JP2015163592A - Method for treating cancer by combined use of anti-cancer agents - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel combination of anti-cancer agents, which can achieve the potentiation of an anti-tumor activity.SOLUTION: The present invention relates to a pharmaceutical composition for treating cancer, which can be used in combination with an existing specific anti-cancer agent or a specific anti-cancer agent that is currently under development and contains N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)-piperidin-1-yl]phenyl}-N'-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition enables the achievement of a potentiated anti-tumor activity compared with an anti-tumor activity achieved when each of the anti-cancer agents is used singly.

Description

  The present invention relates to pharmaceuticals, in particular pharmaceutical compositions for the treatment of cancer, in particular N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof as an active ingredient and other anticancer agents The present invention relates to a pharmaceutical composition for cancer treatment for combined use. N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ′-[2- (propane-2-sulfonyl) phenyl] -1 , 3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof and an anti-cancer agent combination therapy.

  ALK (Anaplastic Lymphoma Kinase) is a receptor tyrosine kinase, a protein having a transmembrane region in the center, a tyrosine kinase region on the carboxyl terminal side, and an extracellular region on the amino terminal side. To date, it has been reported that full-length ALK is expressed in cancer cells originating from several ectoderm, such as neuroblastoma, glioblastoma, breast cancer, melanoma and the like. In some cases of human malignant lymphoma, as a result of chromosomal translocation, ALK gene is fused with other genes (for example, NPM gene, CLTCL gene, TFG gene), and fused tyrosine kinase with carcinogenic potential is used. (Science, vol.263, p.1281, 1994; Blood, vol.86, p.1954, 1995; Blood, vol.95, p.3204, 2000; Blood, vol.94, p.3265, 1999). In inflammatory myofibroblastic tumors, it is known that ALK gene is fused with other genes such as CARS gene and SEC31L1 gene as a result of chromosomal translocation. (Laboratory Investigation, a journal of technical methods and pathology, vol.83, p.1255, 2003; International Journal of Cancer, vol.118, p.1181, 2006). In 2007, it was reported that EML4 (echinoderm microtubule associated protein like-4) gene and ALK gene were fused in non-small cell lung cancer (Nature 448, p.561-566, 2007). It has been shown that TPM4-ALK fusion protein and FN1-ALK fusion protein are also present in cancer (World Journal of Gastroenterology, vol.12, p.7104, 2006; Journal Molecular Medicine, vol.85, p.863, 2007, Cancer Research, OnlineFirst on May 8, 2012). Many partner molecules that fuse with ALK, including EML4, have a complex formation domain, and the fusion itself is thought to form a complex. This complex formation controls the tyrosine kinase activity of ALK. It is thought to cause canceration as a result of abnormal activation of intracellular signals (Cellular and Molecular Life Science, vol. 61, p. 2939, 2004; Nature Reviews Cancer, vol. 8, p.11, 2008).

  ALK inhibitors are thought to inhibit the growth of cells that express the ALK fusion gene and exhibit antitumor activity. Crizotinib, which is actually known as an ALK inhibitor, has shown remarkable effectiveness in patients with non-small cell lung cancer expressing an ALK fusion gene and is used as a therapeutic agent. The overall response rate in clinical trials of crizotinib was more than 50%, but many patients who responded had partial remission and had a duration of efficacy of about 10 months (J. Clin. Oncol., vol.30, suppl, abstr.7553, 2012). As factors of resistance to crizotinib, secondary ALK mutation and activation of alternative pathways such as KRAS, KIT, and EGFR are known (see, for example, Non-Patent Document 1 or Non-Patent Document 2).

  In general, when an anticancer agent is administered alone in chemotherapy of a tumor, particularly a malignant tumor, the effect is limited in terms of side effects and the like, and sufficient antitumor action is often not obtained. Therefore, multi-drug combination therapy combining two or more drugs with different mechanisms of action is performed in clinical settings. This combination therapy combines anticancer drugs with different mechanisms of action to 1) reduce insensitive cell populations, 2) prevent or delay the emergence of drug resistance, and 3) disperse toxicity by combining drugs with different toxicities. The purpose is to enhance the antitumor action and reduce side effects. However, combination therapy with a combination of anticancer drugs with different mechanisms of action does not always result in an increase in antitumor activity, and sometimes only an increase in toxicity is seen, indicating a higher antitumor effect Combinations of anticancer agents are being studied.

In crizotinib-resistant cells, it has been reported that a combination of crizotinib and an EGFR inhibitor exhibits a cell growth inhibitory effect (see, for example, Non-Patent Document 3). In addition, in crizotinib-resistant patients, EGFR mutation and increased phosphorylation have been observed (see, for example, Non-Patent Document 1 or Non-Patent Document 2). In clinical trials, the combination of crizotinib and EGFR inhibitor erlotinib has been studied, because MET is involved in the resistance of EGFR inhibitors in non-small cell lung cancer. The crizotinib possessed is used in combination with an EGFR inhibitor (for example, see Non-Patent Document 4).
Pemetrexed has been reported to be effective in ALK fusion gene-positive patients (see, for example, Non-Patent Document 5). In addition, in two patients with non-small cell lung cancer with meningeal lesions, the combination of crizotinib and pemetrexed shows progression-free survival of 10 months and 6 months, respectively (see, for example, Non-Patent Document 6).

特許文献１には、併用しうる薬剤として、パクリタキセル等が例示されているが、具体的な併用方法やデータについての開示はなく、エルロチニブ等との組み合わせは具体的に記載されていない。
また、特許文献２には、上記構造式で示した化合物の結晶多形が開示されている。
さらに特許文献３には、上記構造式で示した化合物の中間体及び製造方法が記載されている。 N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ′-[2- (propane-2-sulfonyl) phenyl] -1,3 , 5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof has an ALK inhibitory action and an inhibitory action on the kinase activity of EML4-ALK fusion protein and mutant EGFR protein (Patent Document 1). . In Patent Document 1, the compound is a single agent, a therapeutic agent for cancer, lung cancer, non-small cell lung cancer, or small cell lung cancer, or an EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive cancer, It is also disclosed that it is useful as a therapeutic agent for lung cancer, non-small cell lung cancer, or small cell lung cancer. The chemical structure of this compound is as follows, and its free form is disclosed in Example 23 of Patent Document 1.

Patent Document 1 exemplifies paclitaxel and the like as a drug that can be used in combination, but does not disclose a specific combination method or data, and does not specifically describe a combination with erlotinib or the like.
Patent Document 2 discloses a crystal polymorph of the compound represented by the above structural formula.
Further, Patent Document 3 describes an intermediate of the compound represented by the above structural formula and a production method.

International Publication No. 2009/008371 Pamphlet International Publication No. 2011/145548 Pamphlet International Publication No. 2012/102393 Pamphlet

Clin. Cancer Res., 2012, 18, 1472-1482 Sci. Transl. Med., 2012, Volume 4, p.120ra17 Cancer Res., 2011, 71, p.6051-6060 J. Clin. Oncol., 2012, 30, suppl.abstr.2610 Study of Lung Cancer., 2011, Vol. 6, p.774-80 Lung Cancer, 2012, 76, p. 253-254

  When a plurality of anticancer agents are used in combination, side effects are often increased together with the antitumor effect, and it is not easy to combine two or more anticancer agents. Therefore, a new combination of anticancer agents capable of exerting an antitumor action without increasing side effects is desired.

  The inventors have surprisingly found that N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ′-[2- (propane- 2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (hereinafter referred to as “compound A”) is not effective in combination with a certain anticancer agent, while a specific anticancer agent The present invention was completed by finding that the antitumor action is enhanced by the combined use with A.

That is, the present invention
[1] To be used in combination with a pharmaceutical composition containing one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 A pharmaceutical composition for treating cancer comprising Compound A or a pharmaceutically acceptable salt thereof as an active ingredient,
[2] A medicament for treating cancer, characterized by being used in combination with a pharmaceutical composition comprising one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 Use of compound A or a pharmaceutically acceptable salt thereof for the manufacture of a composition;
[3] characterized in that it is used in combination with a pharmaceutical composition containing one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 for cancer treatment Compound A or a pharmaceutically acceptable salt thereof,
[4] Compound A or a pharmaceutical composition comprising one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 for the treatment of cancer Use of its pharmaceutically acceptable salts,
[5] A pharmaceutical composition containing one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, and compound A or a pharmaceutically acceptable salt thereof The pharmaceutical composition for cancer treatment according to [1], wherein the pharmaceutical composition is administered simultaneously, separately, sequentially, or at intervals.
[6] (a) Compound A or a pharmaceutically acceptable salt thereof, and (b) one or more selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 A pharmaceutical composition for treating cancer comprising a compound as an active ingredient,
[7] from the group consisting of (a) Compound A or a pharmaceutically acceptable salt thereof, and (b) paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 for the treatment of cancer A pharmaceutical composition comprising one or more selected compounds,
[8] A therapeutically effective dose of a pharmaceutical composition containing one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, and compound A or a pharmaceutical thereof A therapeutically effective dose of a salt that is administered in combination to a subject,
[9] A therapeutically effective dose of a pharmaceutical composition containing one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, and compound A or a pharmaceutical thereof A method for treating cancer, comprising administering to a subject a therapeutically effective dose of a salt acceptable to the subject simultaneously, separately, sequentially or at intervals,
[10] One or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, containing compound A or a pharmaceutically acceptable salt thereof as an active ingredient Anti-cancer action enhancer,
[11] (a) Compound A or a pharmaceutically acceptable salt thereof, and (B) one or more selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 A kit comprising a combination of compounds,
[12] (a) A pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, and (c) consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 A medicinal product for cancer treatment comprising a package insert indicated to be used in combination with a pharmaceutical composition comprising one or more compounds selected from the group,
[13] One or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, containing compound A or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition for cancer treatment for treating a subject undergoing anti-cancer treatment with the pharmaceutical composition comprising,
[14] The pharmaceutical composition according to [1], [5], [6], or [13], which is used for treatment of lung cancer, non-small cell lung cancer, or small cell lung cancer,
[15] The pharmaceutical composition according to [1], [5], [6], [13], or [14] for the treatment of EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive cancer object,
About.
[16] The pharmaceutical composition according to [1], [5], [6], [13], [14], or [15] for the treatment of ALK inhibitor resistant cancer.
[17] ALK inhibitor resistant cancer is N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ′-[2- (propane- The pharmaceutical composition according to [16], which is a 2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine resistant cancer or a crizotinib resistant cancer.
The “subject” is a human or other animal that needs the prevention or treatment, and as a certain aspect, it is a human that needs the prevention or treatment.

  According to the present invention, a new combination of anticancer agents capable of exerting an antitumor effect can be provided. That is, the combined use with Compound A and a specific anti-cancer agent under development or development can provide a high anti-tumor effect even for a subject that cannot obtain a sufficient anti-tumor effect by itself.

FIG. 1 is a graph showing the results of Example 1 in which Compound A (CompA) and paclitaxel (PTX) were administered in combination. (a) is a graph showing tumor volume (Tumor Volume (mm ³ )), and (b) is a graph showing body weight (Body Weight (g)). The horizontal axis represents the number of days after the start of drug administration (Days). Untreated represents an untreated group. FIG. 2 is a graph showing the results of Example 1 in which Compound A (CompA) and carboplatin (CBDCA) were administered in combination. (a) is a graph showing tumor volume (Tumor Volume (mm ³ )), and (b) is a graph showing body weight (Body Weight (g)). The horizontal axis represents the number of days after the start of drug administration (Days). Untreated represents an untreated group. FIG. 3 is a graph showing the results of Example 1 in which Compound A (CompA) and erlotinib were administered in combination. (a) is a graph showing tumor volume (Tumor Volume (mm ³ )), and (b) is a graph showing body weight (Body Weight (g)). The horizontal axis represents the number of days after the start of drug administration (Days). Control represents a control group. FIG. 4 is a graph showing the results of Example 1 in which Compound A (CompA) and pemetrexed (MTA) were administered in combination. (a) is a graph showing tumor volume (Tumor Volume (mm ³ )), and (b) is a graph showing body weight (Body Weight (g)). The horizontal axis represents the number of days after the start of drug administration (Days). Control represents a control group. FIG. 5 is a graph showing the results of Example 3 in which the cell proliferation inhibitory action of Compound A in the presence of Compound A alone or OSI-906 on crizotinib-resistant H2228 cell line was examined. The horizontal axis represents the concentration of compound A (CompA), and the vertical axis represents the cell viability when the control (DMSO added group) is 100%.

The cancer in the “pharmaceutical composition for cancer treatment” of the present invention includes all solid cancers and lymphomas. Some embodiments include skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, stomach cancer, etc., and other embodiments include lung cancer, non-small cell lung cancer, Or it is small cell lung cancer. Moreover, non-small cell lung cancer is mentioned as another aspect.
Yet another embodiment includes cancers that are EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive. Yet another embodiment includes lung cancer, non-small cell lung cancer, or small cell lung cancer that is EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive. Another aspect includes non-small cell lung cancer that is EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive.
Another embodiment includes a cancer that is positive for an EML4-ALK fusion polynucleotide. Still another embodiment includes lung cancer, non-small cell lung cancer, or small cell lung cancer that is EML4-ALK fusion polynucleotide positive. Another embodiment includes non-small cell lung cancer that is EML4-ALK fusion polynucleotide positive.
Another embodiment includes an ALK inhibitor resistant cancer, another embodiment includes a compound A resistant cancer or a crizotinib resistant cancer, and yet another embodiment includes a compound A resistant cancer. Examples of this include crizotinib-resistant cancer. In another embodiment, lung cancer, non-small cell lung cancer, or small cell lung cancer that is resistant to ALK inhibitors, and in another embodiment, non-small cell lung cancer that is resistant to ALK inhibitors can be mentioned. Yet another aspect includes EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive cancer that is ALK inhibitor resistant, and yet another aspect is ALK inhibitor resistant EML4- ALK fusion polynucleotide positive cancer is mentioned. Another embodiment includes EML4-ALK fusion polynucleotide positive non-small cell lung cancer that is ALK inhibitor resistant.
Another embodiment includes an EML4-ALK fusion polynucleotide positive non-small cell lung cancer that is resistant to Compound A, and another embodiment is an EML4-ALK fusion polynucleotide positive non-small cell lung cancer that is resistant to crizotinib. Is mentioned.

An “ALK inhibitor-resistant cancer” is a cancer that has acquired resistance by administration of an ALK inhibitor and has reduced the anticancer effect of the drug. The ALK inhibitor in ALK inhibitor resistant cancer is not particularly limited, and examples thereof include compound A, crizotinib, LDK378, CH5424802, AP26113, CEP-28122, X-396 and the like. Or crizotinib. Another embodiment includes compound A, and another embodiment includes crizotinib. Cancers in ALK inhibitor resistant cancer include all solid cancers and lymphomas, and specifically include the various cancers described above.
A “compound A resistant cancer” is a cancer that has acquired resistance by administration of compound A and has reduced anticancer activity by compound A. The cancer includes all solid cancers and lymphomas, and specifically includes the various cancers described above.
A “crizotinib-resistant cancer” is a cancer that has acquired resistance by administration of crizotinib and has reduced the anticancer effect of crizotinib. The cancer includes all solid cancers and lymphomas, and specifically includes the various cancers described above.

本発明におけるAZD-4547は、例えば、国際公開第２００８/０７５０６８号パンフレットに記載の方法、若しくは、当業者にとって自明である方法、又はそれらの変法によって容易に入手可能である。AZD-4547の化学構造は以下の通りである。

Compound A or a pharmaceutically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention, is, for example, the method described in Patent Documents 1 to 3, or a method obvious to those skilled in the art, or It can be easily obtained by a modification of
OSI-906 in the present invention can be easily obtained by, for example, the method described in International Publication No. WO 2005/097800, the method obvious to those skilled in the art, or a modification thereof. The chemical structure of OSI-906 is as follows.

AZD-4547 in the present invention can be easily obtained by, for example, the method described in WO2008 / 075068, the method obvious to those skilled in the art, or a modification thereof. The chemical structure of AZD-4547 is as follows.

  Paclitaxel (PTX), erlotinib (Erlotinib), pemetrexed (MTA), lapatinib (Lapatinib) can be purchased commercially and prepared based on the attached materials (for example, information on pharmaceuticals in Japan) Homepage (see http://www.info.pmda.go.jp/) These compounds can be easily obtained by publicly known information, methods obvious to those skilled in the art, or modifications thereof. For example, erlotinib is readily available by the method described in WO 1996/30347, or by methods obvious to those skilled in the art, or modifications thereof. Chem. Lett., Vol.16 p.4686-4691, 2006, or a method obvious to those skilled in the art, or a modification thereof, and can be easily obtained. .

“Compound A or a pharmaceutically acceptable salt thereof” means a salt with an acid described in International Publication No. 2009/008371, specifically, hydrochloric acid, hydrobromic acid, iodination. Inorganic acids such as hydrogen acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, Ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acid addition salts with organic acids such as aspartic acid, glutamic acid, inorganic such as sodium, potassium, magnesium, calcium, aluminum Bases, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, acetylleucine, etc. Include seed amino acids and salts or ammonium salts with amino acids derivatives.
“One or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906” can also include pharmaceutically acceptable salts thereof. Specific examples of these pharmaceutically acceptable salts that may form an acid addition salt or a salt with a base depending on the type of substituent include the salts described above.

  “Compound A or a pharmaceutically acceptable salt thereof” may be various hydrates, solvates, and crystalline polymorphic substances, all of which are active ingredients of the pharmaceutical composition of the present invention. Is included. In addition, “one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, erlotinib, lapatinib, AZD-4547, and OSI-906” includes various hydrates, solvates, and crystalline polymorphs. It may be a compound containing a substance. The present invention also encompasses pharmaceutical compositions containing compounds labeled with various radioactive or non-radioactive isotopes.

The pharmaceutical composition of the present invention can be prepared by a commonly used method using an excipient usually used in the art, that is, a pharmaceutical excipient or a pharmaceutical carrier.
Administration is orally by tablets, pills, capsules, granules, powders, liquids, etc. Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.

As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The composition may contain an inert additive such as a lubricant, a disintegrant, a stabilizer and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.

  Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline. Non-aqueous solvents include alcohols such as ethanol. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.

  A pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof, or one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, erlotinib, lapatinib, AZD-4547, and OSI-906 In general, when administered orally, the daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. This is administered once or divided into 2 to 4 times. In the case of intravenous administration, the daily dose is appropriately about 0.0001 to 10 mg / kg per body weight, and is administered once a day or divided into multiple times. In addition, as a transmucosal agent, about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

  The pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in one embodiment, 0.01 to 50% by weight of the active ingredient, although it varies depending on the administration route, dosage form, administration site, excipient and additive type.

  In the present invention, the anticancer agent that can be used in combination with Compound A or a pharmaceutically acceptable salt thereof is one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906. The pharmaceutical composition containing is mentioned. Another embodiment includes a pharmaceutical composition containing one or more compounds selected from the group consisting of erlotinib, AZD-4547, OSI-906, and lapatinib. Yet another embodiment includes a pharmaceutical composition containing one or more compounds selected from the group consisting of erlotinib, AZD-4547, and OSI-906. Another embodiment includes a pharmaceutical composition containing erlotinib. Yet another embodiment includes a pharmaceutical composition containing OSI-906.

  Among the above-mentioned anticancer agents, those that are already in clinical use will be clear to those skilled in the art how to obtain them, their routes of administration, and their dosages. The appropriate dosage and administration (Dosage ans Administration) varies depending on the type of cancer, symptoms, and concomitant drugs. Detailed information is available in various databases provided by the FDA, such as "Approved Oncology Drugs" (http: //www.accessdata .fda.gov / scripts / cder / drugsatfda /), "Orange Book" (http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm) http://www.info.pmda.go.jp/). Information on each anticancer agent in these databases is incorporated in the present application.

  The following are excerpts of some of the dosage and administration related to each anticancer drug disclosed on the website for providing information on pharmaceuticals and medicines in Japan. It will be appreciated that the following administration conditions are examples and that complete information should be referred to for actual administration.

Paclitaxel (PTX): Applicable cancer types are ovarian cancer, non-small cell lung cancer, breast cancer, stomach cancer, endometrial cancer, head and neck cancer with relapse or distant metastasis, esophageal cancer with relapse or distant metastasis, angiosarcoma Advanced or recurrent cervical cancer. Depending on each cancer type, it is usually administered at one of the following dosages. Once a day, 210 mg / m ² (body surface area) is infused intravenously over 3 hours, and the drug is taken off for at least 3 weeks. Once a day, 100 mg / m ² (body surface area) is infused intravenously over 1 hour, followed by a week. Take one dose for 6 weeks and then take a rest for at least 2 weeks. Once a day, 80 mg / m ² (body surface area) is infused intravenously over 1 hour and administered once a week for 3 weeks, or 1 day A dosage regimen of 135 mg / m ² (body surface area) at a time for intravenous infusion over 24 hours and resting for at least 3 weeks.
Erlotinib: Applicable cancer types include unresectable, recurrent / progressive non-small cell lung cancer that has progressed after cancer chemotherapy, or unresectable pancreatic cancer. Erlotinib is administered orally at a dose of 100 to 150 mg once a day at least 1 hour before meal or 2 hours after meal. The dose should be reduced according to the patient's symptoms.
Pemetrexed (MTA): Applicable cancer types include malignant pleural mesothelioma and unresectable advanced / recurrent non-small cell lung cancer. Depending on each cancer type, one of the following dosages is usually used. In combination with cisplatin, 500 mg / m ² (body surface area) of pemetrexed once a day is infused intravenously over 10 minutes, and the drug is withdrawn for at least 20 days. This is one course and the administration is repeated. As pemetrexed, 500 mg / m ² (body surface area) is administered intravenously over 10 minutes once a day, and the drug is withdrawn for at least 20 days. This is one course and the administration is repeated. In either case, the dose may be reduced as appropriate depending on the patient's condition.
Lapatinib (Lapatinib): Applicable cancer types include inoperable or recurrent breast cancer with confirmed HER2 overexpression. In combination with capecitabine, for adults, 1250 mg of lapatinib is usually given orally once daily, at least 1 hour before meal or 1 hour after meal. The dose may be reduced according to the patient's condition.

AZD-4547: For the administration route and dosage, reference can be made to the dosages described in WO 2008/075068 pamphlet. Specifically, for example, the dose is administered in divided doses if necessary so as to obtain a daily dose in the range of 0.1 mg to 1000 mg of active ingredient per kg body weight. However, the daily dose may be adjusted according to the patient's condition and administration route. In some embodiments, when a parenteral route is used, it is administered at a low dose. Intravenous administration includes, for example, a dose ranging from 0.1 mg to 30 mg of active ingredient per kg body weight. In another embodiment, the pharmaceutical composition for oral administration includes, for example, 0.1 mg to 2 g of active ingredient per kg of body weight.
OSI-906: For the administration route and dosage, reference can be made to the dosages described in WO 2005/097800 pamphlet. Specifically, for example, about 0.01 mg / kg to 150 mg / kg per day, in another embodiment, about 0.5 mg / patient to 7 g / patient, and in another embodiment, 1 day. In another embodiment, it is about 0.5 mg / patient to 3.5 mg / patient per day. As another aspect, J. Clin. Oncol., Vol.28, Abstract 2530, 2010; J. Clin. Oncol., Vol.28, Abstract 2531, 2010; J. Clin. Oncol., Vol.28, Abstract 3016, 2010; J. Clin. Oncol., Vol. 27, Abstract 2559, 2009, etc.

  The “therapeutically effective dose” in the present invention, when used in combination therapy, depends on the route of administration normally administered, the same dose as that usually administered alone or a lower dose, for example, when administered alone. 0.10-0.99 times the highest dose. In the case of a pharmaceutical composition administered in a certain administration cycle, it is preferable to appropriately adjust the administration cycle so as to be suitable for combined use with Compound A. Specific administration frequency, dosage, infusion administration time, administration cycle, and the like are appropriately determined according to individual cases in consideration of patient symptoms, age, sex, and the like.

A pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof and one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 is administered in combination The administration form is not particularly limited as long as the administration route, administration frequency, and dosage suitable for each are employed, but simultaneous administration, separate administration, continuous administration, or administration at desired time intervals. Also good. The simultaneous administration preparation may be a compounding agent or may be separately formulated. Specifically, for example, (1) a pharmaceutical composition containing Compound A and one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, (2) Compound A and one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, separately formulated (3) Compound A, and one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, Administration of two types of preparations obtained by separately formulating at a time interval by the same route of administration (eg, compound A followed by paclitaxel, erlotinib Administration of one or more compounds selected from the group consisting of pemetrexed, lapatinib, AZD-4547, and OSI-906, or administration in the reverse order), (4) compound A, and paclitaxel, erlotinib , Pemetrexed, lapatinib, AZD-4547, and one or more compounds selected from the group consisting of OSI-906, and two different preparations obtained separately, simultaneously administered via different administration routes, (5) compounds A and two pharmaceutical preparations obtained by separately preparing a pharmaceutical composition containing one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 Administration at different intervals of administration (eg, compound A followed by paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 Administration in the order of 1 or more compounds selected from the group, or, in the reverse order) and the like.
In another embodiment, compound A and two or more compounds obtained by separately formulating one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 Examples thereof include a method in which the preparation is administered at an appropriate administration route and administration frequency at the same time or at intervals.
In addition, in the case of administration with a time interval, it can be administered at an interval sufficient to enhance the antitumor action. If drug interaction with Compound A is a concern, it can be administered at intervals necessary to avoid the interaction.

“(A) Compound A or a pharmaceutically acceptable salt thereof, and (b) one or more selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906” “A kit comprising a combination of the above-mentioned compounds” means that a preparation containing the active ingredient (a) (first preparation) and a preparation containing the active ingredient (b) (second preparation) are used in combination therapy of these active ingredients. It is included in combination so that it can be used. If desired, the kit of the present invention may be a packaged product that may contain an additional formulation or a display member that facilitates administration according to each administration time, such as a placebo.
The two types of preparations can be administered with the same or different administration routes under the administration conditions such as formulation formulation, administration route, administration frequency, etc. suitable for each formulation, taking into consideration the bioavailability, stability, etc. of each formulation. They are administered simultaneously or separately. Here, “simultaneously” means that the first formulation and the second formulation are administered together by the same administration route, and “separately” means that the first formulation and the second formulation are the same or different administration routes. It means that they are administered separately at the same or different dosing frequency or dosing interval.

  “(A) a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof as an active ingredient of the present invention; and (c) paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906. A pharmaceutical product for cancer treatment comprising a package insert indicated to be used in combination with a pharmaceutical composition containing one or more compounds selected from the group consisting of a pharmaceutical agent containing a therapeutically effective dose of an active ingredient The composition (a) and said pharmaceutical composition containing one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, said It means a medicine for cancer treatment packaged including both the package insert (c) relating to the pharmaceutical composition of (a).

  One or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, containing “compound A or a pharmaceutically acceptable salt thereof as an active ingredient” In the `` pharmaceutical composition for cancer treatment for treating a subject undergoing anticancer treatment with a pharmaceutical composition containing '', `` subject '' means paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 Other anticancer agents may be administered as long as they are treated with a pharmaceutical composition containing one or more compounds selected from the group consisting of: “Subject” refers to a pharmaceutical composition containing one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, compound A or a pharmaceutically acceptable salt thereof. May be administered simultaneously, separately, successively or at intervals with the pharmaceutical composition for treating cancer containing a salt as an active ingredient.

As shown in the Examples herein, it has been found that the combined use of Compound A and certain existing or developing anticancer agents enhances the antitumor action. That is, Compound A does not affect the antitumor effect of axitinib or carboplatin, while it exhibits an antitumor effect when used in combination with paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, or OSI-906. confirmed.
In particular, as shown in Example 2, when compound A was used in combination with erlotinib, lapatinib, AZD-4547, or OSI-906, it exhibited a synergistic antitumor effect.
In particular, as shown in Example 1, when compound A was used in combination with erlotinib, it was clarified that it exhibits a synergistic effect at a dose at which erlotinib does not exhibit an antitumor effect.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

In the following Examples, the following compounds were used as existing or developing anticancer agents used in combination with Compound A.
Paclitaxel (PTX) and pemetrexed (MTA) were purchased from LCLabs. Erlotinib (EGF receptor inhibitor) was purchased from Chugai Pharmaceutical Co., Ltd. and extracted. Lapatinib (EGF receptor and HER2 inhibitor) was synthesized with reference to the method described in Bioorg. Med. Chem. Lett., Vol.16 p.4686-4691, 2006. AZD-4547 (FGF receptor inhibitor) was synthesized with reference to the method described in International Publication No. 2008/075068. OSI-906 (IGF1 receptor and insulin receptor inhibitor) was synthesized with reference to the method described in WO 2005/097800. Carboplatin (CBDCA) was purchased from Sigma and Bristol Myers. Axitinib (PDGF receptor inhibitor) was synthesized with reference to WO 2006/048745.

Example 1. Anti-tumor test on NCI-H2228 cells (in vivo)
1. experimental method
NCI-H2228 cells suspended in PBS (non-small cell lung cancer cells expressing EML4-ALK fusion protein) (see Cell, vol.131, p.1190, 2007) About 3 × 10 ⁶ male NOD / SCID mice (Nippon Charles River Co., Ltd.) were transplanted subcutaneously in the back, and after confirming tumor growth, administration of the test compound was started. The test was conducted in four groups: a control group or an untreated group, a compound A alone group, a combination agent alone group, and a combination group. A solvent (0.5% methylcellulose aqueous solution) was administered to the control group. In the untreated group, no solvent was administered. Compound A was orally administered as a 0.5% methylcellulose suspension at a dose of 10 mg / kg / day once daily. Paclitaxel was intravenously administered at 12 mg / kg / day for 5 days after the start of administration. Both drugs were administered to the combination group in the same manner as the single agent group. Another three trials included carboplatin (60 mg / kg / day intravenously once every 7 days), erlotinib (60 mg / kg / day orally once daily) or pemetrexed (50 mg / kg / day was administered intravenously once a day for 5 days). Body weight and tumor diameter were measured twice a week, and tumor volume was calculated by the following formula.
[Tumor volume (mm ³ )] = [Tumor major axis (mm)] × [Tumor minor axis (mm)] ² × 0.5

2. Results The results are shown in Figure 1-4.
Compound A (Comp A), paclitaxel (PTX), erlotinib (Erlotinib), and pemetrexed (MTA) inhibited tumor growth in combination studies with paclitaxel (PTX), erlotinib (Erlotinib), and pemetrexed (MTA), respectively . Moreover, in any combination test, the tumor volume in the combination group was small as compared with each single group.
On the other hand, in the combination test with carboplatin, Compound A and carboplatin each independently inhibited tumor growth, but the tumor volume in the combination group was similar to that of Compound A alone group. From the above, it was confirmed that anti-tumor action was enhanced by the combined use of compound A with paclitaxel, erlotinib and pemetrexed.

Example 2 Growth inhibition test using compound A resistant H2228 cell line established from human non-small cell lung cancer cell line NCI-H2228 cell (EML4-ALK fusion protein expressing cell) (in vitro)
1. Experimental Method The compound A resistant H2228 cell line was established by culturing NCI-H2228 cells in the presence of 0.3 and 1 μmol / L of compound A for about 1 year.
NCI-H2228 cells or Compound A resistant H2228 cell lines were seeded in 96-well spheroid plates in RPMI1640 medium (Invitrogen) containing 10% fetal bovine serum. After overnight culture at 37 ° C. in the presence of 5% CO ₂ , the test compound or DMSO was added, and the cells were further cultured for 5 days. Thereafter, the number of cells was measured using a cell number measurement reagent (CellTiter-Glo ™ Luminescent Cell Viability Assay; Promega). The inhibition rate of the test compound was calculated assuming that the measured values in the medium alone and DMSO group were 100% inhibition and 0% inhibition, respectively, and the 50% inhibition concentration (IC ₅₀ value) was determined by the logistic regression method. As test compounds, Compound A, paclitaxel, carboplatin, axitinib, erlotinib, lapatinib, AZD-4547, and OSI-906 were used.

2. Results The results are shown in Tables 1 to 3. Table 1 shows the cell growth inhibitory effects of each compound as a single agent against NCI-H2228 cells and Comp A-resistant H2228 cells. Indicates. Table 2 shows “cell growth inhibitory effects of each compound against Comp A-resistant H2228 cells in the presence of 1” in the presence of 1 μmol / L of Compound A. μmol / L Comp A). Table 3 shows “Cell growth inhibitory effects of Comp A against Comp A-resistant H2228 cells in the presence of each compound”. . The numerical values in the table indicate IC ₅₀ and the unit is μmol / L.

As shown in Table 1, Compound A inhibited proliferation with IC ₅₀ values of 0.065 and 3.85 μmol / L against NCI-H2228 and Compound A resistant H2228 cell lines, respectively. Axitinib, erlotinib, AZD-4547, and OSI-906 did not inhibit the proliferation of both cells by 50% or more at 3 μmol / L. Lapatinib did not inhibit the growth of both cells by more than 50% at 1 μmol / L. On the other hand, as shown in Table 2, in the presence of 1 μmol / L of Compound A, erlotinib, lapatinib, AZD-4547, and OSI-906 are compounds with IC ₅₀ values of 0.48, 0.11, 0.28, and 0.49 μmol / L, respectively. Inhibition of growth of the A resistant H2228 cell line. Compound A did not affect the growth inhibitory effect of axitinib on the ASP3026 resistant H2228 cell line. Compound A also had no effect on the growth inhibitory effect of paclitaxel and carboplatin on the compound A resistant H2228 cell line.
Conversely, as shown in Table 3, the compound A resistant H2228 cell line was cultured in the presence of 1, 1, 0.3, and 3 μmol / L of erlotinib, lapatinib, AZD-4547, and OSI-906, respectively. When the growth inhibitory action was evaluated, Compound A inhibited growth with IC ₅₀ values of 0.40, 0.72, 0.075, and 0.11 μmol / L, respectively.
From the above, it was confirmed that Compound A exhibited a cell growth inhibitory action synergistically with erlotinib, lapatinib, AZD-4547, and OSI-906 in the compound A resistant H2228 cell line.

Example 3 Growth inhibition test using crizotinib-resistant H2228 cell line established from human non-small cell lung cancer cell line NCI-H2228 cell (EML4-ALK fusion protein expressing cell) (in vitro)
1. Experimental method The crizotinib-resistant H2228 cell line was established by culturing NCI-H2228 cells for about 2 months in the presence of 0.01-1 μmol / L of crizotinib.
A 96-well spheroid plate was seeded with crizotinib-resistant H2228 cell line in RPMI1640 medium (Invitrogen) containing 10% fetal bovine serum. After overnight culture at 37 ° C. in the presence of 5% CO 2, the test compound or DMSO was added, and the cells were further cultured for 5 days. Thereafter, the number of cells was measured using a cell number measurement reagent (CellTiter-Glo ™ Luminescent Cell Viability Assay; Promega). The inhibition rate of the test compound was calculated assuming that the measured values in the medium alone and DMSO group were 100% inhibition and 0% inhibition, respectively, and the 50% inhibition concentration (IC ₅₀ value) was determined by the logistic regression method. In addition, IC ₅₀ values in the presence of 1 μmol / L erlotinib or 3 μmol / L OSI-906 were determined in the same manner. Compound A and crizotinib were used as test compounds.

2. Results The results are shown in Table 4, Table 5, and FIG. Table 4 shows “Cell growth inhibitory effects of compound A and crizotinib as a single agent against crizotinib-resistant H2228 cells”. Table 5 shows “Cell growth inhibitory effects of compound A against crizotinib-resistant H2228 cells in the presence of erlotinib or OSI-906”. ). The numerical values in the table indicate IC ₅₀ and the unit is μmol / L. FIG. 5 shows representative examples of the cell growth inhibitory action of Compound A in the presence of Compound A alone or OSI-906 on the crizotinib-resistant H2228 cell line shown in Tables 4 and 5.
Compound A and crizotinib inhibited proliferation against crizotinib resistant H2228 cell line with IC ₅₀ values of 0.54 and 2.19 μmol / L, respectively. Compound A also inhibited the growth of crizotinib-resistant H2228 cell line in the presence of 1 μmol / L erlotinib or 3 μmol / L OSI-906 with IC ₅₀ values of 0.11 and 0.065 μmol / L, respectively.
From the above, it was confirmed that Compound A exhibited a cell growth inhibitory action synergistically with erlotinib or OSI-906 in the crizotinib-resistant H2228 cell line.

  The present invention relates to a pharmaceutical, in particular, a pharmaceutical composition for treating cancer, particularly a pharmaceutical for treating cancer for use in combination with other anticancer agents containing Compound A or a pharmaceutically acceptable salt thereof as an active ingredient. Relates to the composition. Further, the present invention relates to a combination therapy of Compound A or a pharmaceutically acceptable salt thereof and an anticancer agent. According to the present invention, a new combination of anticancer agents capable of exerting an antitumor action can be provided. That is, the combined use with Compound A and a specific anti-cancer agent under development or development can provide a high anti-tumor effect even for a subject that cannot obtain a sufficient anti-tumor effect by itself.

Claims (17)

Characterized in that it is used in combination with a pharmaceutical composition comprising one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane-2-sulfonyl) phenyl] -1, A pharmaceutical composition for treating cancer comprising 3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for treating cancer, characterized by being used in combination with a pharmaceutical composition containing one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 N- {2-Methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane-2-sulfonyl) phenyl for preparation ] Use of 1,3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof. N in combination with a pharmaceutical composition comprising one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 for the treatment of cancer, N -{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane-2-sulfonyl) phenyl] -1,3, 5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof. N- {2-methoxy in combination with a pharmaceutical composition containing one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 for the treatment of cancer -4- [4- (4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ′-[2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2 Use of 1,4-diamine or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 and N- {2-methoxy-4- [4- (4-methyl Piperazin-1-yl) piperidin-1-yl] phenyl} -N ′-[2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine or pharmaceutically The pharmaceutical composition for cancer treatment according to claim 1, wherein the acceptable salt is administered simultaneously, separately, sequentially or at intervals. (a) N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ′-[2- (propane-2-sulfonyl) phenyl]- 1,3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof, and (b) selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 A pharmaceutical composition for treating cancer comprising one or more compounds as active ingredients. (A) N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane-2 -Sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof, and (b) paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI- A pharmaceutical composition comprising one or more compounds selected from the group consisting of 906. A therapeutically effective dose of a pharmaceutical composition comprising one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, and N- {2-methoxy-4- [ 4- (4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ′-[2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine Alternatively, a method for treating cancer, comprising administering to a subject a combination of therapeutically effective doses of a pharmaceutically acceptable salt thereof. A therapeutically effective dose of a pharmaceutical composition comprising one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, and N- {2-methoxy-4- [ 4- (4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ′-[2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine Alternatively, a method for treating cancer, comprising administering a therapeutically effective dose of a pharmaceutically acceptable salt thereof to a subject simultaneously, separately, sequentially, or at intervals. N- [2- (isopropylsulfonyl) phenyl] -N ′-{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -1,3,5- One or more selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, containing triazine-2,4-diamine or a pharmaceutically acceptable salt thereof as an active ingredient Compound anti-cancer action potentiator. (a) N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ′-[2- (propane-2-sulfonyl) phenyl]- 1,3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof, and (B) selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 A kit comprising a combination of one or more compounds. (a) N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ′-[2- (propane-2-sulfonyl) phenyl]- A pharmaceutical composition containing as an active ingredient 1,3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof, and (c) paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and A pharmaceutical product for treating cancer comprising a package insert indicated to be used in combination with a pharmaceutical composition comprising one or more compounds selected from the group consisting of OSI-906. N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ′-[2- (propane-2-sulfonyl) phenyl] -1,3 , 5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof as an active ingredient, selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 A pharmaceutical composition for cancer treatment for treating a subject undergoing anticancer treatment with a pharmaceutical composition comprising one or more compounds. The pharmaceutical composition according to claim 1, 5, 6, or 13, which is used for treatment of lung cancer, non-small cell lung cancer, or small cell lung cancer. 15. The pharmaceutical composition according to claim 1, 5, 6, 13, or 14, which is used for treatment of an EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive cancer. The pharmaceutical composition according to claim 1, 5, 6, 13, 14, or 15, which is used for treatment of ALK inhibitor-resistant cancer. ALK inhibitor resistant cancer is N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane-2-sulfonyl) The pharmaceutical composition according to claim 16, which is a cancer resistant to pheny] -1,3,5-triazine-2,4-diamine or crizotinib.

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