WO2011152515A1 - Agent anti-tumoral contenant un composé indole - Google Patents

Agent anti-tumoral contenant un composé indole Download PDF

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Publication number
WO2011152515A1
WO2011152515A1 PCT/JP2011/062788 JP2011062788W WO2011152515A1 WO 2011152515 A1 WO2011152515 A1 WO 2011152515A1 JP 2011062788 W JP2011062788 W JP 2011062788W WO 2011152515 A1 WO2011152515 A1 WO 2011152515A1
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carboplatin
paclitaxel
tsu
salt
antitumor
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PCT/JP2011/062788
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English (en)
Japanese (ja)
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和久 南口
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大鵬薬品工業株式会社
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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 paclitaxel, carboplatin and (Z) -5-[(1,2-dihydro-2-oxo-3H-indole-3-ylidene) methyl] 2,4-dimethyl-1H-pyrrole-3-propanoic acid (Hereinafter referred to as “TSU-68”) or a novel antitumor agent comprising a combination thereof and an antitumor effect comprising a combination of paclitaxel and carboplatin comprising TSU-68 or a salt thereof as an active ingredient It relates to the agent.
  • TSU-68 novel antitumor agent comprising a combination thereof and an antitumor effect comprising a combination of paclitaxel and carboplatin comprising TSU-68 or a salt thereof as an active ingredient It relates to the agent.
  • An antitumor agent such as paclitaxel or carboplatin is considered to exhibit an antitumor effect by cell killing action on tumor cells.
  • paclitaxel + carboplatin combination therapy a treatment method using paclitaxel and carboplatin in combination
  • this combination therapy is a treatment method having a strong antitumor effect, it is difficult to say that the life prolonging effect is sufficient, and it is also said that there was a certain limit to recurrence and metastasis (Non-patent literature) 1, Non-Patent Document 2).
  • VEGF vascular endothelial growth factor
  • TSU-16 vascular endothelial growth factor-1
  • KDR tyrosine phosphorylation
  • TSU-68 has the same oxoindole skeleton as TSU-16, and is known to inhibit phosphorylation of Flk-1 tyrosine.
  • TSU-68 is a platelet-derived growth factor (hereinafter referred to as “PDGF”) receptor involved in intracellular signal transduction, a fibroblast growth factor (hereinafter referred to as “FGF”) receptor, etc. It has been confirmed in vitro that it also inhibits tyrosine phosphorylation.
  • PDGF platelet-derived growth factor
  • FGF fibroblast growth factor
  • Non-Patent Document 5 As a result of examining the antitumor effect of TSU-68 alone orally in a nude mouse in vivo model in which various human cancer cell lines were subcutaneously transplanted, it was found that the tumor growth inhibitory effect on lung cancer, colon cancer, uterine cancer, etc. It is recognized (Non-Patent Document 5). Furthermore, it has been reported that TSU-68 enhances the antitumor effect when used in combination with paclitaxel (Non-patent Document 6).
  • An object of the present invention is to provide a novel antitumor agent and antitumor effect potentiator that exhibit a remarkable antitumor effect, particularly a tumor growth delaying effect, and have few side effects.
  • the present inventor has conducted research on a novel combination therapy in which paclitaxel + carboplatin combination therapy and other antitumor agents are combined in order to develop a cancer therapy that further contributes to prolonging the survival time of the patient.
  • TSU-68 which is an inhibitor of receptor tyrosine kinases such as VEGF and PDGF involved in angiogenesis, remarkably enhances the antitumor effect of paclitaxel + carboplatin combination therapy, while reducing side effects. It was confirmed that the onset was not enhanced, and the present invention was completed.
  • the present invention provides the following 1) to 7).
  • An antitumor agent comprising a combination of paclitaxel, carboplatin and TSU-68 or a salt thereof.
  • Tumor agent is 1: 0.1 to 500: 0.5 to 1000.
  • paclitaxel in an amount of 1 to 1000 mg / m 2 (per body surface area) / day, carboplatin in an amount of 0.1 to 100 mg / mL / min (AUC), and TSU-68 or a salt thereof in an amount of 50 to 3000 mg / day.
  • the antitumor agent according to 1).
  • the antitumor agent according to any one of 1) to 4 which is a kit preparation comprising a preparation containing paclitaxel, a preparation containing carboplatin, and a preparation containing TSU-68 or a salt thereof.
  • the preparation containing paclitaxel and the preparation containing carboplatin are administered by intravenous, intramuscular or subcutaneous administration route, and the preparation containing TSU-68 or a salt thereof is administered by oral administration route
  • TSU-68 or a salt thereof for the production of an antitumor effect potentiator of an antitumor agent comprising a combination of paclitaxel and carboplatin.
  • 29) Use of TSU-68 or a salt thereof for the production of an antitumor effect potentiator for a combination therapy of an antitumor agent containing paclitaxel and an antitumor agent containing carboplatin.
  • 30) Use of 28) or 29), wherein TSU-68 or a salt thereof is administered at 50 to 3000 mg / day.
  • the antitumor agent comprising a combination of paclitaxel, carboplatin and TSU-68 or a salt thereof according to the present invention has a significantly higher antitumor effect, for example, a reduction in tumor volume or a suppression of tumor growth, compared with the conventional combination of antitumor agents. Surprisingly, the onset of side effects is not enhanced. Therefore, by using the antitumor agent of the present invention, a longer survival period of the tumor patient can be obtained.
  • the paclitaxel used in the present invention is (-)-(1S, 2S, 3R, 4S, 5R, 7S, 8S, 10R, 13S) -4,10-diacetoxy-2-benzoyloxy-5,20-epoxy-1, 7-dihydroxy-9-oxotaxy-11-en-13-yl (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate is a known compound, for example, as described in J. Am. Am. Chem. Soc. 93: 2325, 1971.
  • Paclitaxel alone exerts an antitumor effect by inhibiting the depolymerization of microtubules in the cytoskeleton and inhibiting cell division by arresting the cell cycle at the G2 / M phase, ovarian cancer, non-small
  • This compound is useful for cell lung cancer, breast cancer, stomach cancer, endometrial cancer and the like.
  • Carboplatin used in the present invention is a known compound represented by cis-diamine (1,1-cyclobutanedicarboxylate) -platinum (II) and can be produced, for example, according to a method described in US Pat. No. 4,140,707. .
  • Carboplatin when administered alone, kills tumor cells by binding to intracellular DNA and causing DNA dysfunction and DNA strand breaks, resulting in head and neck cancer, small cell lung cancer, testicular tumor, ovarian cancer, This compound is useful for cervical cancer, malignant lymphoma, non-small cell lung cancer and the like.
  • TSU-68 used in the present invention is (Z) -5-[(1,2, -dihydro-2-oxo-3H-indole-3-ylidene) methyl] 2,4-dimethyl-1H-pyrrole-3- It is a known tyrosine kinase inhibitor such as Flk-1, PDGF receptor represented by propanoic acid, and is known to exhibit antitumor effects on solid cancers such as liver cancer, lung cancer, colon cancer and uterine cancer when administered alone. It has been.
  • TSU-68 or a salt thereof can be produced by a known method, for example, the method described in JP-T-2002-516310.
  • the salt of TSU-68 is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, etc.
  • salts obtained by reaction with organic acids such as p-toluenesulfonic acid and salicylic acid.
  • the ratio of each active ingredient for combining paclitaxel, carboplatin and TSU-68 or a salt thereof in the antitumor agent of the present invention is not particularly limited as long as it exhibits an antitumor effect.
  • paclitaxel 1 as a daily dose Carboplatin is preferably about 0.1 to 500 mol, more preferably about 0.5 to 100 mol, particularly preferably about 1 to 50 mol, and TSU-68 or a salt thereof is preferably 0.5 to The amount may be about 1000 mol, more preferably about 1 to 500 mol, and particularly preferably about 3 to 50 mol.
  • each active ingredient in the antitumor agent or antitumor effect potentiator of the present invention is not particularly limited as long as it is an amount capable of enhancing the antitumor effect or antitumor effect, and the patient's age, cancer type, disease It is appropriately set according to the patient's condition such as stage, presence / absence of metastasis, treatment calendar, presence / absence of other antitumor agents.
  • the dose of paclitaxel is preferably 1 to 1000 mg / m 2 (per body surface area) / day, more preferably 10 to 500 mg / m 2 / day, and particularly preferably 50 to 300 mg / m 2 / day.
  • the dose of carboplatin is preferably 3 to 3000 mg / m 2 / day, more preferably 10 to 2000 mg / m 2 / day, and particularly preferably 200 to 1000 mg / m 2 / day.
  • the dose of TSU-68 or a salt thereof is preferably 50 to 3000 mg / day, more preferably 200 to 1500 mg / day, and particularly preferably 400 to 800 mg / day.
  • the dose of carboplatin is determined by, for example, the area under the time curve of the renal excretion function and the blood concentration of carboplatin (hereinafter referred to as “AUC”) according to Calvert's formula, Chatelut's formula, Jelliff's formula, Cockcroft's formula Can be set as appropriate.
  • the index of renal excretion function can be expressed by, for example, a patient's creatinine clearance value (CCR value), blood urea nitrogen value (BUN value), and glomerular filtration rate (GFR value).
  • CCR value creatinine clearance value
  • BUN value blood urea nitrogen value
  • GFR value glomerular filtration rate
  • the AUC of carboplatin is preferably 0.1 to 100 mg / mL / min, more preferably 0.2 to 20 mg / mL / min, and particularly preferably 1 to 10 mg / mL / min.
  • each active ingredient in the antitumor agent or antitumor effect potentiator of the present invention is not particularly limited as long as it is a schedule that enhances the respective antitumor effect or antitumor effect, and the patient's age, cancer type, It is appropriately set according to the patient's condition such as stage, presence / absence of metastasis, treatment calendar, presence / absence of other antitumor agents.
  • One cycle of the administration period is 7 to 35 days, and 14 to 21 days is more preferable.
  • Paclitaxel and carboplatin may be administered once each in one cycle, preferably once each on the same day in one cycle, more preferably once each on the first day in one cycle. preferable.
  • TSU-68 or a salt thereof may be administered daily for one cycle.
  • TSU-68 or a salt thereof can be administered 1 to 3 times a day, but is preferably administered twice a day. Depending on the patient's condition, this dosing cycle can be repeated. Although a drug holiday of 14 days or less can be provided between dosing cycles, it is preferred not to provide a drug holiday.
  • the antitumor agent of the present invention preferably contains paclitaxel, carboplatin and TSU-68 so that the daily dose is the above dose.
  • the antitumor agent of the present invention was formulated into a single dosage form as a combination drug (preparation containing a plurality of active ingredients) in which paclitaxel, carboplatin and TSU-68 or a salt thereof were mixed so as to have the above mixing ratio.
  • the above active ingredients are formulated into multiple dosage forms as a single agent (preparation containing a single active ingredient) or as a combination so that a product (single-dose preparation) can be used simultaneously or at intervals.
  • Multi-drug preparation may be used. Of these, it is preferable to prepare a preparation containing paclitaxel, a preparation containing carboplatin, and a preparation containing TSU-68 or a salt thereof as a single agent, and use them in a multi-drug form.
  • the dosage form of the above preparation is not particularly limited and can be appropriately selected depending on the purpose of treatment. Specifically, oral preparations (tablets, coated tablets, powders, granules, capsules, liquids, etc.), injections, suppositories Examples thereof include patches and ointments.
  • oral preparations tablets, coated tablets, powders, granules, capsules, liquids, etc.
  • injections suppositories
  • suppositories examples thereof include patches and ointments.
  • the antitumor agent of the present invention is formulated into a plurality of dosage forms, the preparations may be in different dosage forms or in the same dosage form.
  • TSU-68 or a salt thereof is more preferably used as an oral preparation
  • a preparation containing paclitaxel and a preparation containing carboplatin are preferably used as an injection.
  • the antitumor agent or antitumor effect potentiator of the present invention may be manufactured, packaged and distributed individually for each of the above preparations. All or part of the above preparations may be produced, packaged and distributed as a single package (kit preparation) suitable for combined administration.
  • each active ingredient in the present invention can be prepared by a generally known method using a pharmacologically acceptable carrier.
  • pharmacologically acceptable carriers include various types commonly used for ordinary drugs, such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonic agents, pH. Examples thereof include regulators, buffers, stabilizers, colorants, flavoring agents, flavoring agents, and soothing agents.
  • excipients include lactose, sucrose, sodium chloride, glucose, maltose, mannitol, erythritol, xylitol, maltitol, inositol, dextran, sorbitol, albumin, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silica
  • examples include acids, methylcellulose, glycerin, sodium alginate, gum arabic, and mixtures thereof.
  • the lubricant include purified talc, stearate, borax, polyethylene glycol, and a mixture thereof.
  • binder examples include simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, carboxymethyl cellulose, shellac, methyl cellulose, ethyl cellulose, water, ethanol, potassium phosphate, and a mixture thereof.
  • disintegrant examples include dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and mixtures thereof. Is mentioned.
  • Examples of the diluent include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and mixtures thereof.
  • 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.
  • soothing agents include procaine hydrochloride, lidocaine hydrochloride, and mixtures thereof.
  • Preparations containing paclitaxel include, for example, preparations using polyoxyethylene castor oil, preparations using alcohol, or albumin-encapsulated preparations (trade name: Abraxane (registered trademark)), polyglutamated preparations, etc. For example, but not limited to.
  • the tumor that can be treated by 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.
  • Gallbladder / bile duct cancer pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, leukemia, malignant lymphoma, multiple myeloma, skin cancer Brain cancer, testicular tumor, etc., preferably head and neck cancer, lung cancer, testicular tumor, ovarian cancer, cervical cancer, malignant lymphoma, breast cancer, stomach cancer, endometrial cancer, particularly preferably lung cancer, ovarian cancer .
  • TSU-68 or a salt thereof of the present invention alone has an antitumor effect, but when used in combination with paclitaxel + carboplatin combination therapy, the antitumor effect of paclitaxel + carboplatin combination therapy is remarkably enhanced. Therefore, TSU-68 or a salt thereof is useful as an antitumor effect potentiator of paclitaxel + carboplatin combination therapy.
  • TSU-68 or a salt thereof can be administered twice in a day, and the dose per dosage unit is 25 mg. ⁇ 1500 mg (50 mg to 3000 mg as daily dose) is preferable, 100 mg to 750 mg (200 mg to 1500 mg as daily dose) is more preferable, and 200 mg to 400 mg (400 mg to 800 mg as daily dose) is particularly preferable.
  • the antitumor agent of the present invention in which paclitaxel, carboplatin and TSU-68 or a salt thereof are used in combination is used alone or in combination of two agents, and paclitaxel + carboplatin combination therapy Compared with the case where is combined with other angiogenesis inhibitors, it is possible to realize a significantly high antitumor effect while suppressing the onset of side effects.
  • anti-tumor effect and “anti-tumor growth effect enhancing action” are “tumor growth suppression”, “tumor growth delay”, “response rate”, “morbidity control rate” or “progression-free survival” Evaluate by Further, “side effects” and “side effect enhancing action” are evaluated from “weight loss”.
  • Example 1 Effect of combined use of paclitaxel, carboplatin and TSU-68 in human non-small cell lung cancer strain A549 subcutaneous transplantation model
  • An about 2 mm square fragment of human non-small cell lung cancer-derived A549 passaged in vivo was isolated from male nude mice (BALB / c Nude 5 weeks of age, Charles River Japan, Inc.) transplanted subcutaneously in the back so that the average tumor volume is equalized when the tumor volume (tumor major axis x tumor minor axis 2 ⁇ 2) reaches approximately 200 mm 3
  • Each group was divided into 6 animals. This grouping date was defined as day1.
  • paclitaxel + carboplatin administration group paclitaxel was intravenously administered at 36 mg / kg to day 1 and day 5, and carboplatin was intravenously administered at 50 mg / kg to day 1.
  • TSU-68 administration group 200 mg / kg of TSU-68 was orally administered daily from day 1 to day 32.
  • the paclitaxel + carboplatin + TSU-68 administration group was administered with three drugs of paclitaxel, carboplatin and TSU-68 in the same administration dose, administration schedule and administration route.
  • the solvent was administered to the control group instead of the drug.
  • the tumor diameter and body weight of the mice were measured every 3 to 4 days.
  • the antitumor effect and side effect of each drug administration group were evaluated, and the antitumor effect enhancing effect and side effect enhancing effect of TSU-68 on paclitaxel + carboplatin combination therapy were evaluated.
  • the anti-tumor effect was evaluated by comparing each drug-administered group with the control group, and using the mean value of relative tumor volume (relative tumor volume, hereinafter referred to as “RTV”) calculated by Equation 1 as an index, total significance by two-sided Dunnett test When there was a significant suppression of tumor growth with a probability (p value) of less than 0.05, it was determined to have “anti-tumor effect”.
  • RTV relative tumor volume
  • T / C the average value of the tumor growth rate (hereinafter referred to as “T / C”) (%) was calculated according to Equation 2.
  • the antitumor effect enhancing action was evaluated by comparing the paclitaxel + carboplatin + TSU-68 administration group with the TSU-68 administration group and the paclitaxel + carboplatin administration group, and using the average RTV as an index, the Welt's Bilateral Intersection Unit Test (IUT) When there was a significant suppression of tumor growth with a probability (p value) of less than 0.05, it was determined that there was an antitumor effect enhancing action.
  • Table 1 shows the average RTV and T / C of each group in day 33.
  • each drug administration group had significant tumor growth inhibition and antitumor effect as compared with the control group.
  • the paclitaxel + carboplatin + TSU-68 administration group significantly suppressed tumor growth compared to the paclitaxel + carboplatin administration group and the TSU-68 administration group. Therefore, it was confirmed that TSU-68 has a remarkable antitumor effect enhancing action with respect to paclitaxel + carboplatin combination therapy.
  • RTV3 Periods to reach 3 times Relative Tumor Volume, hereinafter referred to as “RTV3”
  • RTV3 the average RTV reaches 3
  • RTV3 between each drug administration group and the control group is calculated.
  • the difference was calculated as the growth delay period (hereinafter referred to as “GDP”).
  • GDP the growth delay period
  • the paclitaxel + carboplatin + TSU-68 administration group had a GDP of 18 days, and the tumor growth delay was 11 days, which is the total of the GDP of each of the TSU-68 administration group and the paclitaxel + carboplatin administration group. It was improved. Therefore, TSU-68 was confirmed to have a significant antitumor effect-enhancing effect on paclitaxel + carboplatin combination therapy.
  • the side effect was evaluated by comparing the drug-administered group with the control group, and using the two-sided Dunnett test as an index for the total significance probability (p value) using the average value of the weight change rate (hereinafter referred to as “BWC”) (%) calculated by Equation 3 as an index. ) was less than 0.05, it was determined that there was a side effect.
  • the paclitaxel + carboplatin + TSU-68 administration group was compared with the paclitaxel + carboplatin administration group, and the total significance probability (p value) was 0 by the Welch's bilateral Intersection Unit Test (IUT) using the average BWC as an index. When there was a significant weight loss of less than 05, it was determined that “it has a side effect enhancing effect”.
  • Table 3 shows the average BWC of each group in day 33.
  • each drug administration group had the same weight loss and no side effects compared to the control group.
  • the weight loss was similar in the paclitaxel + carboplatin + TSU-68 administration group compared to the paclitaxel + carboplatin administration group and the TSU-68 group. Therefore, it was confirmed that TSU-68 has no side effect enhancing action with respect to paclitaxel + carboplatin combination therapy.
  • Example 2 Effect of combined use of TSU-16 and TSU-68 on paclitaxel + carboplatin combination therapy in human non-small cell lung cancer strain A549 subcutaneous transplantation model Fragment of approximately 2 mm square of A549 derived from human non-small cell lung cancer passaged in vivo Implanted subcutaneously in the back of mice (BALB / cAJcl-nu, 5 weeks old, CLEA Japan, Inc.) When the tumor volume reached about 200 mm 3 , each group was divided into 8 animals so that the average tumor volume was uniform. Divided. This grouping date was defined as day1.
  • paclitaxel was intravenously administered at 36 mg / kg to day 1 and day 5, and carboplatin was intravenously administered at 50 mg / kg to day 1.
  • carboplatin was intravenously administered at 50 mg / kg to day 1.
  • 40 mg / kg of TSU-16 was intravenously administered to days 4, 8, 11, 15, and 18 in combination with these.
  • TSU-68 was orally administered at 200 mg / kg daily from day 1 to day 21.
  • intravenous administration of TSU-16 alone at 40 mg / kg to days 4, 8, 11, 15 and 18 and oral administration of TSU-68 alone at 200 mg / kg from day 1 to day 21 It is a dose and usage that show almost the same antitumor effect and side effects.
  • the solvent was administered to the control group instead of the drug.
  • the tumor diameter and body weight of the mice were measured every 3 to 4 days.
  • the antitumor effect and side effect of each drug administration group were evaluated, and the antitumor effect enhancing effect and side effect enhancing effect of TSU-16 and TSU-68 on paclitaxel + carboplatin combination therapy were evaluated.
  • the antitumor effect enhancing action was evaluated by comparing the paclitaxel + carboplatin + TSU-16 administration group and the paclitaxel + carboplatin + TSU-68 administration group with the paclitaxel + carboplatin administration group, and using the Student's t-test as an index to determine the total significance ( When there was a significant suppression of tumor growth with a p value of less than 0.05, it was determined that “there is an antitumor effect enhancing action”.
  • the antitumor effect enhancing action of the paclitaxel + carboplatin + TSU-16 administration group and the paclitaxel + carboplatin + TSU-68 administration group was performed by Student's t-test using the average RTV as an index, and the significance probability (p value) was less than 0.05 In the case where there was a statistically significant difference, it was determined that “there was a more significant antitumor effect enhancing effect”.
  • Table 4 shows the average RTV and T / C of each group in day 22.
  • each drug administration group had significant tumor growth suppression and antitumor effect as compared with the control group.
  • the paclitaxel + carboplatin + TSU-16 administration group and the paclitaxel + carboplatin + TSU-68 administration group significantly suppressed tumor growth as compared to the paclitaxel + carboplatin administration group. Therefore, it was confirmed that TSU-16 and TSU-68 have an antitumor effect enhancing action with respect to paclitaxel + carboplatin combination therapy.
  • the paclitaxel + carboplatin + TSU-68 administration group had a significant suppression of tumor growth compared to the paclitaxel + carboplatin + TSU-16 administration group. Therefore, it was confirmed that TSU-68 has a more significant antitumor effect enhancing action than TSU-16.
  • the side effect enhancing action was evaluated by comparing the paclitaxel + carboplatin + TSU-16 administration group and the paclitaxel + carboplatin + TSU-68 administration group with the paclitaxel + carboplatin administration group, and using the Student's t test as an index, the total significance probability (p value) ) was less than 0.05, it was determined that “it has a side effect enhancing effect”.
  • a patient's t-test was performed on the paclitaxel + carboplatin + TSU-16 administration group and the paclitaxel + carboplatin + TSU-68 administration group using the mean BWC as an index. There was a difference in action ”.
  • Table 5 shows the average BWC results for each group in day 12.
  • Example 3 The combined effect of TSU-68 on paclitaxel + carboplatin combination therapy for patients with non-small cell lung cancer was targeted for patients with Stage IIIB / IV untreated non-small cell lung cancer.
  • one cycle is 21 days from day 1 to day 21, paclitaxel is administered intravenously at 200 mg / m 2 , carboplatin is administered intravenously at 6 mg / mL / min (AUC), and TSU- In 68, 400 mg / day or 800 mg / day was divided into twice a day and orally administered every day from day 1 to day 21. This dosing cycle was repeated depending on the patient's condition.
  • RR response rate
  • DCR disease control rate
  • CR complete response
  • PR partial response
  • RR (%) is the ratio of the number of patients recognized as CR or PR to the total number of cases.
  • DCR (%) is the ratio of the number of patients recognized as CR, PR, or SD to the total number of cases.
  • Table 6 shows the RR and DCR of paclitaxel + carboplatin + TSU-68 in patients with non-small cell lung cancer when 400 mg / day or 800 mg / day TSU-68 was administered.
  • PFS progression-free survival
  • Table 7 shows the PFS of paclitaxel + carboplatin + TSU-68 in patients with non-small cell lung cancer when 400 mg / day or 800 mg / day TSU-68 was administered.
  • TSU-68 in combination with paclitaxel + carboplatin combined with paclitaxel + carboplatin combined has a significantly strong anti-tumor effect without increasing side effects.
  • Combining TSU-68 with paclitaxel + carboplatin combination therapy is a very useful treatment because it has a better balance of antitumor effects and side effects than using TSU-16 with paclitaxel + carboplatin combination therapy. It was confirmed. It was also confirmed that the combined use of TSU-68 with paclitaxel + carboplatin combination therapy is clinically useful in cancer treatment.

Abstract

L'invention porte sur un nouvel agent anti-tumoral qui présente un effet anti-tumoral remarquable ; et sur un renforçateur de l'effet anti-tumoral. Elle porte plus précisément sur un agent anti-tumoral qui est obtenu par combinaison de paclitaxel, de carboplatine et d'acide (Z)-5-[(1,2-dihydro- 2-oxo-3H-indol-3-ylidène)méthyl]2,4-diméthyl-1H-pyrrole-3-propanoïque ou d'un sel de ce dernier.
PCT/JP2011/062788 2010-06-04 2011-06-03 Agent anti-tumoral contenant un composé indole WO2011152515A1 (fr)

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JP2003535038A (ja) * 1999-12-30 2003-11-25 スージェン・インコーポレーテッド 蛋白質キナーゼ活性の調節および癌化学療法において用いるための３−ヘテロアリーリデニル−２−インドリノン化合物

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JP2003535038A (ja) * 1999-12-30 2003-11-25 スージェン・インコーポレーテッド 蛋白質キナーゼ活性の調節および癌化学療法において用いるための３−ヘテロアリーリデニル−２−インドリノン化合物

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