Therapeutic agent for biliary tract cancer

Abstract

The present invention provides a therapeutic agent for biliary tract cancer, which contains an LAT1 inhibitor and is characterized in that the biliary tract cancer is a non-curatively resected biliary tract cancer in which cancer chemotherapy in a subject is ineffective or intolerant and deteriorates, the subject being a patient with high expression of LAT1 having non-fast type N-acetyltransferase 2.

Description

Technical Field

[0001] The present invention relates to a therapeutic agent for biliary tract cancer, containing an L-type amino acid transporter 1 (LAT1) inhibitor, particularly containing O-(5-amino-2-phenylbenzoxazol-7-yl)methyl-3,5-dichloro-L-tyrosine (generic name: Namvuranlat), or a pharmaceutically acceptable salt thereof, and is most suitable for treating incurable resected biliary tract cancer (BTC) with high LAT1 expression and non-rapid type N-acetyltransferase 2 (NAT2) that is non-responsive, intolerant and deteriorated to cancer chemotherapy, especially a specific subtype of biliary tract cancer.

[0002] In particular, the present invention relates to a method for treating biliary tract cancer, comprising administering an LAT1 inhibitor, especially a therapeutic agent for biliary tract cancer containing Namvuranlat or a pharmaceutically acceptable salt thereof, to a patient with incurable resected biliary tract cancer having a specific subtype of biliary tract cancer, being non-responsive, intolerant and deteriorated to cancer chemotherapy, and having high LAT1 expression and non-rapid type NAT2. Background Art

[0003] Biliary tract cancer is a general term for cancers that occur in the biliary tract. According to the site of occurrence, it is divided into intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and duodenal papilla cancer. Extrahepatic cholangiocarcinoma can be further classified into hilar cholangiocarcinoma and distal cholangiocarcinoma. Intrahepatic cholangiocarcinoma occurs in the bile ducts within the liver. Therefore, biliary tract cancer may sometimes be detected by examinations such as physical examinations in the early stage of the disease course, but it mostly progresses asymptomatically. If the disease progresses, symptoms such as jaundice, right abdominal pain, and weight loss appear, and it is mostly diagnosed after reaching this state. Biliary tract cancer originates from the epithelial cells of the inner wall of the bile duct lumen. Since the serosa of the interstitial tissue is fragile, it is easy to invade the peripheral blood vessels or lymphatic vessels. Generally, the cancer has a fast development rate and is progressive, and has the characteristic of easy metastasis.

[0004] According to the 7th edition edited by the Japanese Society of Hepato-Biliary-Pancreatic Surgery, the disease courses of cholangiocarcinoma, gallbladder cancer, and duodenal papilla cancer are all classified into stages I to IV, which are determined by the combination of three categories (TNM classification) of T (Tumor, tumor size), N (Node, degree of lymph node metastasis), and M (Metastasis, distant metastasis). In cholangiocarcinoma and gallbladder cancer, when the tumor is limited to the wall, it is stage I and II. When it invades the serosa and spreads to adjacent organs and lymph nodes, it is stage III. When distant metastasis is also accompanied, it is stage IV. Based on this disease course classification, combined with considering the patient's condition and examination results, the treatment policy (surgery, drug therapy, palliative care) is determined.

[0005] According to the cancer statistics (national cancer registry incidence data, vital statistics death data) released by the National Cancer Center of Japan, the number of people diagnosed with gallbladder and bile duct cancer in Japan was 22,159 (in 2019), ranking 16th among all cancer types. On the other hand, the number of deaths was 18,172 (in 2021), ranking 6th overall; the 5-year relative survival rate (2009 - 2011 regional cancer registry survival rate data) was as low as 24.5%, ranking 2nd after pancreatic cancer. If the clinical progression at the time of diagnosis is divided into primary (confined to the primary organ), regional (metastasis to the regional lymph nodes or invasion of adjacent organs), and distant metastasis (metastasis and invasion to distant organs, distant lymph nodes, etc.), the 5-year relative survival rates (2009 - 2011) for the respective progressions of gallbladder and bile duct cancer are 61.0%, 28.5%, and 2.9%. If limited to patients with distant metastasis, the 5-year relative survival rate for all sites is 18.5%. In contrast, gallbladder and bile duct cancer is the 2nd after pancreatic cancer (1.8%), and the prognosis is very poor.

[0006] In the national statistics of in-hospital cancer registration in Japan (2020), among the 18,750 cases of biliary tract cancer of gallbladder and bile duct cancer, 88% were 65 years old or older at the time of diagnosis, and 60% were 75 years old or older, indicating a relatively high age at diagnosis. In addition, among the gallbladder cancers included in this statistics, the proportion of the TNM classification comprehensive stage IV was very high, at 45.1%, and the proportion of stage IV that could not undergo treatments such as surgery and drug therapy was nearly half, at 42.4%.

[0007] As described above, gallbladder and bile duct cancer is a disease with a relatively high age at the initial diagnosis, a relatively high proportion diagnosed with distant metastasis (stage IV), and limited treatment methods, so it is a disease with a very low survival rate.

[0008] The diagnosis of biliary tract cancer is determined according to the revised 3rd edition of the diagnostic algorithm of the Japanese Society of Hepato-Biliary-Pancreatic Surgery 1The suggested method is as follows: In the first step, perform blood tests and abdominal ultrasound examinations; in the second step, perform localization of lesions and assessment of the degree of progression through Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) images; in the third step, perform cytodiagnosis through direct vision biopsy such as Endoscopic Retrograde Cholangiopancreatography (ERCP) / Intraductal Ultrasonography (IDUS) / Peroral Cholangioscopy (POCS). In intrahepatic cholangiocarcinoma, there are known atypical cases with uneven early staining, so differentiation from hepatocellular carcinoma becomes important. Therefore, identifying the tissue type through tumor biopsy is very important in the selection of drug therapy. In any case, biliary tract cancer is difficult to diagnose early anatomically and clinically, and most (70%) are at Stage III / IV at the time of initial diagnosis.

[0009] Biliary tract cancer (BTC) is a heterogeneous group of tumors arising from epithelial cells of the intrahepatic bile ducts, extrahepatic bile ducts, gallbladder, or the papilla of Vater in the duodenum, and are respectively called intrahepatic cholangiocarcinoma: IHC (Intrahepatic biliary tract cancer), extrahepatic cholangiocarcinoma: EHC (Extrahepatic biliary tract cancer), gallbladder cancer: GBC (Gallbladder cancer), and ampulla of Vater cancer: AVC (ampulla of Vater cancer). BTC is a clinically very difficult-to-manage malignant tumor and often shows resistance to treatment. 2 。

[0010] On the other hand, since individual differences in isoniazid neurotoxicity are caused by genetic differences in N-acetylation ability, N-acetylation polymorphism was discovered more than 50 years ago. In addition to isoniazid, many aromatic amine drugs such as Sulphamethazine are affected by acetylation polymorphism, which affects the therapeutic effects and toxicity of many therapeutic drugs. NAT2 is an enzyme that transfers the acetyl group of acetyl coenzyme A to aromatic amines or hydrazine-containing compounds that are substrates of this enzyme. NAT2 is encoded by an 870-bp gene, and gene polymorphisms of NAT2 are common in humans.

[0011] Moreover, there are three types of rapid, intermediate, and slow acetylators in NAT2 (SNP; single nucleotide polymorphism) (Pharmacogenomics, Vol. 13: pp. 31-41, 2012). These types can be discriminated by their gene polymorphisms.

[0012] The gene polymorphisms of NAT2 are known to modify the efficacy and toxicity of various arylamines and hydrazine drugs and increase the risk of cancers associated with several arylamine carcinogens. In addition, a drug called sulfasalazine (SSZ) is known to be acetylated by NAT2, and side effects often occur frequently in patients with slow acetylation (J Rheumatol. December 2002; 29(12): 2492-2499) (Genotyping the NAT2 gene followed by estimation of diplotype configuration before administration of SSZ is likely to reduce the frequency of adverse effects in Japanese patients with RA. http: / / www.jrheum.org / content / 29 / 12 / 2492).

[0013] Representative gene polymorphisms of NAT2 are the following 7 SNPs: (i) 191G>A (rs1801279), (ii) 282C>T (rs1041983), (iii) 341T>C (rs1801280), (iv) 481C>T (rs1799929), (v) 590G>A (rs1799930), (vi) 803A>G (rs1208), (vii) 857G>A (rs1799931). Among them, the SNPs of (i), (iii), (v), (vi), and (vii) cause amino acid changes (i.e., (i) 191G>A changes arginine to glutamic acid, (iii) 341T>C changes isoleucine to threonine, (v) 590G>A changes arginine to glutamine, (vi) 803A>G changes lysine to arginine, (vii) 857G>A changes glycine to glutamic acid).

[0014] On the other hand, in tumor cells, the expression of transporters that take up nutrients such as sugars and amino acids from the outside is increased in order to maintain rapid cell proliferation and enhanced intracellular metabolism. In particular, LAT1 is a transporter specifically expressed in tumor cells and plays an important role in transporting essential amino acids including leucine as a signaling factor and supplying essential nutrients to tumor cells. In contrast, LAT2 (L-type amino acid transporter 2) is known to be widely expressed in normal cells. Therefore, a compound having selective inhibitory activity against LAT1 can be an anticancer agent with few side effects.

[0015] LAT1 plays a role in transporting large neutral amino acids across the cancer plasma membrane and plays a very important role in energy production. 3 LAT1 is ubiquitously expressed in all subtypes of BTC 4 and is particularly expressed in the actively proliferating stage. 5 LAT is indispensable for cancer proliferation, and its expression level is hypothesized to be a prognostic marker. 6、7

[0016] As a compound having selective inhibitory activity against LAT1, O-(5-amino-2-phenylbenzoxazol-7-yl)methyl-3,5-dichloro-L-tyrosine (Namfulant, development code "JPH203") is known.

[0017] Namfulant is a selective inhibitor of LAT1. Its inhibition of tumor proliferation has been confirmed both in vitro and in vivo using human BTC-derived cell lines. 8 By inhibiting LAT1, it can induce mTORC1 (mammalian target of rapamycin complex 1) signaling, resulting in widespread down-regulation of cancer cell functions such as protein synthesis and cell proliferation. 9、10

[0018] A phase I dose-escalation trial of Namfulant was conducted with 17 patients having various solid tumors including biliary tract, colorectal, pancreatic, esophageal, and breast cancers as subjects. 11 The maximum tolerated dose was set at 60 mg / m 2 The AUC0-∞ (Area Under Curve: total area under the curve from time zero to infinity) increased between 12 and 25 mg / m 2 and no difference was observed at 40 to 60 mg / m 2 The recommended dose for the subsequent phase II trial was set at 25 mg / m 2 ​​。In the subgroup analysis of cancer types, the highest efficacy was achieved in BTC. Further, grade 3 liver dysfunction was observed in only two patients with rapid NAT2. NAT2 is the main hepatic metabolic enzyme in South Africa, and the parent compound and metabolites are excreted into bile. 12 。The rapid type produces more metabolites (NAc-JPH203) compared to the non-rapid type.

[0019] Prior art documents Patent documents Patent document 1: Japanese Patent No. 6734971 Patent document 2: Japanese Patent No. 6894155 Patent document 3: Japanese Patent No. 5826495 Summary of the invention Problems to be solved by the invention The inventors of the present application used LAT1 inhibitors, particularly South Africa, to evaluate the efficacy and safety of patients with progressive biliary tract cancer who have a specific metabolic phenotype of NAT2 and are ineffective (ineffective means that even with treatment such as administration of anticancer agents, the cancer lesion does not shrink or increase, etc., and the agent does not work) or intolerant to standard chemotherapy, and thus found that it has a very excellent effect on a specific subtype of biliary tract cancer.

[0020] Further, the inventors of the present application used LAT1 inhibitors, particularly South Africa, to evaluate the efficacy of patients with incurable resected biliary tract cancer that has deteriorated due to ineffective and intolerant cancer chemotherapy and is highly expressed in LAT1, particularly patients with non-rapid NAT2, and thus found that it can exert a very excellent effect, thereby completing the present invention.

[0021] An object of the present invention is to provide a therapeutic agent for biliary tract cancer. Another object of the present invention is to provide a therapeutic agent that is effective for progressive biliary tract cancer having a specific metabolic phenotype of NAT2 and being ineffective or intolerant to standard chemotherapy, and is also effective for a specific subtype of biliary tract cancer.

[0022] Means for solving the problems That is, the present invention provides the following technical solutions.

[0023] (Technical solution 1) A therapeutic agent for biliary tract cancer, wherein the biliary tract cancer is progressive biliary tract cancer that is ineffective or intolerant to the standard chemotherapy of the subject, and contains a LAT1 inhibitor.

[0024] (Technical solution 2) The therapeutic agent according to Technical Solution 1, wherein the LAT1 inhibitor is O-(5-amino-2-phenylbenzoxazol-7-yl)methyl-3,5-dichloro-L-tyrosine or a pharmaceutically acceptable salt thereof.

[0025] (Technical Solution 3) The therapeutic agent according to Technical Solution 2, wherein the progressive biliary tract cancer for which the standard chemotherapy of the subject is ineffective or intolerant is selected from the group consisting of extrahepatic bile duct cancer and gallbladder cancer.

[0026] (Technical Solution 4) The therapeutic agent according to Technical Solution 3, wherein the biliary tract cancer is extrahepatic bile duct cancer.

[0027] (Technical Solution 5) The therapeutic agent according to Technical Solution 3, wherein the biliary tract cancer is gallbladder cancer.

[0028] (Technical Solution 6) The therapeutic agent according to Technical Solution 3, wherein the subject is a patient with high LAT1 expression.

[0029] (Technical Solution 7) The therapeutic agent according to Technical Solution 3 or 6, wherein the subject is a subject identified as having a non-rapid (slow and / or intermediate) type of NAT2 gene.

[0030] (Technical Solution 8) The therapeutic agent according to Technical Solution 1, wherein the subject is a patient with high LAT1 expression.

[0031] (Technical Solution 9) The therapeutic agent according to Technical Solution 8, wherein the biliary tract cancer is extrahepatic bile duct cancer or gallbladder cancer.

[0032] (Technical Solution 10) The therapeutic agent according to Technical Solution 9, wherein the subject is a subject identified as having a non-rapid (slow and / or intermediate) type of NAT2 gene.

[0033] (Technical Solution 11) The therapeutic agent according to Technical Solution 1, wherein the biliary tract cancer is intrahepatic bile duct cancer.

[0034] (Technical Solution 12) The therapeutic agent according to Technical Solution 11, wherein the subject is a patient with high LAT1 expression.

[0035] (Technical Solution 13) The therapeutic agent according to Technical Solution 12, wherein the subject is a subject identified as having a non-rapid (slow and / or intermediate) type of NAT2 gene.

[0036] (Technical Solution 14) The therapeutic agent according to any one of technical solutions 1 to 3, 8 and 11, wherein the therapeutic agent is 1 to 60 mg / m 2 The drug is administered to a subject.

[0037] (Technical Solution 15) According to the therapeutic agent of technical solution 14, the therapeutic agent is 12.5-60 mg / m 2 The drug is administered to a subject.

[0038] (Technical Solution 16) According to the therapeutic agent of technical solution 15, the therapeutic agent is 12.5-25 mg / m 2 The drug is administered to a subject.

[0039] (Technical Solution 17) According to any one of technical solutions 1 to 3, 8 and 11, a prescribed amount of the therapeutic agent is continuously administered intravenously for a prescribed period of time.

[0040] (Technical Solution 18) According to technical solution 17, 100 mL of the therapeutic agent is continuously administered intravenously for 90 minutes.

[0041] (Technical Solution 19) According to any one of technical solutions 1 to 3, 8 and 11, the subject is a human.

[0042] (Technical Solution 20) A pharmaceutical composition comprising the biliary tract cancer therapeutic agent described in Technical Solution 1 and a pharmacologically acceptable additive.

[0043] (Technical Solution 21) A therapeutic agent for biliary tract cancer, wherein the biliary tract cancer is an incurable resectable biliary tract cancer that has progressed due to ineffectiveness or intolerance to chemotherapy in a subject, and the agent contains a LAT1 inhibitor.

[0044] (Technical Solution 22) According to the therapeutic agent of technical solution 21, the LAT1 inhibitor is O-(5-amino-2-phenylbenzoxazol-7-yl)methyl-3,5-dichloro-L-tyrosine or a pharmacologically acceptable salt thereof.

[0045] (Technical Solution 23) According to the therapeutic agent described in Technical Solution 21, the biliary tract cancer is selected from the group consisting of extrahepatic bile duct cancer and gallbladder cancer.

[0046] (Technical Solution 24) The therapeutic agent according to Technical Solution 23, wherein the biliary tract cancer is extrahepatic bile duct cancer.

[0047] (Technical Solution 25) The therapeutic agent according to Technical Solution 23, wherein the biliary tract cancer is gallbladder cancer.

[0048] (Technical Solution 26) The therapeutic agent according to Technical Solution 23, wherein the subject is a patient with high LAT1 expression.

[0049] (Technical Solution 27) The therapeutic agent according to Technical Solution 23 or 26, wherein the subject is a patient with high LAT1 expression and having non-rapid N-acetyltransferase 2.

[0050] (Technical Solution 28) The therapeutic agent according to Technical Solution 21, wherein the subject is a patient with high LAT1 expression.

[0051] (Technical Solution 29) The therapeutic agent according to Technical Solution 28, wherein the biliary tract cancer is extrahepatic bile duct cancer or gallbladder cancer.

[0052] (Technical Solution 30) The therapeutic agent according to Technical Solution 29, wherein the non-rapid type is slow and / or medium speed.

[0053] (Technical Solution 31) The therapeutic agent according to Technical Solution 21, wherein the biliary tract cancer is intrahepatic bile duct cancer.

[0054] (Technical Solution 32) The therapeutic agent according to Technical Solution 31, wherein the subject is a patient with high LAT1 expression.

[0055] (Technical Solution 33) The therapeutic agent according to Technical Solution 32, wherein the subject is a patient with high LAT1 expression and having non-rapid N-acetyltransferase 2.

[0056] (Technical Solution 34) The therapeutic agent according to any one of Technical Solutions 21 to 23, 28, and 31, wherein the therapeutic agent is administered to the subject at 1 to 60 mg / m 2 to the subject.

[0057] (Technical Solution 35) The therapeutic agent according to Technical Solution 34, wherein the therapeutic agent is administered to the subject at 12.5 to 60 mg / m 2 to the subject.

[0058] (Technical Solution 36) The therapeutic agent according to Technical Solution 35, wherein the therapeutic agent is administered to a subject at 12.5 to 25 mg / m 2 of body surface area.

[0059] (Technical Solution 37) The therapeutic agent according to any one of Technical Solutions 21 to 23, 28, and 31, wherein a specified amount of the therapeutic agent is continuously administered intravenously over a specified period of time.

[0060] (Technical Solution 38) The therapeutic agent according to Technical Solution 37, wherein 100 mL of the therapeutic agent is continuously administered intravenously over 90 minutes.

[0061] (Technical Solution 39) The therapeutic agent according to any one of Technical Solutions 21 to 23, 28, and 31, wherein the subject is a human.

[0062] (Technical Solution 40) A pharmaceutical composition comprising the therapeutic agent for cholangiocarcinoma according to Technical Solution 21 and a pharmaceutically acceptable additive.

[0063] The present invention also provides the following technical solutions.

[0064] (Technical Solution 41) A therapeutic agent for cholangiocarcinoma, wherein the cholangiocarcinoma is an incurable resected cholangiocarcinoma with high expression of LAT1 having non-rapid N-acetyltransferase 2 that has deteriorated due to ineffective or intolerant cancer chemotherapy in a subject, and contains an LAT1 inhibitor.

[0065] (Technical Solution 42) The therapeutic agent according to Technical Solution 41, wherein the subject is a patient with high expression of LAT1 cancer.

[0066] (Technical Solution 43) The therapeutic agent according to Technical Solution 41 or 42, wherein the cholangiocarcinoma is selected from the group consisting of extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, and gallbladder cancer.

[0067] (Technical Solution 44) A method for treating cholangiocarcinoma, wherein the cholangiocarcinoma is a progressive cholangiocarcinoma that is ineffective or intolerant to standard chemotherapy in a subject, and comprises administering to the subject an agent containing an LAT1 inhibitor.

[0068] (Technical Solution 45) Use of an LAT1 inhibitor in the manufacture of a medicament for treating progressive cholangiocarcinoma that is ineffective or intolerant to standard chemotherapy in a subject.

[0069] (Technical solution 46) For the treatment method described in technical solution 44 or the use described in technical solution 45, the LAT1 inhibitor is O-(5-amino-2-phenylbenzoxazol-7-yl)methyl-3,5-dichloro-L-tyrosine or a pharmaceutically acceptable salt thereof.

[0070] (Technical solution 47)For the treatment method described in technical solution 44 or the use described in technical solution 45, the subject is a patient with high LAT1-expressing cancer.

[0071] (Technical solution 48)For the treatment method described in technical solution 44 or the use described in technical solution 45, the biliary tract cancer is selected from the group consisting of extrahepatic bile duct cancer, intrahepatic bile duct cancer, and gallbladder cancer.

[0072] In one embodiment, the subject is a subject identified as having a non-rapid (slow and / or intermediate) type of NAT2 gene.

[0073] "Progressive biliary tract cancer that is ineffective or intolerant to standard chemotherapy", as subtypes, there are 4 known types: IHC, EHC, GBC, and AVC. In the present invention, EHC and GBC are particularly preferred.

[0074] Advantages of the invention It is possible to provide a therapeutic agent for biliary tract cancer. By administering the therapeutic agent for biliary tract cancer of the present invention to a subject identified as having a non-rapid (slow and / or intermediate) type of NAT2 gene and having progressive biliary tract cancer that is ineffective or intolerant to standard chemotherapy, especially a subject with extrahepatic bile duct cancer and gallbladder cancer, the effectiveness of the effect is significantly improved compared to other subtypes of biliary tract cancer. Description of the drawings

[0075] Figure 1 It is a diagram showing the background of biliary tract cancer patients in the FAS population assigned to this clinical trial.

[0076] Figure 2 It is a forest plot of the PFS hazard ratio obtained by BICR for the main subgroups.

[0077] Figure 3 It is a diagram showing all adverse events of grade 3 or above and SAE in the safety assessment items.

[0078] Figure 4 In (A) shows the main PFS obtained by BICR in the high LAT1 expression group, Figure 4 In (B) shows the main PFS obtained by BICR for all patient populations in FAS.

[0079] Figure 5 In (A) shows the overall survival (OS) of the high LAT1 expression group, Figure 5(B) in shows the overall survival (OS) of all patient groups with FAS.

[0080] Figure 6 shows the correlation between the treatment period and the overall survival in the LAT1 high-expression group.

[0081] Figure 7 is a Kaplan-Meier plot of PFS between namflanate and placebo in the patient group with GBC / EHC.

[0082] Figure 8 is a Kaplan-Meier plot of PFS between namflanate and placebo in the patient group with IHC and LAT1 high-expression. Detailed Description of the Invention

[0083] Hereinafter, the present invention will be described in detail.

[0084] O-(5-amino-2-phenylbenzoxazol-7-yl)methyl-3,5-dichloro-L-tyrosine (namflanate) The LAT1 inhibitor as an active ingredient of the present invention is preferably O-(5-amino-2-phenylbenzoxazol-7-yl)methyl-3,5-dichloro-L-tyrosine, which is a compound named namflanate in general name and disclosed in Japanese Patent No. 6734971 (Patent Document 1).

[0085] In addition, after intravenous administration, namflanate is mainly metabolized (acetylated) by liver NAT2 to become an acetylated form (Nac-namflanate), and its physiological activity is significantly reduced (Drug Metab Pharmacokinet, 2012; 27(1): 155-61).

[0086] In the present invention, namflanate can be used as its pharmacologically acceptable salt. For example, the amino group in the molecule of namflanate forms a salt with an acid. Such salts are not particularly limited, but examples include salts formed with inorganic acids such as hydrochloric acid and sulfuric acid or carboxylic acids. Among them, the hydrochloride salt is preferred, and the monohydrochloride monohydrate is particularly preferred.

[0087] Therapeutic agent for biliary tract cancer The therapeutic agent for biliary tract cancer of the present invention contains an LAT1 inhibitor as an active ingredient, and preferably contains nalfurafine or a pharmaceutically acceptable salt thereof. In addition, the therapeutic agent for biliary tract cancer of the present invention can be formulated into a pharmaceutical composition by adding pharmaceutically acceptable additives as needed. Further, the therapeutic agent or pharmaceutical composition for biliary tract cancer of the present invention can be orally administered in the form of solid preparations such as tablets, granules, fine granules, powders, capsules, etc., or in the form of liquids, jellies, syrups, etc., or the therapeutic agent or pharmaceutical composition can also be parenterally administered in the form of injections, nasal preparations, suppositories, inhalants, transdermal preparations, etc.

[0088] As the pharmaceutically acceptable additives of the present invention, conventionally known additives can be used, and examples thereof include pharmaceutically acceptable carriers such as excipients, binders, disintegrants, lubricants, surfactants, stabilizers, pH adjusters, emulsifiers, antioxidants, fillers, preservatives, sweeteners, flavoring agents, dispersants, buffers, suspending agents, solubilizers, tonicity regulators, etc.

[0089] In particular, since the therapeutic agent or pharmaceutical composition for biliary tract cancer of the present invention is used as an anticancer agent, it is preferably formulated into an injection. As such an injection, in the therapeutic agent of the present invention, an injection containing additives such as a pH adjuster and cyclodextrins is exemplified.

[0090] As specific injections, for example, intravenous, subcutaneous, intradermal, intramuscular injections, and intravenous drip preparations can be cited.

[0091] As the pH adjuster that can be added to the injection of the present invention, for example, acids such as hydrochloric acid, citric acid, succinic acid, adipic acid, tartaric acid, lactic acid, fumaric acid, phosphoric acid, etc.; alkali metal hydroxides such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; carbonates of alkali metals or alkaline earth metals, etc. In particular, sodium hydroxide and sodium carbonate are preferred, and sodium hydroxide is more preferred.

[0092] The injection can be appropriately adjusted to an appropriate pH value using a pH adjuster. The pH value of the injection of the present embodiment is preferably 3 to 6, more preferably 3 to 5, further preferably 3 to 4.5, and particularly preferably 3.5 to 4.5.

[0093] Examples of cyclodextrins that can be added to the injection of the present invention include unmodified cyclodextrins and modified cyclodextrins. Examples of unmodified cyclodextrins include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, etc. In addition, examples of modified cyclodextrins include dimethyl-α-cyclodextrin, dimethyl-β-cyclodextrin, dimethyl-γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether-α-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, maltosyl-α-cyclodextrin, etc.

[0094] The cyclodextrins can be used alone or in any combination of two or more. From the viewpoints of reducing the number of insoluble particles formed even when dissolved in a non-strongly acidic aqueous solution and improving the redissolvability of the freeze-dried preparation in a non-strongly acidic aqueous solution, it is preferred that the cyclodextrins are hydroxypropyl-β-cyclodextrin or sulfobutylether-β-cyclodextrin, and more preferably sulfobutylether-β-cyclodextrin.

[0095] Among them, sulfobutylether-cyclodextrin has a structure represented by the following formula 1, and the inside of the cyclic structure has high hydrophobicity. Therefore, it can form a complex with O-(5-amino-2-phenylbenzoxazol-7-yl)methyl-3,5-dichloro-L-tyrosine, which also has high hydrophobicity, through hydrophobic interaction. The "sulfobutylether-cyclodextrin (SBECD: sulfobutylether-β-cyclodextrin) complex" mentioned in this specification refers to the one formed through the above-mentioned hydrophobic interaction.

[0096] [Chemical formula 1]

[0097] Alternatively, nalfurafine, which is also an active ingredient, can be used in the injection as its sulfobutylether-cyclodextrin complex (hereinafter referred to as "nalfurafine-SBECD").

[0098] As needed, a buffer, a suspending agent, a solubilizing agent, a stabilizer, a tonicity regulator, a preservative, etc. can also be added to the injection of the present invention.

[0099] Examples of the buffer include boric acid buffer, phosphate buffer, citrate buffer, acetate buffer, tris(hydroxymethyl)aminomethane (Tris) buffer, etc.

[0100] As a suspending agent, for example, methylcellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate, poloxamer, hydroxypropyl methylcellulose (HPMC), sodium alginate, etc. can be cited.

[0101] As a solubilizing agent, for example, polyoxyethylene hydrogenated castor oil, polysorbate 80, niacinamide, polyoxyethylene sorbitan monolaurate, macrogol, fatty acid glyceride, lipoaminoacid, polyethylene glycol, etc. can be cited.

[0102] As a stabilizer, for example, sodium sulfite, sodium metabisulfite, etc. can be cited; as a tension regulator, for example, glycerol, sodium chloride, etc. can be cited; as a preservative, for example, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, etc. can be cited.

[0103] As the pH value when dissolving the lyophilized preparation in water, it is preferably 3 to 6, more preferably 3 to 5, further preferably 3 to 4.5, and particularly preferably 3.5 to 4.5.

[0104] The lyophilized preparation can be manufactured by a conventionally known method for manufacturing a lyophilized preparation. For example, a method of freezing at a temperature of -25°C or lower and then heating and drying to room temperature while maintaining a vacuum of about 20 Pa or lower can be cited.

[0105] The injection of the present invention may also be a lyophilized preparation. Such a lyophilized preparation can be dissolved in, for example, one or more solvents of distilled water for injection, infusion solution, and electrolyte solution during use and used as a dissolution-type injection during use.

[0106] The therapeutic agent of the present invention is effective against progressive biliary tract cancer that is ineffective or intolerant to standard chemotherapy, and is particularly effective against IHC, EHC, and GBC among the four subtypes of BTC, namely IHC, EHC, GBC, and AVC.

[0107] Dosing regimen The dosing regimen for the biliary tract cancer therapeutic agent to which the present invention is applicable is selected based on the following various factors, namely, the type, race, age, weight, gender, and medical condition of the patient; the severity of the condition to be treated; the administration route; and the liver and kidney functions of the patient. A doctor can easily determine the effective amount of the drug required to prevent, stop, or arrest the progression of the symptom and prescribe it.

[0108] The terms "subject" and "patient" are used interchangeably in the present invention and are preferably human. As described later, in particular, the "patient" is preferably a patient having a non-rapid (slow and / or intermediate) genotype of NAT2.

[0109] In one embodiment, the patient is a patient with biliary tract cancer who has failed or is intolerant to standard chemotherapy and investigational drugs (pre-treatment), and has progressive biliary tract cancer that is ineffective or intolerant to standard chemotherapy.

[0110] In addition, in the biliary tract cancer therapeutic agent of the present invention, the dosage of the active ingredient can be appropriately selected according to the degree of symptoms, patient age, sex, body weight, sensitivity differences, administration period, administration interval, etc. From the viewpoints of effectiveness and safety, it can be exemplified as 1 mg / m 2 ~60 mg / m 2 (body surface area), preferably 12.5 mg / m 2 ~60 mg / m 2 、12.5 mg / m 2 ~25 mg / m 2 、or 10 mg / m 2 ~40 mg / m 2 (body surface area), and particularly 25 mg / m 2 is recommended. In addition, according to the symptoms, it can also be reduced to 12.5 mg / m 2 etc.

[0111] As an example of the administration regimen of the biliary tract cancer therapeutic agent of the present invention, for example, the following regimens can be cited, and these regimens can be combined as needed.

[0112] - The biliary tract cancer therapeutic agent is administered continuously for a specified period, and then discontinued for a specified period as one cycle; - The biliary tract cancer therapeutic agent is administered with a cycle of 14 days in total, including continuous administration for 5 days followed by discontinuation for 9 days; - A specified amount of the biliary tract cancer therapeutic agent is continuously administered intravenously at a specified time; - 100 mL of the biliary tract cancer therapeutic agent is continuously administered intravenously over 90 minutes; - Administer to the patient at 1~60 mg / m 2 ; - Administer to the patient at 12.5~60 mg / m 2 ; - Administer to the patient at 12.5~25 mg / m 2 ; - Administer to the patient at 25 mg / m 2 ;

[0113] When the therapeutic agent for biliary tract cancer of the present invention is administered to a patient with cancer or the like having a non-rapid (slow and / or intermediate) type of NAT2 gene (i.e., a type with slow acetylation of NAT2), good effects can be achieved. In the present specification, the "non-rapid type of NAT2 gene" refers to the intermediate type (Intermediate) and the slow type (Slow) among the three expression types of rapid type (Rapid), intermediate type (Intermediate), and slow type (Slow) of the acetylation rate of the NAT2 gene.

[0114] For seven SNPs (481C>T, 282C>T, 857G>A, 803A>G, 341T>C, 590G>A, 191G>A) representing the gene polymorphisms of NAT2, the expression type (Phenotype) of NAT2 acetylation was analyzed in combinations of 2-SNP, 3-SNP, and 4-SNP (Table 2-1). The NAT2*4 homozygote with no SNP (standard) haplotype was constituted as the rapid type (Rapid) of acetylation, and the heterozygote with any haplotype mutation was the intermediate type (Intermediate) with a medium acetylation rate; and the combination of the homozygote with all mutant haplotypes or the heterozygote with two or more mutant haplotypes was the slow type (Slow) of acetylation (Pharmacogenomics, Volume 13: Pages 31-41, 2012). Among them, the "NAT2*4" allele is a haplotype with no SNP. In addition, according to Pharmacogenomics, Volume 13: Pages 31-41, 2012, for the rapid type, in addition to "NAT2*4", patients with "NAT2*11, NAT2*12, NAT2*13" that do not cause amino acid mutations are also classified as the rapid type.

[0115] Specifically, the expression type of the NAT2 acetylation factor inferred from 2 SNPs is determined by analyzing 2 SNPs: rs1041983 (282C>T) and rs1801280 (341T>C). The expression type of the NAT2 acetylation factor inferred from 3 SNPs is determined by analyzing 3 SNPs: rs1799929 (481C>T), rs1799930 (590G>A), and rs1799931 (857G>A). The expression type of the NAT2 acetylator inferred from 4 SNPs is determined by analyzing 4 SNPs: rs1801279 (191G>A), rs1801280 (341T>C), rs1799930 (590G>A), and rs1799931 (857G>A).

[0116] If Nafamostat is acetylated by NAT2, its inhibitory activity against cancer cells decreases. However, when patients mainly have NAT2 gene expression types that are not easily acetylated, that is, when cancer patients and others have intermediate and slow expression types of acetylation rates in the NAT2 gene (non-rapid NAT2 genes), since the acetylation rate of nafamostat becomes slower, it is not easily acetylated and can maintain the activity of nafamostat for a long time (Japanese Patent No. 6894155). The biliary tract cancer therapeutic agent of the present invention can be used in combination with other cancer treatments. As such cancer treatments, for example, targeted treatments such as chemotherapy and antibody therapy, immunotherapy, radiotherapy, etc. can be cited.

[0117] Examples The following gives specific embodiments to illustrate the present invention, but the present invention is not limited to this embodiment, and it should be understood that those skilled in the art can make various changes and modifications to this embodiment without departing from the scope or gist of the present invention defined by the claims.

[0118] Example 1 As the second-phase trial of nafamostat, patients with progressive biliary tract cancer who are ineffective or intolerant to standard treatment methods were used as subjects, and a second-phase trial of multicenter, random allocation, placebo control, double-blind test, and parallel group comparison was conducted at 14 facilities in Japan. The biliary tract cancer (BTC) subtype and whether or not there was resection were used as grouping factors, and patients were allocated to the administration group of this preparation and the placebo administration group at a ratio of 2:1. In the selection criteria, the non-rapid (slow and / or intermediate) type was set as the NAT2 genotype, and based on the results of the previously conducted first-phase (PI) trial, at a dose of 25 mg / m 2Either the clinical trial drug or placebo was administered intravenously continuously for 5 days, followed by a 9-day drug withdrawal period (14 days: one cycle). The clinical trial drug was continuously administered until the discontinuation criteria were met. The primary evaluation item was the progression-free survival period using version 1.1 of RECIST based on Blinded Independent Central Review (BICR). Images were obtained every six weeks from the start of drug administration and at the time of discontinuation. Progression-free survival (PFS) was defined as the number of days from random assignment until the first recorded progression (progressive disease, PD) or death for any reason. The primary evaluation was performed on the Full Analysis Set (FAS) population consisting of all patients with biliary tract cancer randomly assigned to either group. Safety evaluation was performed on the SAFETY population of patients randomly assigned to either group and administered the clinical trial drug. In addition, navflanide was used as the monohydrochloride monohydrate.

[0119] Validity assessment items A total of 106 patients with biliary tract cancer (ITT (Intention to treat) population) were used and divided into the formulation administration group (n = 70) or the placebo administration group (n = 36). The total number of patients in the FAS population was 104 (formulation administration group: n = 69, placebo administration group: n = 35). In addition, the details of the NAT2 metabolic expression types in the FAS population were NAT2 non-rapid: 81 cases, NAT2 rapid: 5 cases, and NAT2 unknown (unknown) for which the examination was not performed: 20 cases.

[0120] The background of patients with biliary tract cancer in the FAS population assigned to this clinical trial is shown in Figure 1 . Biliary tract cancer is a disease with diverse anatomies, but in this trial, all subtypes of biliary tract cancer (intrahepatic cholangiocarcinoma: IHC (intrahepatic), extrahepatic cholangiocarcinoma: EHC (extrahepatic), gallbladder cancer: GBC (gall bladder), ampullary cancer: AVC (ampulla of Vater)) were targeted. The characteristics of the registered cases included: 1) 83% of the patients were registered in this clinical trial after three courses of treatment, and most of the cases were advanced cancers considered for palliative care; 2) approximately half were elderly patients over 65 years old. Among the patients registered in this clinical trial, more than 98% were patients confirmed to have distant metastases, and most of the patients were under salvage therapy without effective treatment options.

[0121] Biliary tract cancer is an anatomically diverse disease, but this trial targets all subtypes of biliary tract cancer (intrahepatic bile duct cancer: IHC (Intrahepatic biliary tract cancer), extrahepatic bile duct cancer: EHC (Extrahepatic biliary tract cancer), gallbladder cancer: GBC (Gallbladder cancer), and papillary carcinoma: AVC (ampulla of vater cancer)).

[0122] The characteristics of the cases include: 1) 83% of the patients had received three treatments, and most of them were patients with advanced cancer who were considered for palliative care; 2) About half of the patients were over 65 years old. More than 98% of the patients in this clinical trial were confirmed to have distant metastases, and most of them were patients who were receiving salvage therapy without effective treatment options.

[0123] Assessment method: (1) Estimation of hazard ratio (HR) based on stratified Cox proportional hazards model The Kaplan-Meier estimated values corresponding to the time point of the event were calculated and graphed for each dosing group. The confidence interval of the Kaplan-Meier estimated value was constructed by approximating the standard error based on the Greenwood formula and using the log-log method. In addition, the estimated values and 95% confidence intervals for the 25%, 50%, and 75% points of the survival time were calculated and presented in a table. The confidence interval of the percentile of the survival time was calculated using the method of Brookmeyer and Crowley.

[0124] Stratified log-rank test The p-value for the score test of the above model fit is calculated and presented together with the corresponding χΛ2 statistic and degrees of freedom.

[0125] (2) Estimation of hazard ratios based on the stratified Cox proportional hazards model with the addition of the interaction term for NAT2 metabolomic type A stratified Cox proportional hazard model was fitted, and the estimated hazard ratio exp((β_drug)Λ) and its 95% confidence interval were presented in a table and forest plot together with the p-value of the Wald Test corresponding to the null hypothesis "β_drug=0; exp(β_drug)=1".

[0126] Stratification factor 1: "Facility", "gallbladder cancer and other cancers", "history of resection of primary lesion" Stratification factor 2: "Subtypes of biliary tract cancer (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, cancer of the papilla of Vater)", "history of resection of primary lesion" Test results In the PFS evaluated by independent central image evaluation under blind conditions, which was the main evaluation item, a statistically significant effect of this preparation compared to the placebo was confirmed (hazard ratio (HR)=0.557; 95% CI was 0.3435 - 0.9029; p-value (pvalue)=0.0164). Since 83% of the subjects enrolled in this clinical trial were in the advanced stage, about 1 month after starting the administration of the clinical trial drug, PFS events occurred in 70% of both the group administered this preparation and the placebo group. As a result, the progression-free survival rate decreased rapidly. The median PFS of the group administered this preparation and the placebo group were 46.0 days and 43.1 days respectively, and there was no difference between the two groups. When more than about 70% of the total cases had elapsed since the start of administration, a group that responded to this preparation began to appear. Regarding the progression-free survival rate at the time point of 1.5 months after the start of administration, the group administered this preparation was 53.6% (37 / 69 cases), while the placebo group was 40.0% (14 / 35 cases). The progression-free survival rates at the 3-month time point were 14.5% (10 / 69 cases) and 5.7% (2 / 35 cases) respectively ( Figure 4 in (B)).

[0127] In the subgroup analysis using the image evaluation data, in almost all pre-defined subgroups of the administration group, this preparation always showed a preferable hazard ratio compared to the placebo group. Especially, the effect of this preparation was shown in EHC and GBC in the subtypes of biliary tract cancer or in cases of primary resection ( Figure 2 ). That is, it was found that the HR values were IHC: 0.872 (0.4359 - 1.7458), EHC: 0.150 (0.0437 - 0.5153), GBC: 0.287 (0.1009 - 0.8183), AVC: unable to calculate, and the effects of EHC and GBC were significantly higher compared to other subtypes.

[0128] Safety assessment items During the entire clinical trial observation period, no deaths suspected to be related to this preparation were found. Additionally, no cases of discontinuation of administration or reduction of the dosage of this preparation were observed. The frequencies of all adverse events that occurred during the clinical trial were 85.7% (60 / 70 cases) and 82.9% (29 / 35 cases) in the group administered this preparation and the placebo group, respectively. Regarding the frequencies of all adverse events of grade 3 or higher, the group administered this preparation was 30.0%, while the placebo-administered group was 22.9%. Regarding adverse events for which the association with this preparation could not be ruled out, the group administered this preparation was 41.4%, while the placebo-administered group was 57.1%.

[0129] All adverse events of grade 3 or higher and SAE are shown in Figure 3 .

[0130] Among these adverse events, there were 3 cases of adverse events of grade 3 or higher for which the association could not be ruled out, namely 1 case of malaise, 1 case of thrombocytopenia, and 1 case of hypertension. In the placebo-administered group, there were 3 cases, namely 1 case of ascites, 1 case of fatigue, and 1 case of anorexia. One case of fatigue was found in the placebo-administered group as a serious adverse event.

[0131] That is, for extrahepatic cholangiocarcinoma (EHC) and gallbladder cancer (GBC), which are generally considered to have a poor prognosis, very good results of the drug efficacy were obtained, which were unexpected results. Especially for extrahepatic cholangiocarcinoma, the hazard ratio had a value approximately 2 times that of gallbladder cancer, showing a very excellent effect.

[0132] Example 2 According to the following randomized phase II trial, the efficacy and safety of Namflan were investigated in patients with progressive BTC who had received more than one systemic chemotherapy.

[0133] Trial design This trial was a multi-facility, randomized, double-blind, placebo-controlled phase II trial conducted at 14 major cancer centers / hospitals in Japan. Patients were randomly assigned to the Namflan or placebo group (2:1) and stratified based on the BTC subtype and the presence or absence of resection of the primary cancer lesion. Random assignment to the two treatment groups was implemented through IWRS (Interactive Web Response System) and generated by an independent statistical group.

[0134] Namflan 25 mg / m was intravenously administered continuously for 5 days 2either once daily or as a placebo, followed by a 9-day drug withdrawal period (= 14 days: 1 cycle). The investigational drug was administered by infusion over 90 minutes at the facility of the clinical trial responsible physician (all patients were admitted during the first treatment cycle). The patients, investigational drug administrators, and clinical trial coordinators were blinded to the trial treatment. In addition, navitoclax was used as the monohydrochloride monohydrate.

[0135] Treatment in additional cycles continued until disease progression, occurrence of other unacceptable toxicities, confirmed pregnancy, death, withdrawal of consent, loss of follow-up, unblinding of the trial, or end of the trial, as determined by the clinical trial responsible physician. Data cut-off was defined as the end date of six months of treatment for the last patient enrolled in the trial. The survival rate of the patients was followed up until either 95% of the events occurred or nine months from the data cut-off, whichever was earlier.

[0136] Surveillance of clinical trials This clinical trial was conducted in accordance with the principles of the International Conference on Harmonization of Good Clinical Practice guidelines and the Declaration of Helsinki. Each trial site obtained approval from the clinical trial review committee and / or the clinical trial ethics committee. The patients provided written informed consent before participating in the clinical trial. This clinical trial was designed by the clinical trial sponsor based on the opinions from the steering committee and established through communication in the regulatory science strategic meeting with the Pharmaceuticals and Medical Devices Agency (PMDA).

[0137] Patients Eligible patients had high-grade BTC confirmed by imaging contrast or surgery in their past medical history and were 20 years of age or older, and were refractory or intolerant to standard chemotherapy and / or the investigational drug. In the case of EHC, GBC, or AVC, the histology was confirmed as paraganglioma or adenosquamous carcinoma, and in the case of IHC, the histology was confirmed as paraganglioma. Patients with unresectable or recurrent BTC were eligible for this trial and provided FFPE (formalin-fixed and paraffin-embedded) tumor specimens. Additional major eligibility criteria included a mean remaining life expectancy of at least 90 days; a Performance status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG); Measurable lesions as defined by version 1.1 of the Response Evaluation Criteria in Solid Tumors (RECIST) (imaging within four weeks prior to registration); and adequate hematological, hepatic, and renal function.

[0138] Clinical insights based on the first exploratory analysis 11 , namely, that the metabolism of nalfurafine by NAT2 affects the clinical outcome of patients, led to the amendment of the trial protocol for this Phase II trial after the initial 25 patients were registered. Thereafter, patients with non-rapid (slow and intermediate) NAT2 genotypes were registered through pre-defined NAT2 genotype analysis according to the validated SNP analysis procedure. 13 Personal information is strictly managed on the clinical trial website.

[0139] Patients with complications such as heart disease including cerebrovascular disease, airway obstruction, myocardial infarction, unstable angina, myocardial infarction, mental illness, drug / alcohol addiction, etc. were excluded. Additional exclusion criteria included: active infections requiring systemic treatment, HCV-RNA positive hepatitis (known HIV antibody, HB antigen), clinically abnormal electrocardiogram, ascites / pleural effusion / pericardial effusion requiring drainage treatment, brain metastases, history of radiation to the bone marrow, colitis disease, history of shock, or anaphylaxis to sulfobutylether-β-cyclodextrin.

[0140] Endpoints The primary assessment item was progression-free survival (PFS) evaluated using RECIST version 1.1 and according to blinded independent central review (BICR). PFS was defined as the time from the date of random assignment until the earlier of the first documented disease progression or death from any cause. During the entire trial, radiological assessments (CT) for evaluating disease response were performed every six weeks (at the end of every three cycles of treatment or within three days before or after the end of the trial) according to RECIST version 1.1. BICR did not confirm local radiographic progression in real time.

[0141] The secondary endpoints were overall survival (OS), disease control rate (DCR) evaluated according to BICR, and safety. Adverse events were graded using version 24.1 of the Japanese translation of the Medical Dictionary for Regulatory Activities (MedDRA / J). Blood and urine concentrations of nalfurafine and its metabolite N-acetyl JPH203 (NAc-JPH203) were evaluated.

[0142] The tissue expression level of LAT1 was determined by immunohistochemistry and evaluated according to established methods. 7 .

[0143] Specifically, the evaluation of the immunoreactivity of LAT1 was performed using a slightly modified method of Sinicrope's method 3. That is, based on the immunoreactivity of the cancer cell membrane, the following four categories were defined. Expression intensity 0, no reaction; 1, weak or punctate positive; 2, moderately positive throughout the cell membrane; 3, strongly positive throughout the cell membrane. In each case, the highest expression intensity of LAT1 in the cancer tissue was used. Further, the entire cancer tissue was observed and the area of LAT1 expression was expressed as a percentage. That is, 0, no positive; 1, 1 - 10% positive; 2, 11 - 29%; 3, 30% or more. The LAT1 expression score was represented by the value of LAT1 expression intensity × expression area (Patent Document 3).

[0144] That is, the outline of the immune LAT1 determination method for biliary tract cancer is as follows.

[0145] [Table 1]

[0146] Statistical analysis If the hazard ratio (HR) of PFS is assumed to be 0.5, then in order to reject the null hypothesis, more than 81 progression - free survival events are required, which can provide a power of β: 90% with a one - sided α level of 0.025.

[0147] The primary efficacy analysis was performed using the full analysis set (FAS) population that included all BTC patients randomly assigned within the specified treatment groups. The safety analysis population included all patients who received at least one trial treatment (safety population).

[0148] Using the Cox hazard model, the HR and 95% confidence interval (CI) for the comparison of PFS and OS between the nanoflanter and placebo groups were estimated. All time - to - event endpoints were estimated by the Kaplan - Meier method. The stratified log - rank test was used to evaluate statistical significance. According to BICR, subgroup analysis of PFS was performed according to the previous lines of therapy, gender, metastatic site at screening, BTC subtype, and ECOG performance status score.

[0149] Statistics were used to summarize safety data, response rates, pharmacokinetics, and pharmacodynamic data. All reported p - values were one - sided unless otherwise specified. Statistical analysis was performed using SAS software (version 9.4).

[0150] Results Patients A total of 211 patients were enrolled in the trial, including 106 patients (82 with non-rapid NAT2, 4 with rapid NAT2, and 20 with unknown NAT2). These 106 patients were randomly assigned to the nalfurafine group (n = 70) or the placebo group (n = 36). The primary efficacy analysis was performed in the FAS population (total n = 104: n = 69 in the nalfurafine group and n = 35 in the placebo group); among them, 1 patient assigned to the nalfurafine group was excluded due to the discovery of non-biliary cancer, and 1 patient assigned to the placebo group withdrew before the start of treatment.

[0151] The patient backgrounds and baseline characteristics of the nalfurafine group and the placebo group were similar, except that the patients in the nalfurafine group were slightly older than those in the placebo group (65% of the patients in the nalfurafine group were 65 years old or older, and 46% in the placebo group), and the number of IHC patients in the placebo group was slightly higher (Table 2). Most patients had received more than two treatments before enrollment (83% in both groups).

[0152] [Table 2]

[0153] Validity analysis between the LAT1 high-expression subgroup and all patients Immunohistochemical staining method For patients with available archive tissue, LAT1 expression was evaluated by tumor biopsy samples. Formalin-fixed paraffin-embedded tissues were cut into thin sections (3 - 4 μm thick), and the deparaffinized samples were incubated overnight with anti-LAT1 antibody at 4°C. LAT1 expression was microscopically evaluated by a defined score, which was the product of the positivity and the number of cells distributed in the microscopic field.

[0154] Background of the LAT1 high-expression subgroup compared with all patients There were no significant differences in the patient backgrounds between the high-LAT1 expression subgroup and all LAT1 patients (Table 3) [Table 3]

[0155] Results of validity Main assessment item: PFS obtained by BICR A significant difference was observed between the nalfurafine group and the placebo group (hazard ratio = 0.557; 95% CI, 0.3435 - 0.9029, p-value: 0.0164 (one-sided)) ( Figure 4For the PFS at 1.5 months and 3 months, the number in the Namflan group was 43 / 69 (62.3%) and 16 (23.2%) respectively, while in the placebo group it was 14 / 35 (40.0%) and 2 (5.5%). For the median PFS, the Namflan group was 46.0 days and the placebo group was 43.0 days.

[0156] The expression level of LAT1 in tumor tissues was identified as a determinant of response to Namflan. Among 104 patients, immunohistochemical LAT1 analysis was performed on 98 samples (94.2%). Among them, 65 patients (62.5%) were identified as having high LAT1 expression (score: 4 - 9) (Table 4). In the Kaplan - Me analysis of the LAT1 high - expression subgroup, compared with the analysis of all patients (HR = 0.557, p = 0.0164), the hazard ratio in the Namflan group showed further improvement (HR = 0.439; 95% CI, 0.2254 - 0.8535; p = 0.0131, Figure 4 in (A)).

[0157] [Table 4]

[0158] Figure 4 All patient groups showing FAS (n = 104: Figure 4 the primary PFS obtained by BICR in (B) (including 69 in the Namflan group and 35 in the placebo group) and the primary PFS obtained by BICR in the LAT1 high - expression group (n = 65, Figure 4 in (A)). The Namflan group and the placebo group included 47 and 18 patients respectively. The Kaplan - Meier plot of the progression - free survival rate of patients in the Namflan group was compared with that of patients in the placebo group. The hazard ratio was calculated by a stratified Cox proportional hazards model, and the P - value was calculated by a stratified log - rank test.

[0159] Subgroup analysis of PFS obtained by BICR Namflan consistently showed efficacy in the overall pre - defined subgroups ( Figure 2 ). Especially, the efficacy was high in EHC and GBC patients. Since the origins of EHC and GBC are the same 2 , they were combined in the subgroup analysis of PFS. For PFS, patients treated with Namflan were significantly superior to those in the placebo group (HR: 0.218, 95% CI, 0.0975 - 0.4886, p = 0.0001; Figure 7 ).

[0160] Secondary endpoints Overall survival rate Although not statistically significant, in all maternal population analyses of the FAS, the risk ratio was favorable for Namfulant (HR: 0.849, 95% CI: 0.5308 - 1.3574, p = 0.4934) ( Figure 4 in (A) of Figure 4 ). In the case of only analyzing patients with high LAT1, the OS - HR was favorable for Namfulant (HR: 0.670, 95% CI: 0.3463 - 1.2954, p = 0.2313) (

[0161] in (B) of

[0162] [Table 5]

[0163] Safety results The safety analysis was conducted in the safety population (n = 105). Since 1 patient (n = 106) assigned to the placebo group withdrew before the start of treatment, it was excluded from the ITT. During the trial, no treatment - related deaths were confirmed. Nor were any treatment - related discontinuation or dose reduction cases found.

[0164] Events for all causes occurring during the observation period were equal in the Namfulant group (85.7%) and the placebo group (82.9%). Adverse events of grade 3 or above occurred in 30.0% vs. 22.9% in the Namfulant group and the placebo group respectively, and serious adverse events occurred in 21.4% vs. 11.4% (Table 6). Treatment - related adverse events in the Namfulant group were 41.4%, lower than those in the placebo group (57.1%). Three patients treated with Namfulant reported treatment - related adverse events of grade 3 or above, and there were feelings of fatigue, decreased platelet count, and hypertension.

[0165] [Table 6]

[0166] Investigation This trial was the first to confirm the clinical efficacy of single-agent therapy with namflanate as a LAT1 inhibitor in a randomized controlled trial comparing it with a placebo. A significant difference in PFS was observed between the namflanate group and the placebo group in patients with progressive disease refractory or intolerant to standard chemotherapy. The disease course of the BTC patient population of the present invention progressed significantly compared to the group of patients who showed improvement after FOLFOX as a second treatment. 14 83% of the patients were registered for treatment after the third time (Table 1). 26% of the patients did not survive more than 90 days. Since it was very advanced late-stage BTC, the PFS Kaplan-Meier curve of the placebo group dropped rapidly within 1.5 months (90% of the patients reached the event), which was consistent with the observations in other trials conducted in Japan. 15 .

[0167] In the Kaplan-Meier analysis of the LAT1 high-expression subgroup, the namflanate group showed further improvement in PFS compared to the analysis of all patient populations. Since the high expression of LAT1 was recorded as a poor prognostic factor, 6、7、16 the efficacy of namflanate observed in patients with high LAT1 expression was supported. Considering the result that the higher the expression level of the target VEGFR molecule, the higher the ED50 value of the VEGFR inhibitor (i.e., the lower the drug efficacy), this was a surprising result. 17 .

[0168] Although the OS hazard ratio was not statistically significant, the namflanate group showed a median improvement in OS, especially in the LAT1 high-expression patient population, compared to the placebo ( Figure 5 and Figure 6 ). The small number of patients, the overly advanced disease course of the patient population in this phase II trial, and the multiple prior treatments were the reasons for the lack of statistical significance in the OS improvement. To evaluate the efficacy of namflanate in patients at an earlier stage and / or to identify additional major factors such as gene mutations in BTC subtypes for predicting response to this potential treatment, future trials are warranted.

[0169] In the Kaplan-Meier analysis of the LAT1 high-expression subgroup with IHC, the namflanate group showed further improvement in PFS compared to the placebo group (hazard ratio: 0.60, 95% CI, 0.22 - 1.66, p = 0.32; Figure 8 ).

[0170] Regarding the safety of Namflan, the AE incidence rate in the Namflan group was the same as that in the placebo group (Table 6). There were no treatment-related deaths or withdrawals. The treatment period was highly correlated with the OS in the Namflan group, supporting long-term use. This highly tolerable safety profile indicates that Namflan is suitable for the treatment of vulnerable BTC patients such as the elderly. This may be another clinical advantage of LAT1 inhibitors. Namflan selectively acts on cancer cells but not on normal cells. 4 。

[0171] Although the treatment-related causal relationship has been excluded, the occurrence of cholangitis in the Namflan group was particularly obvious (Table 6). In the exploratory analysis of the phase I trial, adverse effects on liver function occurred in NAT2 rapid-type patients, which may be related to the metabolism of Namflan. 11 。

[0172] In conclusion, for patients with advanced and refractory biliary tract cancer, compared with placebo, single-agent Namflan therapy significantly improved PFS. In patients with high LAT1 expression, the response to Namflan (PFS and OS) was enhanced. Single-agent Namflan therapy becomes one of the options for advanced patients with high LAT1 expression and EHC, GBC, or IHC subtypes, and combination use can also be considered.

[0173] The following is the content of the planned phase III trial for the treatment of biliary tract cancer using the agent of the present invention.

[0174] Phase III trial A phase III multi-facility randomized double-blind placebo-controlled trial or other facility external control group-controlled trial will be conducted to evaluate the efficacy and safety of Namflan in patients with advanced BTC with a prior treatment history. (1)Primary evaluation items: For subjects with histologically or cytologically confirmed BTC, non-rapid NAT2 genotype, and high LAT1 score, the progression-free survival (PFS) or overall survival (OS) of the Namflan group will be compared with that of the placebo or external control group through blinded independent central review (BICR).

[0175] (2)Secondary evaluation items ・Comparison among BTC subtypes (IHC, EHC, GBC) ・Comparison between patients with high LAT1 score and those with low LAT1 score ・Comparison among NAT2 genotypes ・Comparison with the placebo group or with the external control group Trial design Continue treatment until PD, unacceptable toxicity, or other discontinuation criteria are met. All subjects are followed at regular intervals for survival until death for at least 24 months after discontinuation of the study therapy.

[0176] In each 14-day or specified treatment cycle, either navflan or placebo is administered intravenously to the subject once a day for 5 consecutive days for 90 minutes or a specified time, or either navflan or placebo is administered intravenously to the subject for 90 minutes or a specified time at specified frequencies during a specified period. Thereafter, a 9-day or specified treatment-free period is set, and treatment of the subject is continued in 14-day or specified cycles until PD, unacceptable toxicity, or other discontinuation criteria are met. Radiographic imaging for the determination of tumor lesions and disease assessment is performed after 3 cycles (i.e., 6 weeks later) and can also be performed outside the schedule at the discretion of the responsible physician of the clinical trial.

[0177] References 1. Nagino M, Hirano S, Yoshitomi H, et al. Clinical practice guidelines for the management of biliary tract cancers 2019: The 3rd English edition. J Hepatobiliary Pancreat Sci. 2021;28:26 - 54. 2. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020;17:557 - 588. 3. Sato M, Harada-Shoji N, Toyohara T et, al., L-type amino acid transporter 1 is associated with chemoresistance in breast cancer via the promotion of amino acid metabolism. Sci Rep 2021;11:589. 4. Kanai Y, Amino acid transporter LAT1 (SLC7A5) as a molecular target for cancer diagnosis and therapeutics. Pharmacol Ther 2022;230:107964. 5. Yanagida, O, Kanai Y, Chairoungduaet A, et al. Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim Biophys Acta 2001;1514 291-302. 6. Kaira K, Sunose Y, Ohshima Y, et al. Clinical significance of L-type amino acid transporter 1 expression as a prognostic marker and potential of new targeting therapy in biliary tract cancer. BMC Cancer 2013;13:482. 7. Yanagisawa N, Hana K, Nakada N, et al. High expression of L-type amino acid transporter 1 as a prognosis marker in bile duct adrenocarcinomas. Cancer Med 2014;3:1246-1255. 8. Yothaisong S, Dokduang H, Anzai N, et al. Inhibition of L-type amino acid transporter I activity as a new therapeutic target for cholangiocarcinoma treatment. Tumor Biology;39:1010428317694545. 9. Okanishi H, Ohgaki R, Okuda S, et al. Proteomics and phosphoproteomics reveal key regulators associated with cytostatic effect of amino acid transporter. Cancer Science 2021;112:871-883. 10. Nishikubo K, Ohgaki R, Okanishi H, et al. Pharmacologic inhibition of LAT1 predominantly suppresses transport of large neutral amino acids and downregulates global translation in cancer cells. J Cell Mol Med 2022;26:5246-5256. 11. Okano N, Naruge D, Kawai K, et al. First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors. Invest New Drugs 2020;38:1495-1506. 12. Toyoshima J, Kusuhara H, Wempe MF, et al. Investigation of the Role of Transporters on the Hepatic Elimination of an LAT1 Selective Inhibitor JPH203. J Pharm Sci 2013;102:3228-38. 13. Hein DW, Doll MA, Accuracy of various human NAT2 SNP genotyping panels to infer rapid, intermediate and slow acetylator phenotypes. Pharmacogenomics 2012; 13(1):31-41. 14. Lamarca A, Palmer DH, Wasan HS, et al., Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer(ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncology 2021;22 690-701. 15. Ueno M, et al, Ikeda M, Morizane C, et al., Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study. Lancet Gastroenterol Hepatol. 2019;4:611-621. 16. Rina Otani, Hidehiko Takigawa, Ryo Yuge et at, Cancers,2023,15:1383. 17. I K Dev, R E Dornsife, T M Hopper, et al, British Journal of Cancer(2004) 91,1391-1398. Industrial applicability According to the present invention, it is possible to provide a therapeutic agent for biliary tract cancer, which is effective for biliary tract cancer that is currently difficult to treat effectively. Alternatively, through the present invention, it is possible to provide a therapeutic agent for biliary tract cancer, which is effective for BTC, especially for EHC and GBC in BTC, in patients with a specific NAT2 genotype, especially those with a non-rapid (slow and / or intermediate) type of NAT2 genotype.

Claims

1. A therapeutic agent for biliary tract cancer, which is advanced biliary tract cancer for which standard chemotherapy of a subject is ineffective or intolerant, wherein, Contains an LAT1 inhibitor.

2. The therapeutic agent according to claim 1, wherein, The LAT1 inhibitor is O-(5-amino-2-phenylbenzoxazol-7-yl)methyl-3,5-dichloro-L-tyrosine or a pharmaceutically acceptable salt thereof.

3. The therapeutic agent according to claim 2, wherein, The progressive biliary tract cancer for which the standard chemotherapy of the subject is ineffective or intolerant is selected from the group consisting of extrahepatic bile duct cancer and gallbladder cancer.

4. The therapeutic agent according to claim 3, wherein, The biliary tract cancer is extrahepatic bile duct cancer.

5. The therapeutic agent according to claim 3, wherein, The biliary tract cancer is gallbladder cancer.

6. The therapeutic agent according to claim 3, wherein, The subject is a patient with high LAT1 expression.

7. The therapeutic agent according to claim 3 or 6, wherein The subject is a subject identified as having a non-rapid, i.e., slow and / or intermediate, NAT2 gene.

8. The therapeutic agent according to claim 1, wherein, The subject is a patient with high LAT1 expression.

9. The therapeutic agent according to claim 8, wherein, The biliary tract cancer is extrahepatic bile duct cancer or gallbladder cancer.

10. The therapeutic agent according to claim 9, wherein, The subject is a subject identified as having a non-rapid, i.e., slow and / or intermediate, NAT2 gene.

11. The therapeutic agent according to claim 1, wherein, The biliary tract cancer is intrahepatic bile duct cancer.

12. The therapeutic agent according to claim 11, wherein, The subject is a patient with high LAT1 expression.

13. The therapeutic agent according to claim 12, wherein, The subject is a subject identified as having a non-rapid, i.e., slow and / or intermediate, NAT2 gene.

14. The therapeutic agent according to any one of claims 1 to 3, 8, and 11, wherein, The therapeutic agent is administered to the subject at a dose of 1 to 60 mg / m 2 .

15. The therapeutic agent according to claim 14, wherein, The therapeutic agent is administered to the subject at 12.5 to 60 mg / m 2 .

16. The therapeutic agent according to claim 15, wherein, The therapeutic agent is administered to the subject at 12.5 to 25 mg / m 2 .

17. The therapeutic agent according to any one of claims 1 to 3, 8, and 11, wherein, A specified amount of the therapeutic agent is continuously administered intravenously at a specified time.

18. The therapeutic agent according to claim 17, wherein, 100 mL of the therapeutic agent is continuously administered intravenously over 90 minutes.

19. The therapeutic agent according to any one of claims 1 to 3, 8, and 11, wherein, The subject is a human.

20. A pharmaceutical composition containing the therapeutic agent for biliary tract cancer according to claim 1 and a pharmaceutically acceptable additive.

21. A therapeutic agent for biliary tract cancer, which is incurable and inoperable biliary tract cancer that has deteriorated due to ineffectiveness or intolerance to cancer chemotherapy in a subject, wherein, Contains an LAT1 inhibitor.

22. The therapeutic agent according to claim 21, wherein, The LAT1 inhibitor is O-(5-amino-2-phenylbenzoxazol-7-yl)methyl-3,5-dichloro-L-tyrosine or a pharmaceutically acceptable salt thereof.

23. The therapeutic agent according to claim 21, wherein, The biliary tract cancer is selected from the group consisting of extrahepatic bile duct cancer and gallbladder cancer.

24. The therapeutic agent according to claim 23, wherein, The biliary tract cancer is extrahepatic bile duct cancer.

25. The therapeutic agent according to claim 23, wherein, The biliary tract cancer is gallbladder cancer.

26. The therapeutic agent according to claim 23, wherein, The subject is a patient with high LAT1 expression.

27. The therapeutic agent according to claim 23 or 26, wherein, The subject is a patient with high LAT1 expression having non-rapid N-acetyltransferase 2.

28. The therapeutic agent according to claim 21, wherein, The subject is a patient with high LAT1 expression.

29. The therapeutic agent according to claim 28, wherein, The biliary tract cancer is extrahepatic bile duct cancer or gallbladder cancer.

30. The therapeutic agent according to claim 29, wherein, The non-rapid type is slow and / or intermediate.

31. The therapeutic agent according to claim 21, wherein, The biliary tract cancer is intrahepatic bile duct cancer.

32. The therapeutic agent according to claim 31, wherein, The subject is a patient with high LAT1 expression.

33. The therapeutic agent according to claim 32, wherein, The subject is a patient with high LAT1 expression having non-rapid N-acetyltransferase 2.

34. The therapeutic agent according to any one of claims 21 to 23, 28, and 31, wherein, The therapeutic agent is administered to the subject at 1 to 60 mg / m 2 2.

35. The therapeutic agent according to claim 34, wherein, The therapeutic agent is administered to the subject at 12.5 to 60 mg / m 2 .

36. The therapeutic agent according to claim 35, wherein, The therapeutic agent is administered to the subject at 12.5 to 25 mg / m 2 .

37. The therapeutic agent according to any one of claims 21 to 23, 28, and 31, wherein, A specified amount of the therapeutic agent is continuously administered intravenously at a specified time.

38. The therapeutic agent according to claim 37, wherein, 100 mL of the therapeutic agent is continuously administered intravenously over 90 minutes.

39. The therapeutic agent according to any one of claims 21 to 23, 28, and 31, wherein, The subject is a human.

40. A pharmaceutical composition, wherein, Contains the therapeutic agent for biliary tract cancer according to claim 21 and a pharmaceutically acceptable additive.

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