In Vitro

(35) DFP-10917 alone, venetoclax alone, and the combined use of DFP-10917 and venetoclax were allowed to act on KG-1, SKM-1, OCI-AML-2, MV4-11, and SKNO-1, which are acute myelogenous leukemia (AML) cell lines derived from humans, at various concentrations separately. The number of cells was counted by CellTiter-Glo assay after 72 hours, and the IC.sub.50 value, which is a concentration at which the number of cells is reduced by 50%, was calculated.

(36) Consequently, the effect of the combined use of DFP-10917 and venetoclax was observed in four types of AML cells (KG-1, OCI-AML-2, MV4-11, and SKNO-1).

Example 2

Effect of Combined Use of DFP-10917 and Venetoclax Under the Condition of a Low Protein Content

(37) The effect of the combined use of DFP-10917 and venetoclax was investigated under the condition of a low protein content in view of a high protein binding rate of venetoclax (>99.9%).

(38) DFP-10917 alone, venetoclax alone, and combined use of DFP-10917 and venetoclax were allowed to act on MV4-11, which is an AML cell line, at various concentrations separately. The number of cells was counted by MTT assay using thiazolyl blue tetrazolium bromide after 48 hours, and the IC.sub.50 value, which is a concentration at which the number of cells is reduced by 50%, was calculated.

(39) FIG. 1 shows the results. In the groups to which DFP-10917 was added (FIG. 1(A)), slight increase in cytostatic effect was seen in the combined use of DFP-10917 and venetoclax (96.8 pM) as compared with DFP-10917 alone. The IC.sub.50 value was 1.53 ?M for DFP-10917 alone, and 0.51 ?M for the combined use of DFP-10917 and venetoclax.

(40) Meanwhile, in the groups to which venetoclax was added (FIG. 1(B)), remarkable increase in cytostatic effect was observed in the combined use of venetoclax and DFP-10917 (1.53 ?M) as compared with venetoclax alone. The IC.sub.50 value was 96.8 pM for venetoclax alone, and 9.14 pM for the combined use of venetoclax and DFP-10917. This result shows that the cytostatic effect increased around 10.6 folds by the combined use of venetoclax and DFP-10917 as compared with venetoclax alone. The CI (Combination Index) value was calculated from each IC.sub.50 value based on the following expression (F. Bruzzese, et al. Clin. Cancer Res. 2006, 12, 617-625).

(41) CI value=IC.sub.50 value of DFP-10917 in combined use (0.51 ?M)/IC.sub.50 value of DFP-10917 alone (1.53 ?M)+IC.sub.50 value of venetoclax in combined use (9.14 pM)/IC.sub.50 value of venetoclax alone (96.8 pM)+[IC.sub.50 value of DFP-10917 alone (1.53 ?M)?IC.sub.50 value of venetoclax alone (96.8 pM)]/[IC.sub.50 value of DFP-10917 in combined use (0.51 ?M)+IC.sub.50 value of venetoclax in combined use (9.14 pM)]

(42) The CI value has 1 as a standard. In the case of CI value=1, the CI value shows an additive effect. In the case of CI value<1, the CI value shows a synergistic effect.

(43) Since the CI value was around 0.43 according to the above-mentioned expression, it was confirmed that the effect obtained by the combined use of DFP-10917 and venetoclax was a synergistic effect.

Example 3

Effect of Combined Use of DFP-10917 and Venetoclax in Animal Models

(44) OCI-AML-2, which is an AML cell line, was hypodermically transplanted into NOD SCID mice (5?10.sup.6 cells/mouse), and cancer-bearing model mice were produced.

(45) An Alzet (R) osmotic mini-pump was implanted in the mouse body, and DFP-10917 was continuously administered in a dose of 3 mg/kg/day for 7 days.

(46) Venetoclax was orally administered in a dose of 100 mg/kg/day for 14 days.

(47) Only a vehicle was administered to control mice.

(48) Administration was started seven days after transplant.

(49) FIG. 2 shows the results.

(50) It was confirmed that when DFP-10917 and venetoclax was administered in combination, proliferation of the tumor was more suppressed as compared with the use of either alone. Meanwhile, a significant weight change was not observed in mice over the study period, and side effects (toxicity) of combined use of DFP-10917 and venetoclax were not observed (FIG. 3).