WO2017030146A1 - 胆道癌治療剤 - Google Patents
胆道癌治療剤 Download PDFInfo
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- WO2017030146A1 WO2017030146A1 PCT/JP2016/074017 JP2016074017W WO2017030146A1 WO 2017030146 A1 WO2017030146 A1 WO 2017030146A1 JP 2016074017 W JP2016074017 W JP 2016074017W WO 2017030146 A1 WO2017030146 A1 WO 2017030146A1
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- cancer
- biliary tract
- therapeutic agent
- tract cancer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
Definitions
- the present invention relates to a therapeutic agent for biliary tract cancer containing a compound having a kinase inhibitory action. More specifically, 4- [3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy] -7-methoxy-6-quinolinecarboxamide or a pharmacologically acceptable compound thereof is a compound having a multi-tyrosine kinase inhibitory action.
- the present invention relates to a therapeutic agent for biliary tract cancer containing a salt.
- Compound A 4- [3-Chloro-4- (cyclopropylaminocarbonyl) aminophenoxy] -7-methoxy-6-quinolinecarboxamide represented by the formula (I) (hereinafter sometimes referred to as Compound A) is a blood vessel. Inhibitory action against new tyrosine kinases (Non-patent document 1 to Non-patent document 5) (Patent document 2 to Patent document 5), etc. Have Methanesulfonate (mesylate) of Compound A has been approved as a therapeutic drug for thyroid cancer and renal cell carcinoma, such as lung cancer, melanoma, endometrial cancer, glioma, hepatocellular carcinoma, ovarian cancer, etc. Clinical trials are also being conducted on various tumors.
- Biliary tract cancer is cancer of the intrahepatic bile duct, extrahepatic bile duct, gallbladder duct, gallbladder and duodenal papilla, and is known as a tumor with a poor prognosis, although its incidence is low.
- the radical treatment method for biliary tract cancer is surgical removal, but there are few cases where surgery is possible at the time of diagnosis, and even if surgery is possible, complete removal is often impossible. When surgery is not possible, combination administration of gemcitabine and cisplatin is performed (Non-patent Documents 6 and 7).
- the present invention provides the following [1] to [17].
- a therapeutic agent for biliary tract cancer comprising Compound A or a pharmacologically acceptable salt thereof.
- a pharmaceutical composition for treating biliary tract cancer comprising Compound A or a pharmacologically acceptable salt thereof.
- a method for treating biliary tract cancer comprising administering Compound A or a pharmaceutically acceptable salt thereof to a patient in need thereof.
- Compound A or a pharmacologically acceptable salt thereof for treating biliary tract cancer comprising Compound A or a pharmacologically acceptable salt thereof.
- a pharmaceutical composition comprising Compound A or a pharmacologically acceptable salt thereof for treating biliary tract cancer.
- the therapeutic agent or pharmaceutical composition further containing an excipient.
- the therapeutic agent, pharmaceutical composition, therapeutic method, use or compound, wherein the compound A or a pharmacologically acceptable salt thereof is the methanesulfonate salt of the compound A.
- the therapeutic agent, pharmaceutical composition, therapeutic method, use or compound described above, wherein the biliary tract cancer is intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, gallbladder cancer or duodenal papilla cancer.
- the therapeutic agent, pharmaceutical composition, therapeutic method, use or compound, wherein the biliary tract cancer is intrahepatic cholangiocarcinoma.
- the therapeutic agent, pharmaceutical composition, therapeutic method, use or compound described above, wherein the biliary tract cancer is extrahepatic cholangiocarcinoma.
- the aforementioned therapeutic agent, pharmaceutical composition, therapeutic method, use or compound, wherein the biliary tract cancer is gallbladder duct cancer.
- the therapeutic agent, pharmaceutical composition, therapeutic method, use or compound, wherein the biliary tract cancer is gallbladder cancer.
- the therapeutic agent, pharmaceutical composition, therapeutic method, use or compound, wherein the biliary tract cancer is duodenal papilla cancer.
- the above-mentioned therapeutic agent, pharmaceutical composition, therapeutic method, use, or compound A or a pharmacologically acceptable salt thereof is orally administered at a dose of 1 to 100 mg per day Compound.
- the present invention provides a biliary tract cancer therapeutic agent containing Compound A having a multi-tyrosine kinase inhibitory action.
- Compound A according to the present invention or a pharmacologically acceptable salt thereof can be produced by the method described in Patent Document 1.
- An example of a pharmaceutically acceptable salt of Compound A is methanesulfonate (mesylate).
- the pharmacologically acceptable salt is not limited to a specific salt type.
- a salt with an inorganic acid a salt with an organic acid, a salt with an inorganic base, a salt with an organic base, an acidic or basic amino acid And salt.
- the salt with an inorganic acid is not limited to a specific salt type, and examples thereof include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
- the salt with an organic acid is not limited to a specific salt type. For example, acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid (mesylate) And salts with ethanesulfonic acid, p-toluenesulfonic acid and the like.
- the salt with an inorganic base is not limited to a specific salt type, but examples thereof include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt. It is done.
- the salt with an organic base is not limited to a specific salt type, and examples thereof include salts with diethylamine, diethanolamine, meglumine, N, N-dibenzylethylenediamine and the like.
- the salt with an acidic amino acid is not limited to a specific salt type, and examples thereof include salts with aspartic acid, glutamic acid and the like.
- the salt with a basic amino acid is not limited to a specific salt type, and examples thereof include salts with arginine, lysine, ornithine and the like.
- One embodiment of the pharmacologically acceptable salt of Compound A is methanesulfonate (mesylate).
- the dose of Compound A or a pharmacologically acceptable salt thereof depends on the degree of symptoms, patient age, sex, body weight, sensitivity difference, administration method, administration timing, administration interval, type of pharmaceutical preparation, etc. It can be selected appropriately. Usually, when administered orally to an adult (body weight 60 kg), the dose is 0.1 to 500 mg, preferably 0.5 to 300 mg, more preferably 1.0 to 100 mg per day. This can be administered once a day or divided into 2-3 times.
- One embodiment of the dose of Compound A or a pharmacologically acceptable salt thereof when orally administered to an adult (body weight 60 kg) is 24 mg per day in terms of free form Compound A.
- the therapeutic agent of the present invention can be formulated, for example, by the method described in the 16th revision Japanese Pharmacopoeia (JP), US Pharmacopoeia (USP) or European Pharmacopoeia (EP).
- JP Japanese Pharmacopoeia
- USP US Pharmacopoeia
- EP European Pharmacopoeia
- the therapeutic agent of the present invention can be orally administered in the form of solid preparations such as tablets, granules, fine granules, powders, capsules or liquids, jelly preparations, syrup preparations and the like.
- the therapeutic agent of the present invention may be administered parenterally in the form of injections, suppositories, ointments, cataplasms and the like.
- an oral solid preparation When preparing an oral solid preparation, it is added to the main agent, ie, compound A or a pharmacologically acceptable salt thereof, as an additive, an excipient, and optionally a binder, a disintegrant, and a lubricant.
- the main agent ie, compound A or a pharmacologically acceptable salt thereof
- an excipient ie, compound A or a pharmacologically acceptable salt thereof
- a binder ie, compound A or a pharmacologically acceptable salt thereof
- a disintegrant e.g., a granules, powders, capsules and the like
- a lubricant ie, a lubricant.
- excipients include lactose, sucrose, glucose, corn starch, mannitol, sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, and calcium hydrogen phosphate.
- binder examples include methyl cellulose, ethyl cellulose, gum arabic, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and the like.
- disintegrant examples include low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, and the like.
- lubricant examples include talc, silica, magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol and the like.
- colorant examples include iron sesquioxide, yellow iron sesquioxide, carmine, ⁇ -carotene, titanium oxide, riboflavin sodium phosphate, yellow aluminum lake, and cochineal.
- flavoring agents examples include cocoa powder, ascorbic acid, tartaric acid, mint oil, borneol, and cinnamon powder.
- pH adjuster and buffer examples include hydrochloric acid, sodium carbonate, sodium hydrogen carbonate, citric acid, sodium citrate, sodium dihydrogen citrate, phosphoric acid, sodium dihydrogen phosphate, sodium monohydrogen phosphate, Examples thereof include sodium hydroxide, acetic acid, sodium acetate, meglumine and the like.
- suspending agent examples include sodium alginate, sucrose fatty acid ester, polysorbate 80, gum arabic, tragacanth powder, polyoxyethylene sorbitan monolaurate and the like.
- solubilizers include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, glycerin fatty acid ester, polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, triethanolamine, Etc.
- Examples of the stabilizer include sodium sulfite and sodium metasulfite.
- tonicity agents examples include glucose, mannitol, sorbitol and the like.
- preservative examples include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol and the like.
- biliary tract cancer means intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder duct cancer, gallbladder cancer, or duodenal papilla cancer.
- Intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma are collectively referred to as cholangiocarcinoma.
- the biliary tract cancer includes those in which these cancers have metastasized to a site other than the biliary tract.
- Example 1 Tumor growth inhibitory action of compound A on human extrahepatic cholangiocarcinoma cell line (TFK-1 strain) subcutaneous transplantation model
- Six nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj, female, Charles Japan) in each group River Co.) was used to evaluate the antitumor effect when Compound A was administered.
- a human-derived extrahepatic cholangiocarcinoma cell line TFK-1 (RIKEN BioResource Center) was suspended in RPMI 1640 medium (Wako Pure Chemical Industries, Ltd., containing 10% FBS) to a concentration of 2 ⁇ 10 8 cells / mL. It became cloudy and mixed well.
- the mixture was further mixed with an equal amount of Matrigel basement membrane matrix (Corning) to prepare a cell mixture of 1 ⁇ 10 8 cells / mL, and 0.1 mL each was transplanted into the right flank subcutaneous part of each mouse. .
- the major axis and minor axis of the tumor were measured with an electronic digital caliper (ABS Digimatic Caliper, Mitutoyo Corporation).
- the mice were divided into groups so that the average values of the tumor volumes in each group were approximately equal.
- the tumor volume was calculated according to the following formula.
- Tumor volume (mm 3 ) major axis (mm) ⁇ minor axis (mm) ⁇ minor axis (mm) / 2
- the mesylate salt of Compound A was dissolved in a 3 mmol / L hydrochloric acid solution so as to have concentrations of 0.05, 0.15, 0.5, 1.5 and 5 mg / mL.
- Control group Compound A group (1, 3, 10, 30, 100 mg / kg) were set.
- the control group was orally administered with a 3 mmol / L hydrochloric acid solution and the compound A group with a 3 mmol / L hydrochloric acid solution containing the mesylate salt of Compound A at a dose of 20 mL / kg once a day.
- the administration period was 14 days.
- the tumor volume was measured on the administration start date (1st day), 4, 8, 11 and the day after the last administration day (15th day). The change over time is shown in FIG. 1, and the average value of the tumor volume of each group on the 15th day is shown in FIG. Further, based on the tumor volume on the 15th day, the control group and each compound A group were compared by Dunnett's multiple test, and a P value of less than 0.05 was regarded as a significant difference. As a result, it was revealed that Compound A has an antitumor effect in a dose-dependent manner in a human extrahepatic cholangiocarcinoma-derived cell line (TFK-1 strain) subcutaneous transplantation model (FIGS. 1 and 2). *** in FIG. 2 indicates that tumor growth was statistically significantly inhibited (P value is less than 0.0001).
- Example 2 Tumor growth inhibitory action of Compound A on human cholangiocarcinoma cell line (OZ strain) subcutaneous transplantation model
- Nude mice of 5 cases in each group (CAnN.Cg-Foxn1 nu / CrlCrlj, female, Charles River Japan Co., Ltd.) was used to evaluate the antitumor effect when Compound A was administered.
- the human cholangiocarcinoma cell line OZ (JCRB cell bank) was added to Williams'E (Sigma Aldrich, 2 mmol / L L-glutamine, containing 10% FBS) at a concentration of 2 ⁇ 10 8 cells / mL. Suspended and mixed thoroughly.
- the mesylate salt of Compound A was dissolved in a 3 mmol / L hydrochloric acid solution so as to have concentrations of 0.05, 0.15, 0.5, 1.5 and 5 mg / mL.
- Control group Compound A group (1, 3, 10, 30, 100 mg / kg) were set.
- the control group was orally administered with a 3 mmol / L hydrochloric acid solution and the compound A group with a 3 mmol / L hydrochloric acid solution containing the mesylate salt of Compound A at a dose of 20 mL / kg once a day.
- the administration period was 14 days.
- the tumor volume was measured on the first day of administration (day 1), 5, 8, 12 and the day after the last day of administration (day 15). The change over time is shown in FIG. 3, and the average value of the tumor volume of each group on the 15th day is shown in FIG. Further, based on the tumor volume on the 15th day, the control group and each compound A group were compared by Dunnett's multiple test, and a P value of less than 0.05 was regarded as a significant difference. As a result, it was revealed that Compound A has an antitumor effect in a dose-dependent manner in a human cholangiocarcinoma-derived cell line (OZ line) subcutaneous transplantation model (FIGS. 3 and 4). *** in FIG. 4 indicates that the tumor growth was inhibited statistically significantly (P value is less than 0.0001).
- OZ line human cholangiocarcinoma-derived cell line
- Example 3 Tumor growth inhibitory action of compound A on human duodenal papilla cancer cell line (SNU-869 strain) subcutaneous transplantation model Nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj, female, Charles, Japan) in each group River Co.) was used to evaluate the antitumor effect when Compound A was administered.
- Human-derived human duodenal papilla cancer cell line SNU-869 (Creative Bioarray) was added to RPMI1640 medium (Wako Pure Chemical Industries, Ltd., containing 25 mM HEPES, 10% FBS) at a concentration of 2 ⁇ 10 8 cells / mL. Suspended and mixed well.
- the mixture was further mixed with an equal amount of Matrigel basement membrane matrix (Corning) to prepare a cell mixture of 1 ⁇ 10 8 cells / mL, and 0.1 mL each was transplanted into the right flank subcutaneous part of each mouse. .
- the major axis and minor axis of the tumor were measured with an electronic digital caliper (ABS Digimatic Caliper, Mitutoyo Corporation).
- the mice were divided into groups so that the average values of the tumor volumes in each group were approximately equal.
- the tumor volume was calculated according to the following formula.
- Tumor volume (mm 3 ) major axis (mm) ⁇ minor axis (mm) ⁇ minor axis (mm) / 2
- the mesylate salt of Compound A was dissolved in a 3 mmol / L hydrochloric acid solution so as to have concentrations of 0.05, 0.15, 0.5, 1.5 and 5 mg / mL.
- Control group Compound A group (1, 3, 10, 30, 100 mg / kg) were set.
- the control group was orally administered with a 3 mmol / L hydrochloric acid solution and the compound A group with a 3 mmol / L hydrochloric acid solution containing the mesylate salt of Compound A at a dose of 20 mL / kg once a day.
- the administration period was 14 days.
- the tumor volume was measured on the administration start date (1st day), 4, 8, 11 and the day after the last administration day (15th day). The change over time is shown in FIG. 5, and the average value of the tumor volume of each group on the 15th day is shown in FIG. Further, based on the tumor volume on the 15th day, the control group and each compound A group were compared by Dunnett's multiple test, and a P value of less than 0.05 was regarded as a significant difference. As a result, it was revealed that Compound A has an antitumor effect in a dose-dependent manner in a human duodenal papilla cancer cell line (SNU-869 strain) subcutaneous transplantation model (FIGS. 5 and 6). *** in FIG. 6 indicates that tumor growth was statistically significantly inhibited (P value is less than 0.0001).
- Example 4 An open-label, multicenter phase II clinical study of Compound A for patients with unresectable biliary tract cancer after chemotherapy with gemcitabine This study was conducted to treat gemcitabine against unresectable biliary tract cancer. Multicenter, single group, for patients with a previous regimen of two-drug chemotherapy (gemcitabine and cisplatin, or gemcitabine and other platinum or fluoropyrimidine combinations) It was an open-label clinical trial.
- This trial consisted of three phases: the first phase of administration, the administration phase, and the follow-up phase.
- the administration phase consisted of administration of the mesylate salt of compound A, which is the investigational drug, and tumor evaluation every 6 to 8 weeks in each cycle.
- the follow-up period started immediately after the date of discontinuation and continued for the duration of the subject's survival until withdrawal of consent by the subject or termination of the trial.
- the primary objective of this study was to evaluate the objective response rate (ORR) of the study drug in patients with unresectable biliary tract cancer after chemotherapy with gemcitabine.
- ORR is defined as the proportion of subjects whose best overall effect (BOR) is complete response (CR) or partial response (PR).
- PFS is defined as the period from the first administration date of the study drug to the date when the first event is confirmed (the progression of disease or death regardless of cause of death, whichever comes first).
- OS is defined as the period from the first day of study drug administration to the date of death regardless of cause of death.
- DCR is defined as the proportion of CR, PR or stable (SD) subjects.
- CBR is also defined as the proportion of subjects with CR, PR or long-term SD. Long-term SD has an SD period of 23 weeks or more.
- the major axis is 1.0 cm for non-lymph nodes using CT or MRI.
- the target lesion is a lesion that has undergone local therapy such as external radiation therapy (EBRT) or radiofrequency (RF) ablation, progression of the disease based on RECIST 1.1 has been observed.
- EBRT external radiation therapy
- RF radiofrequency
- Subjects who met any of the following criteria were excluded from the study.
- Patients who received anticancer treatment (excluding BSC) within 21 days before the start of the study drug administration (2) Major surgery (anesthesia or respiratory assistance is required within 21 days before the start of the study drug administration Patients who have undergone surgery) or who are scheduled for surgery during this trial (excluding biliary drainage) (3) Patients with moderate, high or drainage ascites (4) Patients with urine test paper with 2+ proteinuria (qualify if grade 1 or less in quantitative evaluation) (5) Patients with gastrointestinal malabsorption or other physical condition that may be affected by the investigator or study investigator that may affect the absorption of the investigational drug (6) Administration of the investigational drug Patients with severe arrhythmias associated with congestive heart failure, unstable angina, myocardial infarction or clinically significant cardiovascular disorders of class 2 or higher within the previous 6 months within the New York Heart Association classification (7 ) Patients with QT / QTc interval extension (QTcF> 480 ms) (8) Patients with positive HIV antibody test (9) Patients with active
- results of interim analysis An interim analysis of this clinical study was conducted. The total number of patients subject to the interim analysis was 17, of which 3 were extrahepatic bile duct cancer patients, 4 intrahepatic bile duct cancer patients, 9 gallbladder cancer patients, and 1 duodenal papilla cancer patient. As a result of the interim analysis, the partial response (PR) was 1 (5.9%), and the stable (SD; 6 weeks or more) was 13 (76.5%). Moreover, the tendency of tumor shrinkage was confirmed in 8 out of 13 SDs.
Abstract
Description
[1] 化合物Aまたはその薬理学的に許容される塩を含有する胆道癌治療剤。
[2] 化合物Aまたはその薬理学的に許容される塩を含有する胆道癌治療用医薬組成物。
[3] 化合物Aまたはその薬理学的に許容される塩を、それを必要とする患者に投与することを含む、胆道癌を治療する方法。
[4] さらに少なくとも1種の抗腫瘍剤を当該患者に投与することを含む、上記方法。
[5] 胆道癌治療のための化合物Aまたはその薬理学的に許容される塩。
[6] 胆道癌治療のための化合物Aまたはその薬理学的に許容される塩を含有する医薬組成物。
[7] 化合物Aまたはその薬理学的に許容される塩の胆道癌治療のための使用。
[8] 胆道癌治療剤または胆道癌治療用医薬組成物を製造するための化合物Aまたはその薬理学的に許容される塩の使用。
[9] さらに賦形剤を含有する、上記治療剤または医薬組成物。
[10] 上記化合物Aまたはその薬理学的に許容される塩が、化合物Aのメタンスルホン酸塩である、上記治療剤、医薬組成物、治療方法、使用または化合物。
[11] 胆道癌が肝内胆管癌、肝外胆管癌、胆嚢管癌、胆嚢癌または十二指腸乳頭部癌である、上記治療剤、医薬組成物、治療方法、使用または化合物。
[12] 胆道癌が肝内胆管癌である、上記治療剤、医薬組成物、治療方法、使用または化合物。
[13] 胆道癌が肝外胆管癌である、上記治療剤、医薬組成物、治療方法、使用または化合物。
[14] 胆道癌が胆嚢管癌である、上記治療剤、医薬組成物、治療方法、使用または化合物。
[15] 胆道癌が胆嚢癌である、上記治療剤、医薬組成物、治療方法、使用または化合物。
[16] 胆道癌が十二指腸乳頭部癌である、上記治療剤、医薬組成物、治療方法、使用または化合物。
[17] 化合物Aまたはその薬理学的に許容される塩が、1日あたり1~100mgの投与量で経口投与されることを特徴とする、上記治療剤、医薬組成物、治療方法、使用または化合物。
各群6例のヌードマウス(CAnN.Cg-Foxn1nu/CrlCrlj、雌、日本チャールズリバー株式会社)を使用して、化合物Aを投与した場合の抗腫瘍効果を評価した。ヒト由来の肝外胆管癌細胞株TFK-1(理研バイオリソースセンター)を、RPMI1640培地(和光純薬工業株式会社、10%FBS含有)に、2×108個/mLの濃度となるように懸濁し、十分に混和した。その混和液をさらに等量のマトリゲル基底膜マトリクス(コーニング社)と混合して1×108個/mLの細胞混和液を調製し、各マウスの右脇腹皮下部に、0.1mLずつ移植した。移植から7日後に、腫瘍の長径および短径を電子デジタルノギス(ABSデジマチックキャリパ、株式会社ミツトヨ)で測定した。各群の腫瘍体積の平均値がほぼ等しくなるように、マウスを群分けした。なお、腫瘍の体積を、以下の式に従って算出した。
腫瘍体積(mm3)=長径(mm)×短径(mm)×短径(mm)/2
各群5例のヌードマウス(CAnN.Cg-Foxn1nu/CrlCrlj、雌、日本チャールズリバー株式会社)を使用して、化合物Aを投与した場合の抗腫瘍効果を評価した。ヒト由来の胆管癌細胞株OZ(JCRB細胞バンク)を、Williams’E(シグマアルドリッチ社、2mmol/L L-グルタミン,10%FBS含有)に、2×108個/mLの濃度となるように懸濁し、十分に混和した。その混和液をさらに等量のマトリゲル基底膜マトリクス(コーニング社)と混合して1×108個/mLの細胞混和液を調製し、各マウスの右脇腹皮下部に、0.1mLずつ移植した。移植から13日後に、腫瘍の長径および短径を電子デジタルノギス(ABSデジマチックキャリパ、株式会社ミツトヨ)で測定した。各群の腫瘍体積の平均値がほぼ等しくなるように、マウスを群分けした。なお、腫瘍の体積を、以下の式に従って算出した。
腫瘍体積(mm3)=長径(mm)×短径(mm)×短径(mm)/2
各群6例のヌードマウス(CAnN.Cg-Foxn1nu/CrlCrlj、雌、日本チャールズリバー株式会社)を使用して、化合物Aを投与した場合の抗腫瘍効果を評価した。ヒト由来のヒト十二指腸乳頭部癌細胞株SNU-869(Creative Bioarray社)を、RPMI1640培地(和光純薬工業株式会社、25mM HEPES、10%FBS含有)に、2×108個/mLの濃度となるように懸濁し、十分に混和した。その混和液をさらに等量のマトリゲル基底膜マトリクス(コーニング社)と混合して1×108個/mLの細胞混和液を調製し、各マウスの右脇腹皮下部に、0.1mLずつ移植した。移植から7日後に、腫瘍の長径および短径を電子デジタルノギス(ABSデジマチックキャリパ、株式会社ミツトヨ)で測定した。各群の腫瘍体積の平均値がほぼ等しくなるように、マウスを群分けした。なお、腫瘍の体積を、以下の式に従って算出した。
腫瘍体積(mm3)=長径(mm)×短径(mm)×短径(mm)/2
本治験は、切除不能の胆道癌に対しゲムシタビンを含む2剤併用化学療法(ゲムシタビンおよびシスプラチン、またはゲムシタビンおよび他の白金製剤もしくはフッ化ピリミジン製剤の2剤併用化学療法)の前治療歴1レジメンを有する患者を対象とした多施設共同、単群、非盲検の臨床試験であった。
(1)組織学的または細胞学的に腺癌と診断された胆道癌(肝内胆管癌、肝外胆管癌、胆嚢癌、Vater膨大部癌)患者
(2)切除不能(例:局所進行または転移を有する)の胆道癌を有する患者
(3)切除不能の胆道癌に対してゲムシタビンを含む2剤併用化学療法(例:ゲムシタビンおよびシスプラチン)の前治療を1レジメン受けており、それ以外の胆道癌に対する化学療法を受けていない患者
ここで、術後補助化学療法を受けた患者は、当該療法が完了しており、完了後6ヵ月間再発が認められない場合には適格とする。
(4)以下の基準を満たす測定可能な病変を有する患者
Response Evaluation Criteria in Solid Tumors 1.1(RECIST1.1)に基づき、CTまたはMRIを用いて、非リンパ節の場合は長径が1.0cm以上またはリンパ節の場合は短径が1.5cm以上の継続的に測定可能な病変を少なくとも1つ有する。
放射線外照射療法(EBRT)またはラジオ波(RF)焼灼などの局所療法を受けた病変を標的病変とする場合は、RECIST1.1に基づく病勢の進行が認められていること。
(5)Eastern Cooperative Oncology Group(ECOG)Performance Statusが0~1の患者
(6)本治験薬投与開始後、3ヵ月以上の生存が見込まれる患者
(7)同意取得時の年齢が20歳以上の男性または女性
(8)脱毛、不妊および選択基準の範囲内の有害事象を除く、化学療法または放射線療法に関連した全ての毒性がCommon Terminology Criteria for Adverse Events(CACAE v4.03)でGrade0~1まで回復している患者
(9)降圧剤使用の有無にかかわらず血圧(BP)が十分にコントロールされている(定義:収縮期血圧150mmHg以下および拡張期血圧90mmHg以下、かつ、本治験薬投与開始前の1週間以内に降圧剤の変更がない)患者
(10)主要臓器機能および抗凝固能が十分保たれている患者
1)好中球数(ANC)≧1500/mm3(≧1.5×103/μL)
2)血小板数≧100,000/mm3(≧100×109/L)
3)ヘモグロビン≧9.0g/dL
4)総ビリルビン≦2.0 mg/dL(非抱合型高ビリルビン血症またはGilbert症候群の場合を除く)
5)ALP、AST およびALT≦3.0×ULN(施設基準値上限)(肝転移を有する場合は≦5.0×ULN)
6)クレアチニン・クリアランス≧40 mL/min(Cockcroft-Gault法)
7)プロトロンビン時間国際標準比(PT-INR)≦1.5
(11)自由意志により本治験参加に文書で同意した患者
(12)治験実施計画書を遵守する意思があり、かつ、遵守することができる患者
(1)本治験薬投与開始前の21日以内に抗がん治療(BSCを除く)を受けた患者
(2)本治験薬投与開始前の21日以内に大手術(麻酔または呼吸補助を要する手術)を受けた患者、または本治験中に手術が計画されている患者(胆道ドレナージを除く)
(3)中等度、高度またはドレナージを要する腹水を有する患者
(4)尿試験紙で2+以上の蛋白尿を有する患者(定量評価でGrade1以下の場合は適格とする)
(5)消化管の吸収不良、または治験責任医師もしくは治験分担医師により本治験薬の吸収に影響を与える可能性があると判断されるその他の身体状態を示す患者
(6)本治験薬投与開始前の6ヵ月以内に、New York Heart Association分類でクラス2以上のうっ血性心不全、不安定狭心症、心筋梗塞または臨床的意義のある心血管障害に関連した重篤な不整脈を有する患者
(7)QT/QTc間隔延長(QTcF>480ms)を有する患者
(8)HIV抗体検査で陽性と判明している患者
(9)全身療法を要する活動性の感染症を有する患者
(10)出血性もしくは血栓性疾患を有する、またはINRモニタリングを要するワーファリンもしくは同種の薬剤などの抗凝固薬(低分子量へパリンの使用は可)を慢性使用している患者
(11)本治験薬投与開始前の21日以内に消化管出血または活動性喀血(小さじ1/2以上の鮮血)が認められた患者
(12)本治験薬投与開始前の24ヵ月以内に活動性の悪性腫瘍を有する患者(胆道癌、完全に処置された非浸潤性メラノーマ、皮膚の基底細胞癌または扁平上皮癌、非浸潤性子宮頚部癌および早期胃癌/大腸癌は除く)
(13)髄膜癌腫症と診断された患者
(14)脳または硬膜下転移を有する患者。ただし、本治験薬投与開始の28日以上前に、局所の治療が既に完了しており、当該転移の治療として副腎皮質ホルモンの投与を中止している患者は除く。本治験薬投与開始の28日以上前に脳転移の徴候(例えば放射線検査上)または症状が安定していなければならない。
(15)本治験薬または賦形剤の成分に忍容性がないと判明している患者
(16)本治験薬投与開始前の24ヵ月以内に薬物もしくはアルコールの依存または乱用の既往がある患者
(17)医学的またはその他の理由により、治験責任医師または治験分担医師が本治験の参加対象として不適格と判断した患者
(18)女性の場合には、スクリーニング時またはベースライン時に、授乳中または妊娠している患者(ヒト絨毛性ゴナドトロピン[hCGまたはβ-hCG]検査で陽性が確認された患者)。スクリーニング時の検査が本治験薬投与開始より3日以上前に行われた場合には、当該検査で陰性であったとしても、再度検査をする必要がある。
(19)生殖能力のある男性および妊娠する可能性のある女性の場合、本人およびそのパートナーが治験期間を通じて医学的に適切な避妊方法を用いることに同意しない患者
上記避妊方法においては、コンドーム、避妊用スポンジ、避妊用フォーム、避妊用ゼリー、避妊用ペッサリーもしくは避妊リングを使用、または本治験薬投与開始の28日以上前から経口(経皮または経膣も可能)の避妊薬を使用すること。
本臨床試験の中間解析を行った。中間解析対象の患者総数は17人であり、そのうち肝外胆管癌患者は3人、肝内胆管癌患者4人、胆嚢癌患者は9人、十二指腸乳頭部癌患者は1人であった。
中間解析の結果、部分奏効(PR)は1人(5.9%)、安定(SD;6週以上)は13人(76.5%)であった。また、SD13人のうち8人において、腫瘍縮小傾向が確認された。
Claims (15)
- 4-[3-クロロ-4-(シクロプロピルアミノカルボニル)アミノフェノキシ]-7-メトキシ-6-キノリンカルボキサミドまたはその薬理学的に許容される塩を含有する胆道癌治療剤。
- 4-[3-クロロ-4-(シクロプロピルアミノカルボニル)アミノフェノキシ]-7-メトキシ-6-キノリンカルボキサミドまたはその薬理学的に許容される塩を含有する胆道癌治療用医薬組成物。
- 薬理学的に許容される塩が、メタンスルホン酸塩である請求項1に記載の治療剤または請求項2に記載の医薬組成物。
- さらに賦形剤を含有する請求項1~3のいずれか1項に記載の治療剤または医薬組成物。
- 胆道癌が肝内胆管癌、肝外胆管癌、胆嚢管癌、胆嚢癌または十二指腸乳頭部癌である、請求項1~4のいずれか1項に記載の治療剤または医薬組成物。
- 胆道癌が肝内胆管癌である、請求項5に記載の治療剤または医薬組成物。
- 胆道癌が肝外胆管癌である、請求項5に記載の治療剤または医薬組成物。
- 胆道癌が胆嚢管癌である、請求項5に記載の治療剤または医薬組成物。
- 胆道癌が胆嚢癌である、請求項5に記載の治療剤または医薬組成物。
- 胆道癌が十二指腸乳頭部癌である、請求項5に記載の治療剤または医薬組成物。
- 4-[3-クロロ-4-(シクロプロピルアミノカルボニル)アミノフェノキシ]-7-メトキシ-6-キノリンカルボキサミドまたはその薬理学的に許容される塩が、1日あたり1~100mgの投与量で経口投与されることを特徴とする、請求項1~10のいずれか1項に記載の治療剤または医薬組成物。
- 4-[3-クロロ-4-(シクロプロピルアミノカルボニル)アミノフェノキシ]-7-メトキシ-6-キノリンカルボキサミドまたはその薬理学的に許容される塩を、それを必要とする患者に投与することを含む、胆道癌を治療する方法。
- さらに少なくとも1種の抗腫瘍剤を当該患者に投与することを含む、請求項12の方法。
- 胆道癌治療のための4-[3-クロロ-4-(シクロプロピルアミノカルボニル)アミノフェノキシ]-7-メトキシ-6-キノリンカルボキサミドまたはその薬理学的に許容される塩を含有する医薬組成物。
- 胆道癌治療用医薬組成物を製造するための4-[3-クロロ-4-(シクロプロピルアミノカルボニル)アミノフェノキシ]-7-メトキシ-6-キノリンカルボキサミドまたはその薬理学的に許容される塩の使用。
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CN201680044979.XA CN107921039A (zh) | 2015-08-19 | 2016-08-17 | 用于胆道癌的治疗剂 |
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MX2018001439A (es) | 2018-05-28 |
EP3338778A4 (en) | 2019-04-17 |
AU2016308390A1 (en) | 2018-02-22 |
US20190000829A1 (en) | 2019-01-03 |
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