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WO2011152516A1 - Agent anti-tumoral combiné à un inhibiteur des kinases - Google Patents

Agent anti-tumoral combiné à un inhibiteur des kinases Download PDF

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Publication number
WO2011152516A1
WO2011152516A1 PCT/JP2011/062789 JP2011062789W WO2011152516A1 WO 2011152516 A1 WO2011152516 A1 WO 2011152516A1 JP 2011062789 W JP2011062789 W JP 2011062789W WO 2011152516 A1 WO2011152516 A1 WO 2011152516A1
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Prior art keywords
tegafur
cisplatin
combination
gimeracil
salt
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Ceased
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PCT/JP2011/062789
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English (en)
Japanese (ja)
Inventor
裕介 中立
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Taiho Pharmaceutical Co Ltd
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Taiho Pharmaceutical Co Ltd
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Publication of WO2011152516A1 publication Critical patent/WO2011152516A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel antitumor agent comprising a combination of a plurality of cancer chemotherapeutic agents and an antitumor effect enhancer comprising TSU-68 or a salt thereof as an active ingredient.
  • 5-fluorouracil hereinafter also referred to as “5-FU”
  • cisplatin irinotecan
  • docetaxel have been clinically applied as chemotherapy for advanced gastric cancer.
  • UFT trade name
  • S-1 has been analyzed in a comparative study between S-1 monotherapy and S-1 and cisplatin combination therapy (hereinafter referred to as “S-1 / cisplatin combination therapy”), which was previously standard therapy in Japan.
  • S-1 / cisplatin combination therapy was published to provide better survival (11 months vs. 13 months), suggesting that S-1 / cisplatin combination therapy could be the standard therapy for advanced gastric cancer ( Non-patent document 1).
  • the S-1 / cisplatin combination therapy is a useful treatment that provides a high therapeutic effect for advanced / recurrent gastric cancer, but has a stronger antitumor effect in order to contribute to further long-term survival of the patient, and A method for treating gastric cancer with few side effects is desired.
  • Non-Patent Document 2 TSU-68 has been reported to have therapeutic effects on cancer types such as hepatocellular carcinoma in clinical trials (Non-patent Document 3). In addition, it has been reported that the antitumor effect is enhanced by combining TSU-68 with S-1 (Non-patent Document 4).
  • An object of the present invention is to provide a novel antitumor agent and antitumor effect potentiator exhibiting a remarkable antitumor effect, particularly a tumor growth delaying effect.
  • the present inventor has conducted research on a novel combination therapy in which S-1 / cisplatin combination therapy is combined with another anti-tumor agent in order to develop a cancer treatment method that contributes to longer survival of patients.
  • the antitumor effect of the S-1 / cisplatin combination therapy was remarkably enhanced by using TSU-68, which is an inhibitor of receptor tyrosine kinases such as VEGF and PDGF involved in angiogenesis.
  • TSU-68 which is an inhibitor of receptor tyrosine kinases such as VEGF and PDGF involved in angiogenesis.
  • the inventors have found that the occurrence of side effects is not enhanced, and have completed the present invention.
  • an anti-tumor agent when used in combination with another anti-tumor agent, side effects are generally enhanced with the enhancement of the anti-tumor effect. It is surprising that the effect, particularly the tumor growth delay effect, and the risk of developing low side effects were compatible.
  • the present invention provides the following 1) to 32).
  • An antitumor agent comprising a combination of a combination drug containing tegafur, gimeracil and oteracil potassium, cisplatin and TSU-68 or a salt thereof.
  • a combination of tegafur, gimeracil and oteracil potassium as a daily dose is 50 to 120 mg / m 2 in terms of tegafur, 50 to 60 mg / m 2 as a daily dose of cisplatin, TSU-68 or a salt thereof
  • Any one of the above 1) to 4) comprising a combination of a combination drug containing tegafur, gimeracil and oteracil potassium, a preparation containing cisplatin, and a preparation containing TSU-68 or a salt thereof.
  • the antitumor agent according to Item is 50 to 120 mg / m 2 in terms of tegafur, 50 to 60 mg / m 2 as a daily dose of cisplatin, TSU-68 or a salt thereof.
  • Antitumor agent 7)
  • An antitumor effect enhancer of a combination therapy comprising a combination drug containing tegafur, gimeracil and oteracil potassium and cisplatin, comprising TSU-68 or a salt thereof as an active ingredient.
  • a combination of tegafur, gimeracil and oteracil potassium as a daily dose is 50 to 120 mg / m 2 in terms of tegafur, 50 to 60 mg / m 2 as a daily dose of cisplatin, TSU-68 or a salt thereof The method according to 11), wherein the daily dose is 400 to 800 mg, respectively.
  • composition according to any one of 15) to 18 comprising a combination of a combination preparation containing tegafur, gimeracil and oteracil potassium, a preparation containing cisplatin, and a preparation containing TSU-68 or a salt thereof. combination.
  • a combination of tegafur, gimeracil and oteracil potassium as a daily dose is 50 to 120 mg / m 2 in terms of tegafur, 50 to 60 mg / m 2 as a daily dose of cisplatin, TSU-68 or a salt thereof Use as described in 25), in which 400 to 800 mg is combined as a daily dose, each combined.
  • the antitumor agent comprising the combination of tegafur, gimeracil and oteracil potassium of the present invention, cisplatin, and TSU-68 or a salt thereof is significantly higher than the conventional combination of antitumor agents Although it has an antitumor effect, such as a decrease in tumor volume and stagnation of tumor growth, the onset of side effects is not enhanced. That is, as shown in the Examples below, the antitumor agent of the present invention has a significantly high antitumor effect while suppressing the onset of side effects as compared to the case where each is used alone or in combination with two agents. realizable.
  • the antitumor effect is evaluated as a tumor reduction effect, a tumor growth delay effect, a life extension effect, or the like. Therefore, by using the antitumor agent of the present invention, a longer survival period of the tumor patient can be obtained.
  • FIG. 4 is a graph showing survival curves of a control group, a TSU-68 single group, an S-1 / cisplatin combination group, and an S-1 / cisplatin / TSU-68 combination group in a nude mouse peritoneal dissemination model of human gastric cancer strain MKN-45.
  • FIG. 4 is a graph showing survival curves of a control group and a S-1 / cisplatin / TSU-68 combination group administered with TSU-68 for 35 days or 70 days in a nude mouse peritoneal dissemination model of human gastric cancer strain MKN-45.
  • tegafur, gimeracil and oteracil potassium are mixed in an arbitrary ratio, and a pharmaceutically acceptable carrier as described later is appropriately added. Preparations prepared in this way.
  • Tegafur is a known compound represented by 5-fluoro-1- (2-tetrahydrofuryl) -2,4- (1H, 3H) -pyrimidinedione, and is activated in vivo. It is a drug that releases 5-FU, which is the main body of antitumor activity. Tegafur can be produced according to a known method, for example, the method described in JP-B-49-10510.
  • “Gimeracil” is a known compound represented by 2,4-dihydroxy-5-chloropyridine, which itself has no antitumor activity. However, 5-FU is metabolized in vivo. It suppresses inactivation and can enhance the antitumor effect.
  • “Oteracyl potassium” is a known compound represented by monopotassium 1,2,3,4-tetrahydro-2,4-dioxo-1,3,5-triazine-6-carboxylate, Although it does not have antitumor activity, it is mainly distributed in the gastrointestinal tract and suppresses 5-FU activation at that site, thereby suppressing gastrointestinal disorders.
  • the antitumor agent of the present invention comprises a combination preparation containing tegafur, gimeracil and oteracil potassium, a combination preparation comprising cisplatin and TSU-68 or a salt thereof in a proportion of each of the above active ingredients (a plurality of active ingredients).
  • the above active ingredient is a single agent (single containing an active ingredient) so that it can be used at the same time or separately at intervals, even if it is formulated into one dosage form as a preparation containing Or a compounded formulation (multi-drug form).
  • a preparation containing cisplatin, a preparation containing TSU-68 or a salt thereof, and a combination preparation containing tegafur, gimeracil and oteracil potassium were each prepared as a single agent, and these were combined to form a multi-drug type. It is preferably used in the form.
  • the antitumor agent or antitumor effect potentiator of the present invention is produced, packaged, or individually prepared for each of the above preparations as long as the combination of tegafur, gimeracil, and oteracil potassium, cisplatin and TSU-68 or a salt thereof are administered in combination. It may be distributed, or may be manufactured, packaged and distributed as a single package (kit formulation) suitable for combined administration of all or part of the above preparation.
  • Examples of the stabilizer include sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid, and a mixture thereof.
  • Examples of the isotonic agent include sodium chloride, boric acid, glucose, glycerin and a mixture thereof.
  • Examples of the pH adjuster and buffer include sodium citrate, citric acid, sodium acetate, sodium phosphate, and mixtures thereof.
  • Examples of soothing agents include procaine hydrochloride, lidocaine hydrochloride, and mixtures thereof.
  • the cancer that can be treated with the antitumor agent or antitumor effect potentiator of the present invention is not particularly limited, and examples thereof include colorectal cancer, liver cancer, kidney cancer, head and neck cancer, esophageal cancer, gastric cancer, and biliary tract cancer.
  • the antitumor agent of the present invention is preferably a combination of tegafur, gimeracil and oteracil potassium-containing combination drug, cisplatin and TSU-68 or a salt thereof so that the daily dose becomes the above dose.
  • a combination drug containing tegafur, gimeracil and oteracil potassium is 20 to 500 mg / m 2 , preferably 50 to 120 mg / m 2 in terms of tegafur as a daily dose, and 20 to 200 mg as a daily dose of cisplatin.
  • the administration schedule (administration order and administration interval) of each active ingredient in the antitumor agent or antitumor effect potentiator of the present invention is not particularly limited as long as the antitumor effect or the antitumor effect enhancement effect is achieved. It is appropriately set according to the patient's condition such as the patient's age, cancer type, stage, presence / absence of metastasis, treatment history, and other antitumor agents. For example, in a cycle of 21 to 42 days, S-1 is administered from day 1 to day 14 to 28, cisplatin is administered on day 1 or day 8, and TSU-68 or a salt thereof is administered for 1 day.
  • Administration is repeated one or more times, and particularly preferably, S-1 is administered from the first day to the 21st day, and cisplatin is administered on the first or eighth day, with 35 days as one cycle.
  • SSU-68 or its salt administered from day 1 to day 35 once or multiple times, or 28 days as one cycle
  • S-1 on day 1 From day 1 to day 21 cisplatin is administered on day 1 and TSU-68 or a salt thereof is administered from day 1 to day 28 one or more times, or 21 days
  • S-1 is administered from day 1 to day 14
  • cisplatin is administered from day 1 or day 8
  • TSU-68 or a salt thereof is administered from day 1 to day 21. It is a dosing schedule that repeats administration over one or more times.
  • Example 1 Combined effect of TSU-68 for S-1 / cisplatin combination therapy in human gastric cancer SC-2 nude mouse subcutaneous transplantation model
  • TSU-68 was orally administered once a day from day 1 to day 14 at 200 or 400 mg / kg / day.
  • the S-1 / cisplatin / TSU-68 combination was administered by the same dose, schedule and route as these.
  • the drug non-administration group was used as a control group.
  • the maximum value (Overall Maximum p value) obtained in all comparison pairs is less than 0.05, and the S-1 / cisplatin / TSU-68 combination group When the average RTV is low compared to the S-1 / cisplatin combination group and the TSU-68 single group, it is determined that “there is an additional effect on the antitumor effect”.
  • the S-15 / cisplatin combination group and the TSU-68 single group in day 15 were each compared with the control group, and both were found to have a statistically significant “anti-tumor effect”.
  • the S-1 / cisplatin / TSU-68 combination group compared with the S-1 / cisplatin combination group and the TSU-68 single group at each dose, and both have a statistically significant “additional antitumor effect”. It was recognized that
  • the weight loss was equal or less than that of the S-1 + cisplatin combination group. From this, it was confirmed that the side effect (weight loss) enhancement by the combined administration of TSU-68 with S-1 / cisplatin therapy is extremely small.
  • Example 2 Combined effect of TSU-68 on S-1 / cisplatin combination therapy in nude mouse subcutaneous transplantation model of human gastric cancer strain NUGC-3
  • Test model Human gastric cancer strain NUGC-3 was used and grouped when the average tumor volume reached approximately 125 mm 3 , and S-1 was 6.9 mg / kg / day in terms of tegafur from day 1 to day 14 for 1 day. Except for single oral administration, the combined effect of TSU-68 on S-1 / cisplatin combination therapy was examined in the same manner as in Example 1.
  • Antitumor effect Table 3 shows the average RTV and IR results for day15.
  • Example 2 Tumor growth delay effect According to the growth delay effect of Example 1, instead of RTV5, the day (RTV3 (day)) at which the average RTV of each group was 3.0 was determined. Similarly, instead of GDP5, GDP3 was determined from the difference between RTV3 in the drug administration group and RTV3 in the control group. Table 4 shows the results of RTV3 value and GDP3 value of each group.
  • the S-1 / cisplatin / TSU-68 combination group was found to have a “tumor growth delaying effect” at each dose compared to the S-1 / cisplatin combination group and the TSU-68 alone group.
  • Example 3 Life prolongation effect of combined use of TSU-68 for S-1 / cisplatin combination therapy in nude mouse peritoneal dissemination model of human gastric cancer strain MKN-45
  • Test Model Human gastric cancer strain MKN-45 cells were transplanted into the peritoneal cavity 2 ⁇ 10 7 cells per nude mouse and grouped so that the average body weight was equal on the same day (day 0).
  • S-1 is orally administered once daily from day 1 to day 35 at a dose of 8.3 mg / kg / day in terms of tegafur
  • TSU-68 at a dose of 400 mg / kg / day
  • cisplatin is 7.0 mg / kg. kg / day was administered to day 1 via the tail vein.
  • Example 4 Survival effect of combined use of TSU-68 for S-1 / cisplatin combination therapy in nude mouse peritoneal dissemination model of human gastric cancer strain MKN-45 (2) Test Model Human gastric cancer strain MKN-45 cells were transplanted into the peritoneal cavity 2 ⁇ 10 7 cells per nude mouse and grouped so that the average body weight was equal on the same day (day 0). S-1 was orally administered at a daily dose of 8.3 mg / kg / day in terms of tegafur, and cisplatin was administered via tail vein to day 1 at 7.0 mg / kg / day.
  • TSU-68 For TSU-68, a group was administered orally once a day from day 1 to 35, and a group in which only TSU-68 was continuously administered from day 35 to day 70.
  • the drug non-administration group was used as a control group.
  • the life-prolonging effect with and without continuous administration of TSU-68 was compared.

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Abstract

L'invention porte sur un nouvel agent thérapeutique en combinaison, ayant un effet anti-tumoral significatif. Elle porte plus précisément sur un agent anti-tumoral comprenant une combinaison d'un agent mélangé comprenant du tégafur, du giméracil et de l'otéracil-potassium, du cisplatine, et du TSU-68 ou un sel de ce dernier.
PCT/JP2011/062789 2010-06-04 2011-06-03 Agent anti-tumoral combiné à un inhibiteur des kinases Ceased WO2011152516A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2010-128607 2010-06-04
JP2010128607A JP2013166702A (ja) 2010-06-04 2010-06-04 キナーゼ阻害剤を組み合わせた抗腫瘍剤

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WO2011152516A1 true WO2011152516A1 (fr) 2011-12-08

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PCT/JP2011/062789 Ceased WO2011152516A1 (fr) 2010-06-04 2011-06-03 Agent anti-tumoral combiné à un inhibiteur des kinases

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JP (1) JP2013166702A (fr)
TW (1) TW201143769A (fr)
WO (1) WO2011152516A1 (fr)

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HIDENORI FUJITA ET AL.: "Shinki Keiko Kekkan Shinsei Sogaizai TSU-68 (SU006668) no Kakushu Koganzai tono Heiyo Koka", DAI 60 KAI PROCEEDINGS OF THE JAPANESE CANCER ASSOCIATION, 25 August 2001 (2001-08-25), pages 580 *
KOIZUMI W ET AL.: "S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial", THE LANCET ONCOLOGY, vol. 9, 2008, pages 215 - 221 *
MANABU OTA ET AL.: "Tyrosine Kinase Sogai Kekkan Shinsei Sogaizai TSU68 no Koshuyo Koka no Kento", JOURNAL OF JAPAN SURGICAL SOCIETY, vol. 110, 2009, pages 649 *

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TW201143769A (en) 2011-12-16
JP2013166702A (ja) 2013-08-29

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