Methods of treating cholangiocarcinoma

Abstract

To provide methods of treating cholangiocarcinoma.SOLUTION: Provided is a method for treating advanced or metastatic cholangiocarcinoma in a patient in need thereof, comprising administering an effective amount of infigratinib or a pharmaceutically acceptable salt thereof, wherein the patient has progression of the cholangiocarcinoma after previous administration of another therapy.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of and priority to U.S. Patent Application No. 62 / 853,431, filed on May 28, 2019 and is hereby incorporated by reference in its entirety.

Background Art

[0002] Cholangiocarcinoma, also known as bile duct cancer, is a rare and heterogeneous malignant disease that results from the malignant transformation of bile duct cells into intrahepatic, perihilar, or distal extrahepatic tumors (Alpini et al., 2001). In the United States, approximately 5,000 - 10,000 patients are diagnosed with cholangiocarcinoma of both the intrahepatic and extrahepatic biliary systems each year. Cholangiocarcinoma is more prevalent in Asia and the Middle East and is most often thought to be due to parasitic infections of the bile duct (American Cancer Society, 2 012). Men are slightly more likely to develop cholangiocarcinoma, but the incidence increases with age in both men and women (Patel et al., 2002). Typically, cholangiocarcinoma is an adenocarcinoma with a poor prognosis and limited treatment options. This is due in part to the late onset of symptoms and relative resistance to currently available therapies. Furthermore, conventional chemotherapy and radiation therapy (RT) have not been shown to be effective in prolonging long - term survival. Photodynamic therapy combined with stenting has been reported to be effective as a palliative treatment, but it is not curative (Sirica,

[0003] ​​​​​​​​​In 2005. In April 2010, the ABC-02 clinical trial was published, which was the first Phase III randomized controlled clinical trial in a patient population randomly assigned to receive cisplatin and gemcitabine or gemcitabine alone (Valle et al., 2010). In this trial, the combination of gemcitabine / cisplatin demonstrated improvement in progression-free survival (PFS) and overall survival (OS) compared to gemcitabine alone. The median overall survival was 11.7 months in the cisplatin-gemcitabine group and 8.1 months in the gemcitabine group. The median progression-free survival was 8.0 months in the cisplatin-gemcitabine group and 5.0 months in the gemcitabine-only group. Nevertheless, patients with cholangiocarcinoma who relapse after first-line therapy have few treatment options and no established second-line standard treatment. The response rates to currently available therapies are in the single digits (Lamarca et al., 2014). patients to receive cisplatin and gemcitabine or gemcitabine alone, the first Phase III randomized controlled clinical trial in a patient population randomly assigned to receive cisplatin and gemcitabine or gemcitabine alone (Valle et al., , 2010). In this trial, the combination of gemcitabine / cisplatin demonstrated improvement in progression-free survival (PFS) and overall survival (OS) compared to gemcitabine alone. The median overall survival was 11.7 months in the cisplatin-gemcitabine group and 8.1 months in the gemcitabine group. The median progression-free survival was 8.0 months in the cisplatin-gemcitabine group and 5.0 months in the gemcitabine-only group. Nevertheless, patients with cholangiocarcinoma who relapse after first-line therapy have few treatment options and no established second-line standard treatment. The response rates to currently available therapies are in the single digits (Lamarca et al., 2014). 8.1 months in the gemcitabine group. The median progression-free survival was 8.0 months in the cisplatin-gemcitabine group and 5.0 months in the gemcitabine-only group. Nevertheless, patients with cholangiocarcinoma who relapse after first-line therapy have few treatment options and no established second-line standard treatment. The response rates to currently available therapies are in the single digits (Lamarca et al., 2014). 8.1 months in the gemcitabine group. The median progression-free survival was 8.0 months in the cisplatin-gemcitabine group and 5.0 months in the gemcitabine-only group. Nevertheless, patients with cholangiocarcinoma who relapse after first-line therapy have few treatment options and no established second-line standard treatment. The response rates to currently available therapies are in the single digits (Lamarca et al., 2014). 8.0 months in the cisplatin-gemcitabine group and 5.0 months in the gemcitabine-only group. Nevertheless, patients with cholangiocarcinoma who relapse after first-line therapy have few treatment options and no established second-line standard treatment. The response rates to currently available therapies are in the single digits (Lamarca et al., 2014). 8.0 months in the cisplatin-gemcitabine group and 5.0 months in the gemcitabine-only group. Nevertheless, patients with cholangiocarcinoma who relapse after first-line therapy have few treatment options and no established second-line standard treatment. The response rates to currently available therapies are in the single digits (Lamarca et al., 2014). 8.0 months in the cisplatin-gemcitabine group and 5.0 months in the gemcitabine-only group. Nevertheless, patients with cholangiocarcinoma who relapse after first-line therapy have few treatment options and no established second-line standard treatment. The response rates to currently available therapies are in the single digits (Lamarca et al., 2014). 8.0 months in the cisplatin-gemcitabine group and 5.0 months in the gemcitabine-only group. Nevertheless, patients with cholangiocarcinoma who relapse after first-line therapy have few treatment options and no established second-line standard treatment. The response rates to currently available therapies are in the single digits (Lamarca et al., 2014).

[0004] The most recent guidelines for the treatment of advanced biliary cancer, developed by the National Comprehensive Cancer Network (N CCN), recommend the use of gemcitabine, capecitabine, or 5-fluorouracil (5-FU) either as a single agent or in combination with a platinum analogue (oxaliplatin or cisplatin), or the combination of gemcitabine and capecitabine, in Category 1 of the recommended categories for first-line treatment of biliary cancer, together with the combination of gemcitabine and cisplatin, which has received Category 1 of the recommended categories for first-line treatment of biliary cancer. None of these drugs have been approved by the FDA primarily for use in biliary cancer. CCN), recommend the use of gemcitabine, capecitabine, or 5-fluorouracil (5-FU) either as a single agent or in combination with a platinum analogue (oxaliplatin or cisplatin), or the combination of gemcitabine and capecitabine, in Category 1 of the recommended categories for first-line treatment of biliary cancer, together with the combination of gemcitabine and cisplatin, which has received Category 1 of the recommended categories for first-line treatment of biliary cancer. None of these drugs have been approved by the FDA primarily for use in biliary cancer. CCN), recommend the use of gemcitabine, capecitabine, or 5-fluorouracil (5-FU) either as a single agent or in combination with a platinum analogue (oxaliplatin or cisplatin), or the combination of gemcitabine and capecitabine, in Category 1 of the recommended categories for first-line treatment of biliary cancer, together with the combination of gemcitabine and cisplatin, which has received Category 1 of the recommended categories for first-line treatment of biliary cancer. None of these drugs have been approved by the FDA primarily for use in biliary cancer. CCN), recommend the use of gemcitabine, capecitabine, or 5-fluorouracil (5-FU) either as a single agent or in combination with a platinum analogue (oxaliplatin or cisplatin), or the combination of gemcitabine and capecitabine, in Category 1 of the recommended categories for first-line treatment of biliary cancer, together with the combination of gemcitabine and cisplatin, which has received Category 1 of the recommended categories for first-line treatment of biliary cancer. None of these drugs have been approved by the FDA primarily for use in biliary cancer. CCN), recommend the use of gemcitabine, capecitabine, or 5-fluorouracil (5-FU) either as a single agent or in combination with a platinum analogue (oxaliplatin or cisplatin), or the combination of gemcitabine and capecitabine, in Category 1 of the recommended categories for first-line treatment of biliary cancer, together with the combination of gemcitabine and cisplatin, which has received Category 1 of the recommended categories for first-line treatment of biliary cancer. None of these drugs have been approved by the FDA primarily for use in biliary cancer. CCN), recommend the use of gemcitabine, capecitabine, or 5-fluorouracil (5-FU) either as a single agent or in combination with a platinum analogue (oxaliplatin or cisplatin), or the combination of gemcitabine and capecitabine, in Category 1 of the recommended categories for first-line treatment of biliary cancer, together with the combination of gemcitabine and cisplatin, which has received Category 1 of the recommended categories for first-line treatment of biliary cancer. None of these drugs have been approved by the FDA primarily for use in biliary cancer. Furthermore, the approach with multi-agent chemotherapy drugs does not provide a continuous benefit to patients with metastatic and / or recurrent diseases, and less than 5% of patients survive for 5 years after the diagnosis of advanced disease.

[0005] Regarding second-line treatment of cholangiocarcinoma (e.g., treatment for patients who relapse after receiving gemcitabine and / or cisplatin therapy), the current NCCN guidelines indicate that there is insufficient evidence for specific treatment methods recommended for second-line treatment in this group of patients.

[0006] The current European Society for Medical Oncology (ESMO) guidelines indicate that although fluoropyrimidine-based therapy (either alone or in combination with other cytotoxics) may be used, there is no established second-line systemic therapy after progression following first-line treatment.

[0007] Therefore, there is actually a need to develop a new treatment strategy for cholangiocarcinoma based on the use of select molecular targets that are thought to significantly affect clinical outcomes.

Summary of the Invention

Means for Solving the Problems

[0008] In one aspect, there is provided a method for treating advanced or metastatic cholangiocarcinoma in patients in need thereof, comprising administering an effective amount of infigratinib or a pharmaceutically acceptable salt thereof, wherein the patient has had cholangiocarcinoma progress after a previous administration of another therapy.

[0009] In certain embodiments, the other therapy previously administered is a therapy for advanced or metastatic cholangiocarcinoma There is. In some embodiments, the other therapy previously administered is the administration of a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent previously administered is a treatment regimen containing gemcitabine By.

[0010] In certain embodiments, cholangiocarcinoma has an FGFR1 gene fusion, translocation, or other genetic alteration There is. In certain embodiments, cholangiocarcinoma has an FGFR2 gene fusion, translocation, or other genetic alteration Have. In some embodiments, the FGFR2 gene fusion is 10Q26.13, AF F1, AFF4, AHCYL1, ALDH1L2, ARFIP1, BICC1, C10o rf118, C7, CCDC147, CCDC6, CELF2, CREB5, CREM, DNAJC12, HOOK1, KCTD1, KIAA1217, KIAA1598, KI FC3, MGEA5, NOL4, NRAP, OPTN, PARK2, PAWR, PCMI , PHLDB2, PPHLN1, RASAL2, SFMBT2, SLMAP, SLMAP 2, SORBS1, STK26, STK3, TACC3, TBC1D1, TFEC, TR A2B, UBQLN1, VCL, WAC, and a FG selected from the group consisting of ZMYM4 FR2 gene fusion partner. In certain embodiments, cholangiocarcinoma has an FGFR3 gene fusion , translocation, or other genetic alteration.

[0011] In certain embodiments, administering an effective amount of infigratinib or a pharmaceutically acceptable salt thereof Is to orally administer about 125 mg of infigratinib or a pharmaceutically acceptable thereof once a day Salt.

[0012] In certain embodiments, administering an effective amount of infigratinib or a pharmaceutically acceptable salt thereof is included in a 28-day cycle, and about 125 mg of infigratinib or its pharmaceutically acceptable salt is administered once daily to the patient for 3 consecutive weeks (21 days), and infigratinib is not administered for 1 week (7 consecutive days).

[0013] In certain embodiments, about 125 mg of infigratinib or a pharmaceutically acceptable salt thereof is provided as unit doses of 100 mg and 25 mg. In certain embodiments about 125 mg of infigratinib or a pharmaceutically acceptable salt thereof is provided as a unit dose

[0014] In certain embodiments, advanced or metastatic cholangiocarcinoma is confirmed histologically or cytologically.

[0015] In certain embodiments, cholangiocarcinoma has FGFR1, FGFR2, and / or FGFR3 mutations In some embodiments, the FGFR1, FGFR2, and / or FGFR3 mutations are FGFR1 G818R, FGFR1 K656E, FGFR1 N546K , FGFR1 R445W, FGFR1 T141R, FGFR2 A315T, FGF R2 C382R, FGFR2 D336N, FGFR2 D471N, FGFR2 E 565A, FGFR2 I547V, FGFR2 K641R, FGFR2 K659E , FGFR2 K659M, FGFR2 L617V, FGFR2 N549H, FGF R2 N549K, FGFR2 N549S, FGFR2 N549Y, FGFR2 N 550K, FGFR2 P253R, FGFR2 S252W, FGFR2 V395D ​​, FGFR2 V564F, FGFR2 Y375C, FGFR3 A391E, FGF R3 D785Y, FGFR3 E627K, FGFR3 G370C, FGFR3 G 380R, FGFR3 K650E, FGFR3 K650M, FGFR3 K650N , FGFR3 K650T, FGFR3 K652E, FGFR3 N540S, FGF R3 R248C, FGFR3 R399C, FGFR3 S131L, FGFR3 S 249C, FGFR3 S371C, FGFR3 V555M, FGFR3 V677I , FGFR3 Y373C, FGFR4 D425N, FGFR4 R183S, FGF R4 R394Q, FGFR4 R610H, FGFR4 V510L, and combinations thereof are selected from the group consisting of.

[0016] In certain embodiments, cholangiocarcinoma has FGFR2 gene fusions and FGFR2 mutations .

[0017] In certain embodiments, cholangiocarcinoma has amplification of FGFR1, FGFR2, and / or FGFR3 .

[0018] In certain embodiments, a previously administered other therapy is administration of a receptor tyrosine kinase inhibitor . In certain embodiments, the receptor tyrosine kinase inhibitor is a selective non-covalent inhibitor of FGFR1, FGFR2 , and / or FGFR3. In some embodiments, the selective non-covalent inhibitor of FGFR1, FGFR2 , and / or FGFR3 is pemigatinib , lorlatinib, derazantinib, Debio1347, AZD4547, and combinations thereof are selected from the group consisting of. In certain embodiments, the receptor tyrosine kinase inhibitor is a selective non-covalent inhibitor of FGFR1, FGFR2, FGFR3, and / or FGFR4. In some embodiments, the selective non-covalent inhibitor of FGFR1, FGFR2, FGFR3, and / or FGFR4 is selected from the group consisting of erdafitinib, LY2874455, PRN 1371, ASP5878, and combinations thereof. In certain embodiments, the receptor tyrosine kinase inhibitor is a selective covalent inhibitor of FGFR1, FGFR2, FGFR3 , and / or FGFR4. In some embodiments, the selective covalent inhibitor of FGFR1, FGFR2, FGFR3, and / or FGFR4 is TAS120. In certain embodiments, the receptor tyrosine kinase inhibitor is a non-selective tyrosine kinase inhibitor. In some embodiments, the non-selective tyrosine kinase inhibitor is selected from the group consisting of ponatinib, dovitinib, levatanib, ACTB-1003 , Ki8751, lucitinib, masitinib, mubritinib, nintedanib, olatinib, PD089828, and combinations thereof.

[0019] In certain embodiments, a previously administered different therapy is administration of another selective FGFR inhibitor. In some embodiments, the another selective FGFR inhibitor is selected from the group consisting of pemigatinib, rogaratinib, derazantinib, AZD4547, Debio1347, ASP5878, erdafitinib, LY2874455, PRN1371, TAS120, and combinations thereof. In certain embodiments, the another selective FGFR inhibitor is a selective covalent FGFR inhibitor. In some embodiments, the selective covalent FGFR inhibitor is , it is TAS120. In certain embodiments, another selective FGFR inhibitor is a selective non-covalent binding FGFR inhibitor. In some embodiments, the selective non-covalent binding FGFR inhibitor is pemigatinib, rogaratinib, derazantinib, AZD4547, and combinations thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0020]

Figure 1

Figure 2

Figure 3

Figure 4

Mode for Carrying Out the Invention

[0021] As generally described herein, the present disclosure provides, for example, a method for treating advanced or metastatic cholangiocarcinoma in patients in need thereof when the cholangiocarcinoma has progressed after the patient has previously been administered another therapy.

[0022] Definitions For ease of understanding of the present invention, many terms and phrases are defined below. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The abbreviations used herein have their conventional meanings within the scope of chemical and biological arts. The chemical structures and chemical formulas described herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0023] Throughout the description, when a composition and a kit are described as having, including, or comprising specific components, or when a process and a method are described as having, including, or comprising specific steps, in addition, consisting essentially of or There is a composition and a kit according to the present invention, and it is assumed that there is a process and a method according to the present invention which consists essentially of or consists of the recited processing steps. It is assumed that there is a process and a method according to the present invention which consists essentially of or consists of.

[0024] In the present application, when an element or a component is said to be included in and / or selected from a series of recited elements or components, the element or the component can be any one of the recited elements or components, or the element or the component can be selected from a group consisting of two or more recited elements or components. It should be understood. It should be understood that when an element or a component is said to be included in and / or selected from a series of recited elements or components, the element or the component can be any one of the recited elements or components, or the element or the component can be selected from a group consisting of two or more recited elements or components. It should be understood that when an element or a component is said to be included in and / or selected from a series of recited elements or components, the element or the component can be any one of the recited elements or components, or the element or the component can be selected from a group consisting of two or more recited elements or components. It should be understood that when an element or a component is said to be included in and / or selected from a series of recited elements or components, the element or the component can be any one of the recited elements or components, or the element or the component can be selected from a group consisting of two or more recited elements or components. It should be understood.

[0025] Furthermore, the elements and / or features of the composition or method described in the present specification can be combined in various ways without departing from the spirit and scope of the present invention, whether explicitly or implicitly disclosed in the present specification. For example, when a particular compound is mentioned, the compound can be used in various embodiments of the composition of the present invention and / or in the method of the present invention, unless otherwise understood from the context. In other words, in the present application, the embodiments are described and presented as clearly and concisely as possible for the application, but the embodiments are intended to be combinable or separable in various ways without departing from the teachings of the present invention and the present invention, and it will be understood. For example, it will be understood that all the features described and presented in the present specification can be applicable to all aspects of the present invention described and presented in the present specification. It should be understood that the elements and / or features of the composition or method described in the present specification can be combined in various ways without departing from the spirit and scope of the present invention, whether explicitly or implicitly disclosed in the present specification. It should be understood that the elements and / or features of the composition or method described in the present specification can be combined in various ways without departing from the spirit and scope of the present invention, whether explicitly or implicitly disclosed in the present specification. For example, when a particular compound is mentioned, the compound can be used in various embodiments of the composition of the present invention and / or in the method of the present invention, unless otherwise understood from the context. It should be understood that when a particular compound is mentioned, the compound can be used in various embodiments of the composition of the present invention and / or in the method of the present invention, unless otherwise understood from the context. It should be understood that when a particular compound is mentioned, the compound can be used in various embodiments of the composition of the present invention and / or in the method of the present invention, unless otherwise understood from the context. In other words, in the present application, the embodiments are described and presented as clearly and concisely as possible for the application, but the embodiments are intended to be combinable or separable in various ways without departing from the teachings of the present invention and the present invention, and it will be understood. In other words, in the present application, the embodiments are described and presented as clearly and concisely as possible for the application, but the embodiments are intended to be combinable or separable in various ways without departing from the teachings of the present invention and the present invention, and it will be understood. In other words, in the present application, the embodiments are described and presented as clearly and concisely as possible for the application, but the embodiments are intended to be combinable or separable in various ways without departing from the teachings of the present invention and the present invention, and it will be understood. It will be understood. For example, it will be understood that all the features described and presented in the present specification can be applicable to all aspects of the present invention described and presented in the present specification. It will be understood that all the features described and presented in the present specification can be applicable to all aspects of the present invention described and presented in the present specification. It will be understood.

[0026] The articles "a" and "an" are used unless the context is inappropriate. Refers to one or to more than one (i.e., at least one) of the grammatical object of the article By way of example, "an element" refers to one element or one It means the element that transcends.

[0027] The term "and / or" means "and" or "or" unless otherwise indicated. It is used in this disclosure to refer to taste.

[0028] The phrase "at least one" is used unless otherwise understood from context and usage. Each of the objects listed after the term and two or more species of the objects listed It should be understood that each of the above-mentioned embodiments individually includes each of the above-mentioned combinations. The phrase "and / or" has the same meaning, unless otherwise understood from the context. It should be understood that

[0029] The terms "include", "includes", "inclusion" and " "cluding", "have", "has", "having having," "contain," "contains The use of "containing" includes its grammatical equivalents. Therefore, the present disclosure should generally be understood as open-ended and non-limiting, e.g. Unless expressly stated or understood from the context, additional enumerations are not included. It does not exclude elements or steps that are not included in the specification.

[0030] When the term "about" is used before a quantitative value, the invention also relates to the extent that is so expressly stated. Unless otherwise excluded, it includes the value itself for a specific quantity. As used herein the term "about" refers to a variation of ± 10% from the reference value, unless otherwise indicated or inferred from the context is excluded.

[0031] At various places herein, variables or parameters are disclosed in groups or ranges . It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges . For example, integers in the range of 0 to 40 are specifically intended to disclose 0, 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40 individually, and integers in the range of 1 to 20 are specifically intended to disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 1 2, 13, 14, 15, 16, 17, 18, 19, and 20 individually .

[0032] Any and all examples or exemplary language herein, such as "such as" or "including", is intended only to more appropriately illustrate the invention and is not intended to limit the scope of the invention, unless specifically claimed . No language in the specification should be construed as indicating any unclaimed element as essential to the practice of the invention .

[0033] As a general matter, compositions specifying percentages are by weight, unless otherwise specified . Further, where a variable is not accompanied by a definition, the variable cont The above definition for roll applies.

[0034] As used herein, "pharmaceutical composition" or "pharmaceutical formulation" refers to a composition that renders a combination of an active agent with an inert or active carrier particularly suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0035] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government or the corresponding agency in countries outside the United States or an agency listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, more particularly in humans.

[0036] As used herein, "pharmaceutically acceptable salt" refers to any salt of an acidic or basic group that may be present in a compound of the invention (e.g., infliximab), and this salt is compatible with the administration of the medicine.

[0037] As is known to those skilled in the art, "salts" of a compound may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, mandelic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Other acids, such as oxalic acid, are not pharmaceutically acceptable per se but are intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts. It may also be used in the preparation of useful salts.

[0038] Examples of bases include alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of the formula NW4 where W is C 1~4 alkyl, and the like, but are not limited thereto. + not limited to these.

[0039] Examples of salts include acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, peroxosulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like, but are not limited thereto. Other examples of salts include suitable cations such as Na and the like, but are not limited thereto. Other examples of salts include suitable cations such as Na + + 2+ + + 1~4 alkyl group), and the like. It contains an anion of the compound of the present invention mixed with that of

[0040] For therapeutic use, salts of the compounds of the present invention are assumed to be pharmaceutically acceptable . However, salts of pharmaceutically unacceptable acids and bases may also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0041] As used herein, "pharmaceutically acceptable excipient" refers to a substance that aids in the administration of the active agent to a subject and / or its absorption by the subject, and can be included in the compositions of the present invention without causing a serious and harmful toxic effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, physiological saline such as NaCl, phosphate-buffered saline, emulsions (such as oil / water or water / oil emulsions), lactated Ringer's solution, physiological sucrose, physiological glucose, binders, bulking agents, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions ( such as Ringer's solution), alcohols, oils, gelatin, lactose, amylose, or carbohydrates such as dextrin, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents and other similar ones. Such preparations can be sterilized and, if desired, mixed with auxiliaries such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts that affect osmotic pressure, buffers, coloring agents, and / or aromatic substances and other similar ones that do not react detrimentally with the compounds of the present invention. For examples of excipients, see Martin, Remington’s Phar macology, stabilizers, wetting agents, emulsifying agents, salts that affect osmotic pressure, buffers, coloring agents, and / or aromatic substances and other similar ones that do not react detrimentally with the compounds of the present invention. For examples of excipients, see Martin, Remington’s Phar macology, Mack Publ., 15th Ed., Pharmaceutical Sciences See Co., Easton, PA (1975).

[0042] The term "AUC" refers to the area under the time / plasma concentration curve after administration of a pharmaceutical composition. AUC 0-infinity represents the area under the plasma concentration vs. time curve from 0 hours to infinity ; AUC 0-t represents the area under the plasma concentration vs. time curve from 0 hours to t hours. A UC values can be determined by methods known in the art, as should be understood.

[0043] The "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, toddlers, youths) or adult subjects (e.g., young adults, middle-aged, or elderly)) and / or non-human animals, such as mammals including primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0044] The term "C max " refers to the maximum concentration of a therapeutic agent (e.g., infigratinib) in blood (e.g., plasma) after administration of a pharmaceutical composition.

[0045] The term "t max " refers to the time when C is reached after administration of a pharmaceutical composition containing a therapeutic agent (e.g., infigratinib). max

[0046] As used herein, "solid dosage form" refers to a solid form, such as tablets, capsules​​​​​​​​ in the form of tablets, granules, powders, capsules, reconstitutable powders, dry powder inhalers, and chewable tablets refers to the dosage of the medicament thus formulated.

[0047] As used herein, "administering" includes oral administration to a subject, administration by suppository and the like, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration , intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration or implantation of a sustained release device, e.g., a mini osmotic pump. Administration can be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal , gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, arterial, intradermal, subcutaneous, intraperitoneal, intracerebroventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous drip, transdermal patches, etc. "Co-administration" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies (e.g., anti-cancer agents, chemotherapeutic agents, or treatments for neurodegenerative diseases). Infliximab or a pharmaceutically acceptable salt thereof can be administered to a patient alone or can be co-administered . Co-administration means the simultaneous or sequential administration of the compound, individually or in combination (more than one compound or drug), and thus the preparation can also, if desired, be combined with other active substances (e.g., for reducing degradation by metabolism). The terms "disease", "disorder" and "condition" are used interchangeably herein.

[0048] The terms "disease", "disorder" and "condition" are used herein without distinction.

[0049] As used herein, unless otherwise specified, the terms "treat", "treating", and "treatment" are used during a subject's affliction with a particular disease, disorder, or condition, and contemplate an activity (e.g., a "therapeutic treatment") that reduces the severity of the disease, disorder, or condition or delays or retards the progression of the disease, disorder, or condition. In general, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response, e.g., to treat cholangiocarcinoma. As will be appreciated by those skilled in the art, the effective amount of a compound of the present disclosure may vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and factors such as the age, weight, health, and condition of the subject.

[0050]

[0051] Infigratinib Infigratinib, represented by formula (I), is a selective and ATP-competitive pan-fibroblast growth factor receptor (FGFR) kinase inhibitor also known as 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4-ethyl-1-piperazin-1-yl)phenylamino]-pyrimidin-4-yl}-1-methylurea. Infigratinib selectively inhibits the kinase activities of FGFR1, FGFR2, and FGFR3. JPEG2025106456000001.jpg37170

[0052] Methods for chemically synthesizing infigratinib (including Example 1 provided herein), several crystalline and amorphous forms of infigratinib (as provided herein) ​​​​​​​​​​​​​(including the anhydrous crystalline monophosphate described therein), and a method for preparing said form (including Example 2 provided in this specification) are described in U.S. Patent No. 9,067,896, which is hereby incorporated by reference in its entirety. including Example 2 provided in this specification) are described in U.S. Patent No. 9,067,896, which is hereby incorporated by reference in its entirety.

[0053] In one aspect, infigratinib or a pharmaceutically acceptable salt thereof is provided herein for use in treating patients in need thereof suffering from advanced or metastatic cholangiocarcinoma. In some embodiments, a pharmaceutically acceptable salt of infigratinib for use in treating patients in need thereof suffering from advanced or metastatic cholangiocarcinoma is provided herein.

[0054] In certain embodiments, a pharmaceutically acceptable salt of infigratinib for use in treating patients in need thereof suffering from advanced or metastatic cholangiocarcinoma is provided herein. In some embodiments, the pharmaceutically acceptable salt of infigratinib is a monophosphate. The monophosphate of infigratinib may also be referred to as BGJ398. In some embodiments, the pharmaceutically acceptable salt of infigratinib is an anhydrous crystalline monophosphate. In some embodiments, the anhydrous crystalline monophosphate has a powder X-ray diffraction (XRPD) pattern comprising characteristic peaks at about 15.0° or 15.0° ± 0.2° with respect to 2θ.

[0055] In some embodiments, the powder X-ray diffraction pattern of the anhydrous crystalline monophosphate further comprises one or more characteristic peaks at 2θ selected from the peaks at about 13.7° ± 0.2°, about 16.8° ± 0.2°, about 21.3° ± 0.2°, and about 22.4° ± 0.2°. In some embodiments, the powder X-ray diffraction pattern of the anhydrous crystalline monophosphate further comprises peaks at about 9.2°, about 9.6°, about 18.7°, about 20.0°, about 22.9°, and about 27.2°. In some embodiments, the powder X-ray diffraction pattern of the anhydrous crystalline monophosphate has characteristic peaks at about 15.0° or 15.0° ± 0.2° with respect to 2θ. In some embodiments, the powder X-ray diffraction pattern of the anhydrous crystalline monophosphate further comprises one or more characteristic peaks at 2θ selected from the peaks at about 13.7° ± 0.2°, about 16.8° ± 0.2°, about 21.3° ± 0.2°, and about 22.4° ± 0.2°. In some embodiments, the powder X-ray diffraction pattern of the anhydrous crystalline monophosphate further comprises peaks at about 9.2°, about 9.6°, about 18.7°, about 20.0°, about 22.9°, and about 27.2°. In some embodiments, the powder X-ray diffraction pattern of the anhydrous crystalline monophosphate further comprises one or more characteristic peaks at 2θ selected from the peaks at about 13.7° ± 0.2°, about 16.8° ± 0.2°, about 21.3° ± 0.2°, and about 22.4° ± 0.2°. In some embodiments, the powder X-ray diffraction pattern of the anhydrous crystalline monophosphate further comprises peaks at about 9.2°, about 9.6°, about 18.7°, about 20.0°, about 22.9°, and about 27.2°. In some embodiments, the powder X-ray diffraction pattern of the anhydrous crystalline monophosphate further comprises peaks at about 9.2°, about 9.6°, about 18.7°, about 20.0°, about 22.9°, and about 27.2°. Further includes one or more characteristic peaks related to 2θ selected from K. In some examples In embodiments, the anhydrous crystalline monophosphate is about 13.7°, about 15°, about 16.8, about 21.3 °, and at least three characteristic peaks related to 2θ selected from the peaks of about 22.4° Has an XRPD pattern containing peaks. In some embodiments, the anhydrous crystalline monophosphate The powder X-ray diffraction pattern for may be about 9.2°, about 9.6°, about 13.7°, about 15° , about 16.8°, about 18.7°, about 20.0°, about 21.3° and about 22.4°, about 22 .9°, and one, two, three, four, five, Six, seven, eight, nine, ten, or eleven characteristic peaks related to 2θ selected from the peaks of about 27.2 may be included.

[0056] Pharmaceutical composition The pharmaceutical composition of infigratinib and methods for preparing said pharmaceutical composition (e.g., Including Example 3 described herein) are described in U.S. Patent Application Publication No. 2017 / 000 No. 7602, which is incorporated herein by reference in its entirety .

[0057] In one aspect, for use in treating patients in need thereof with advanced or metastatic cholangiocarcinoma, A pharmaceutical composition comprising infigratinib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient Is provided herein.

[0058] In certain embodiments, the pharmaceutical composition of the teachings of the present invention (a) About 20% to about 60% by weight of infigratinib or Its pharmaceutically acceptable salts in its free base form; (b) About 0.5% to about 5% by weight of hydroxypropyl methylcellulose; (c) about 1 wt% to about 4 wt% of crosslinked polyvinylpyrrolidone; and (d) a bulking agent selected from the group consisting of cellulose, lactose, mannitol, and combinations thereof; and the weight percentages are based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises, in its free base form, about 30% to about 45

[0059] % by weight of infliximab or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises about 2% to about 4% hydroxypropylmethylcellulose

[0060] . In certain embodiments, the pharmaceutical composition comprises about 2% to about 4% crosslinked polyvinylpyrrolidone . In certain embodiments, the pharmaceutical composition comprises:

[0061] (e) one or more bulking agents in an amount of about 10% to about 95% by weight, based on the total weight of the pharmaceutical composition ; (f) one or more lubricants in an amount of about 0.1% to about 3% by weight, based on the total weight of the pharmaceutical composition ; and (g) one or more glidants in an amount of about 0.1% to about 2% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the one or more bulking agents are selected from the group consisting of crystalline cellulose, lactose, and / or mannitol. In certain embodiments, the one or more lubricants are present in an amount of about 0.2% to about 2% by weight, based on the total weight of the pharmaceutical composition. In some embodiments, the one or more lubricants are magnesium stearate.

[0062]

[0063]

[0064] ​​​​​In certain embodiments, one or more glidants are present in the pharmaceutical formulation in an amount of about 0.1% to about 0.5% by weight, based on the total weight of the pharmaceutical composition. In some embodiments, one or more glidants are colloidal silicon dioxide (colloidal silica).

[0065] In certain embodiments, the amount of infliximab or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 25 mg to about 150 mg, about 50 mg to about 150 mg, about 75 mg to about 150 mg, about 100 mg to about 150 mg, about 125 mg to about 150 mg, about 25 mg to about 12 5 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 25 mg to about 50 mg , about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 50 mg to about 75 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, or about 100 mg to about 125 mg . In some embodiments, the amount of infliximab or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 100 mg to about 150 mg of infliximab or a pharmaceutically acceptable salt thereof.

[0066] In certain embodiments, the amount of infliximab or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg. In some embodiments, the amount of infliximab or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 125 mg. In some embodiments, the amount of infliximab or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 100 mg. In some embodiments, the amount of infliximab or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 25 mg.

[0067] In another aspect, for use in treating patients in need thereof with advanced or metastatic cholangiocarcinoma , a pharmaceutical composition comprising about 125 mg of infigratinib or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient is provided herein.

[0068] In certain embodiments, the pharmaceutical composition comprises an effective amount of a pharmaceutically acceptable salt of infigratinib. In some embodiments, the pharmaceutically acceptable salt of infigratinib is a phosphate. In some embodiments, the pharmaceutically acceptable salt of infigratinib is a monophosphate anhydrate. In some embodiments, the pharmaceutically acceptable salt of infigratinib is a monophosphate anhydrate having a polymorphic form characterized by a powder X-ray diffraction (XRPD) peak (2θ) at 15.0° ± 0.2° (and may include other XRPD peaks for this form as described herein).

[0069] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. In some embodiments, the pharmaceutical compositions disclosed herein are administered orally.

[0070] The pharmaceutical compositions provided herein may also be administered over a long period of time ( " extended administration"). Extended administration is over a long period of time, e.g., for example, 3 months, 6 months, 1 year, 2 ​​Refers to the administration of a compound or its pharmaceutical composition over a period of, for example, 1 year, 3 years, 5 years, etc., or indefinitely, e.g., May be continued throughout the life of the subject. In certain embodiments, long-term administration is intended to provide a constant level of the compound, e.g., within the therapeutic concentration range, in the blood over an extended period.

[0071] The pharmaceutical compositions provided herein may be presented in unit dosage form to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as a single dosage for human subjects and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical carrier. Typical unit dosage forms include pre-measured ampoules or syringes filled with liquid compositions or, in the case of solid compositions, tablets, pills, capsules, or other similar articles. Included.

[0072] In certain embodiments, the pharmaceutical compositions provided herein are administered to a patient as solid dosage forms. In some embodiments, the solid dosage form is a capsule.

[0073] In certain embodiments, the compounds provided herein can be administered as the sole active agent or they can be administered in combination with other active agents.

[0074] The description of the pharmaceutical compositions provided herein relates primarily to pharmaceutical compositions suitable for administration to humans, but it will be understood by those skilled in the art that such compositions are generally suitable for administration to animals of all kinds. The compositions can be Modifications of pharmaceutical compositions suitable for administration to humans, in order to render them suitable, are well understood and can be designed and / or effected by a routine skilled veterinary pharmacologist using routine experimental methods. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 ed., Lippincott Williams st & Wilkins, 2005.

[0075] Methods of Use and Treatment Cholangiocarcinoma is a rare and heterogeneous malignant disease that results from the malignant transformation of cholangiocytes into intrahepatic, perihilar, or distal extrahepatic tumors (Alpini et al., 2001 ).

[0076] In one aspect, a method for treating cholangiocarcinoma in a patient in need thereof is provided herein . In certain embodiments, the cholangiocarcinoma is advanced or metastatic cholangiocarcinoma. In certain embodiments, the patient has had cholangiocarcinoma progress after prior administration of another therapy

[0077] In certain embodiments, a method for treating advanced or metastatic cholangiocarcinoma in a patient in need thereof, comprising: administering an effective amount of infigratinib or a pharmaceutically acceptable salt thereof , wherein the patient has had cholangiocarcinoma progress after prior administration of another therapy, is provided herein .

[0078] In certain embodiments, the prior other therapy is a therapy for treating advanced or metastatic cholangiocarcinoma. In some embodiments, the prior other therapy is administration of a chemotherapeutic agent It is. In some embodiments, the previously administered chemotherapeutic agent is by a treatment method containing gemcitabine such. In some embodiments, the treatment method containing gemcitabine includes gemcitabine. In some embodiments, the treatment method containing gemcitabine is including gemcitabine and cisplatin.

[0079] In certain embodiments, another previously administered therapy is 5-fluorouracil, gemcitabine , cisplatin, capecitabine, oxaliplatin, and combinations thereof selected from the group consisting of the administration of another chemotherapeutic agent.

[0080] In certain embodiments, another previously administered therapy is the administration of a receptor tyrosine kinase inhibitor .

[0081] In certain embodiments, the receptor tyrosine kinase inhibitor is a selective non-covalent inhibitor of FGFR1, FGFR2 and / or FGFR3. In some embodiments, FGFR1 , the selective non-covalent inhibitor of FGFR2 and / or FGFR3 is pemigatinib, rogaratinib , derazantinib, Debio1347, AZD4547 and combinations thereof selected from the group consisting of.

[0082] In certain embodiments, the receptor tyrosine kinase inhibitor is a selective non-covalent inhibitor of FGFR1, FGFR2, FG FR3 and / or FGFR4. In some embodiments , the selective non-covalent inhibitor of FGFR1, FGFR2, FGFR3 and / or FGFR4 is erdafitinib, LY2874455, PRN 1371, ASP5878 and combinations thereof selected from the group consisting of.

[0083] In certain embodiments, the receptor tyrosine kinase inhibitor is a selective covalent inhibitor of FGFR1, FGFR2, FG FR3 and / or FGFR4. In some embodiments, the selective covalent inhibitor of FGFR1, FGFR2, FGFR3, and / or FGFR4 is , TAS120.

[0084] In certain embodiments, the receptor tyrosine kinase inhibitor is a non-selective tyrosine kinase inhibitor . In some embodiments, the non-selective tyrosine kinase inhibitor is ponatinib, dovitinib, lenvatinib, ACTB-1003, Ki8751, lucitanib, masitinib , mubritinib, nintedanib, orantinib, PD089828, and combinations thereof, selected from the group consisting of.

[0085] In certain embodiments, a previously administered different therapy is the administration of a different selective FGFR inhibitor . In some embodiments, the different selective FGFR inhibitor is pemigatinib, rogaratinib , derazantinib, AZD4547, Debio1347, ASP5878, erdafitinib , LY2874455, PRN1371, TAS120, and combinations thereof, selected from the group consisting of. In some embodiments, the different selective FGFR inhibitor is a selective covalent inhibitor. In some embodiments, the selective covalent inhibitor is TAS1 20. In some embodiments, the different selective FGFR inhibitor is a selective non-covalent inhibitor. In some embodiments, the selective non-covalent inhibitor is pemigatinib, rogaratinib , derazantinib, AZD4547, and combinations thereof.

[0086] In certain embodiments, cholangiocarcinoma has an FGFR1 gene fusion, translocation, or another genetic alteration. In some embodiments, the FGFR1 gene fusion includes an FGFR1 gene fusion partner selected from the group consisting of BAG4, ERLIN2, N TM, FGFR1OP2, TACC3, and TRP.

[0087] In certain embodiments, cholangiocarcinoma has an FGFR2 gene fusion, translocation, or another genetic alteration. In some embodiments, the FGFR2 gene fusion includes an FGFR2 gene fusion partner selected from the group consisting of 10Q26.13, AFF1 , AFF3, AFF4, AHCYL1, ALDH1L2, ARFIP1, BAG4, BA IAP2L1, BICC1, C10orf118, C10orf68, C7, CASC1 5, CASP7, CCDC147, CCDC6, CELF2, CIT, COL14A1, CREB5, CREM, DNAJC12, ERLIN2, HOOK1, INA, KCTD 1, KIAA1217, KIAA1598, KIAA1967, KIFC3, MGEA5 , NCALD, NOL4, NPM1, NRAP, OFD1, OPTN, PARK2, PA WR, PCMI, PDHX, PHLDB2, PPAPDC1A, PPHLN1, RASA L2, SFMBT2, SLC45A3, SLMAP, SLMAP2, SORBS1, ST K26, STK3, TACC1, TACC2, TACC3, TBC1D1, TEL, TF EC, TRA2B, UBQLN1, VCL, WAC, ZMYM4, and FGFROP2. In some embodiments, the FGFR2 gene fusion includes an FGFR2 gene fusion partner selected from the group consisting of 10Q26.13, AFF1, AFF4, AHCYL1, ALDH1L2, ARFIP1, BICC1, C10orf118, C7, CCDC14 ​ 7, CCDC6, CELF2, CREB5, CREM, DNAJC12, HOOK1, K CTD1, KIAA1217, KIAA1598, KIFC3, MGEA5, NOL4, NRAP, OPTN, PARK2, PAWR, PCMI, PHLDB2, PPHLN1, RASAL2, SFMBT2, SLMAP, SLMAP2, SORBS1, STK26, STK3, TACC3, TBC1D1, TFEC, TRA2B, UBQLN1, VCL, comprising an FGFR2 gene fusion partner selected from the group consisting of WAC, and ZMYM4 and.

[0088] In certain embodiments, cholangiocarcinoma has an FGFR3 gene fusion, translocation, or other genetic change to do. In some embodiments, the FGFR3 gene fusion is BAIAP2L1, JAKM IP1, TACC3, TNIP2, and an FGFR2 selected from the group consisting of WHSC1 gene fusion partner. In some embodiments, the FGFR3 gene fusion comprises an FG FR3 gene fusion partner, and the FGFR gene fusion partner is TACC3 is.

[0089] In certain embodiments, a patient determines whether cholangiocarcinoma has an FGFR1, FGFR2, or FGFR3 gene fusion, translocation, or other genetic change, e.g., next-generation sequencing, circulating tumor DNA analysis, or fluorescence emission in situ hybridization assay. In some embodiments, the molecular pre-screening is performed prior to administration of an effective amount of infigratinib or a pharmaceutically acceptable salt thereof be. In some embodiments, the molecular pre-screening is prior to another therapy It is given prior to the previous administration.

[0090] In one embodiment, the cholangiocarcinoma is characterized by FGFR1, FGFR2, and / or FGFR3 mutations. In some embodiments, FGFR1, FGFR 2 and / or FGFR3 The mutations were FGFR1 G818R, FGFR1 K656E, and FGFR1 N546 K, FGFR1 R445W, FGFR1 T141R, FGFR2 A315T, FG FR2 C382R, FGFR2 D336N, FGFR2 D471N, FGFR2 E565A, FGFR2 I547V, FGFR2 K641R, FGFR2 K659 E, FGFR2 K659M, FGFR2 L617V, FGFR2 N549H, FG FR2 N549K, FGFR2 N549S, FGFR2 N549Y, FGFR2 N550K, FGFR2 P253R, FGFR2 S252W, FGFR2 V395 D, FGFR2 V564F, FGFR2 Y375C, FGFR3 A391E, FG FR3 D785Y, FGFR3 E627K, FGFR3 G370C, FGFR3 G380R, FGFR3 K650E, FGFR3 K650M, FGFR3 K650 N, FGFR3 K650T, FGFR3 K652E, FGFR3 N540S, FG FR3 R248C, FGFR3 R399C, FGFR3 S131L, FGFR3 S249C, FGFR3 S371C, FGFR3 V555M, FGFR3 V677 I, FGFR3 Y373C, FGFR4 D425N, FGFR4 R183S, FG FR4 R394Q, FGFR4 R610H, FGFR4 V510L, and combinations thereof In some embodiments, the FGFR1, FGFR2, and / or FGFR3 mutations are selected from the group consisting of FGFR1 N546K, FGFR1 K656E, FGFR2 S252W, FGFR2 P253R, FGFR2 A315T, FGFR 2 Y375C, FGFR2 C382R, FGFR2 N549K, FGFR2 K6 59E, FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR3 S371C, FGFR3 Y373C, FGFR3 G380R, FGFR 3 K650E, FGFR3 K650M, and combinations thereof.

[0091] In certain embodiments, cholangiocarcinoma has an FGFR1 gene fusion and an FGFR1 mutation In certain embodiments, cholangiocarcinoma has an FGFR1 gene fusion and an FGFR2 mutation In certain embodiments, cholangiocarcinoma has an FGFR1 gene fusion and an FGFR3 mutation

[0092] In certain embodiments, cholangiocarcinoma has an FGFR2 gene fusion and an FGFR1 mutation In certain embodiments, cholangiocarcinoma has an FGFR2 gene fusion and an FGFR2 mutation In certain embodiments, cholangiocarcinoma has an FGFR2 gene fusion and an FGFR3 mutation

[0093] In certain embodiments, cholangiocarcinoma has an FGFR3 gene fusion and an FGFR1 mutation In certain embodiments, cholangiocarcinoma has an FGFR3 gene fusion and an FGFR2 mutation In certain embodiments, cholangiocarcinoma has an FGFR3 gene fusion and an FGFR3 mutation

[0094] In certain embodiments, cholangiocarcinoma has amplification of FGFR1, FGFR2, and / or FGFR3​​​​ has.

[0095] In certain embodiments, administering an effective amount of infliximab or a pharmaceutically acceptable salt thereof comprises administering about 125 mg of infliximab or a pharmaceutically acceptable salt thereof. comprises.

[0096] In certain embodiments, an effective amount of infliximab or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

[0097] In certain embodiments, an effective amount of infliximab or a pharmaceutically acceptable salt thereof is administered orally to the patient.

[0098] In certain embodiments, administering an effective amount of infliximab or a pharmaceutically acceptable salt thereof comprises orally administering about 25 mg of infliximab or a pharmaceutically acceptable salt thereof once daily.

[0099] In certain embodiments, administering an effective amount of infliximab or a pharmaceutically acceptable salt thereof comprises orally administering about 50 mg of infliximab or a pharmaceutically acceptable salt thereof once daily.

[0100] In certain embodiments, administering an effective amount of infliximab or a pharmaceutically acceptable salt thereof comprises orally administering about 75 mg of infliximab or a pharmaceutically acceptable salt thereof once daily.

[0101] In certain embodiments, administering an effective amount of infliximab or a pharmaceutically acceptable salt thereof comprises orally administering about 100 mg of infliximab or a pharmaceutically acceptable salt thereof once daily.

[0102] In certain embodiments, administering an effective amount of infliximab or a pharmaceutically acceptable salt thereof comprises orally administering about 125 mg of infliximab or a pharmaceutically acceptable salt thereof once daily.

[0103] In certain embodiments, administering an effective amount of infliximab or a pharmaceutically acceptable salt thereof comprises a 28-day cycle in which about 25 mg of infliximab or a pharmaceutically acceptable salt thereof is administered to the patient once daily for 3 consecutive weeks (21 days), followed by infliximab not being administered for 1 week (7 days).

[0104] In certain embodiments, administering an effective amount of infliximab or a pharmaceutically acceptable salt thereof comprises a 28-day cycle in which about 50 mg of infliximab or a pharmaceutically acceptable salt thereof is administered to the patient once daily for 3 consecutive weeks (21 days), followed by infliximab not being administered for 1 week (7 days).

[0105] In certain embodiments, administering an effective amount of infliximab or a pharmaceutically acceptable salt thereof comprises a 28-day cycle in which about 75 mg of infliximab or a pharmaceutically acceptable salt thereof is administered to the patient once daily for 3 consecutive weeks (21 days), followed by infliximab not being administered for 1 week (7 days).

[0106] In certain embodiments, administering an effective amount of infliximab or a pharmaceutically acceptable salt thereof comprises a 28-day cycle in which about 100 mg of infliximab or a pharmaceutically acceptable salt thereof is administered to the patient once daily for 3 consecutive weeks (21 days), followed by Figratinib is not administered for one week (7 days).

[0107] In certain embodiments, administration of an effective amount of figratinib or a pharmaceutically acceptable salt thereof comprises a 28-day cycle and about 125 mg of figratinib or a pharmaceutically acceptable salt thereof is administered to the patient once daily for 3 consecutive weeks (21 days), followed by a week during which figratinib is not administered.

[0108] In certain embodiments, an effective amount of figratinib or a pharmaceutically acceptable salt thereof is administered to the patient during 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive 28-day cycles.

[0109] In certain embodiments, about 125 mg of figratinib or a pharmaceutically acceptable salt thereof is provided as a unit dose. In certain embodiments, about 100 mg of figratinib or a pharmaceutically acceptable salt thereof is provided as a unit dose. In certain embodiments, about 7 5 mg of figratinib or a pharmaceutically acceptable salt thereof is provided as a unit dose . In certain embodiments, about 50 mg of figratinib or a pharmaceutically acceptable salt thereof is provided as a unit dose. In certain embodiments, about 25 mg of figratinib or a pharmaceutically acceptable salt thereof is provided as a unit dose.

[0110] In some embodiments, about 125 mg of figratinib or a pharmaceutically acceptable salt thereof is provided as a unit dose. In some embodiments, about 125 mg of figratinib or a pharmaceutically acceptable salt thereof is provided as a unit dose of 100 mg and 25 mg single ​is provided as a unit dose. In some embodiments, about 125 mg of infigratinib or a pharmaceutically acceptable salt thereof is provided as unit doses of 75 mg and 50 mg respectively.

[0111] In certain embodiments, about 100 mg of infigratinib or a pharmaceutically acceptable salt thereof is provided as unit doses of 75 mg and 25 mg. In some embodiments about 100 mg of infigratinib or a pharmaceutically acceptable salt thereof is provided as two 50 mg unit doses.

[0112] In certain embodiments, about 75 mg of infigratinib or a pharmaceutically acceptable salt thereof is provided as unit doses of 50 mg and 25 mg.

[0113] In certain embodiments, about 50 mg of infigratinib or a pharmaceutically acceptable salt thereof is provided as two 25 mg unit doses.

[0114] In certain embodiments, about 125 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered orally to a patient. In certain embodiments, about 100 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered orally to a patient. In certain embodiments, about 75 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered orally to a patient. In certain embodiments, about 50 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered orally to a patient. In certain embodiments, about 25 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered orally to a patient.

[0115] In some embodiments, the method comprises administering to a subject an effective amount of infigratinib or a pharma- ceutical acceptable salt thereof. The method further includes administering the salt to a patient in need thereof on an empty stomach. In embodiments, an effective amount of infigratinib or a pharma- ceutical acceptable salt thereof is administered to a patient in a diet. It should be administered to patients who need it at least one hour before taking In some embodiments, an effective amount of infigratinib or a pharma- ceutical acceptable salt thereof is administered to a patient. should be administered to patients in need thereof at least 2 hours after ingestion of food.

[0116] In some embodiments, advanced or metastatic cholangiocarcinoma is histologically or cytologically confirmed. In some embodiments, the advanced or metastatic cholangiocarcinoma is histologically confirmed. In embodiments, advanced or metastatic cholangiocarcinoma is cytologically confirmed.

[0117] In certain embodiments, the method includes administering an effective amount of a pharma- ceutically acceptable salt of infigratinib to a patient. In some embodiments, infigratinib is administered to a patient in need thereof. A pharma- ceutically acceptable salt of is a monophosphate. A pharma- ceutically acceptable salt of tinib is the anhydrous monophosphate salt. The pharma- ceutical acceptable salts of nigratinib have a powder X-ray diffraction (XRD) of 15.0°±0.2°. It is the anhydrous monophosphate salt in a polymorphic form characterized by RPD peaks (2θ). In some embodiments, the polymorphic form of the anhydrous crystalline monophosphate salt of infigratinib is This is described in the subsection.

[0118] In another aspect, the present invention provides a method for treating advanced or metastatic cholangiocarcinoma in a patient in need thereof. A method comprising administering any one of the pharmaceutical compositions disclosed herein, wherein the patient has had cholangiocarcinoma progress after having previously received another therapy, is provided herein. For a more complete understanding of the disclosure described herein, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should in no way be construed as limiting their scope. Example 1: Synthesis of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-4-

Example

[0119] (4-ethyl-piperazin-1-yl)-phenylamino}-pyrimidin-4-yl}-1-methyl-urea (infigratinib) Step A: Synthesis of N-4-(4-ethyl-piperazin-1-yl)-phenyl)-N'-methyl-pyrimidine-4,6-diamine A mixture of 4-(4-ethylpiperazin-1-yl)-aniline (1 g, 4.88 mmol), (6-chloro-pyrimidin-4-yl)-methyl-amine (1. 81 g, 12.68 mmol, 1.3 eq.), and 4 N HCl in dioxane (15 mL) is heated in a sealed tube to 150 °C for 5 hours. The reaction mixture is concentrated and diluted with dichloromethane (DCM) and saturated aqueous sodium bicarbonate. The aqueous layer is separated with DCM and extracted. The organic phase is washed with brine, dried (sodium sulfate), filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH, 93:7).

[0120] (4-ethyl-piperazin-1-yl)-phenylamino}-pyrimidin-4-yl}-1-methyl-urea (infigratinib) -1-methyl-urea (infigratinib) Step A: Synthesis of N-4-(4-ethyl-piperazin-1-yl)-phenyl)-N'-methyl-pyrimidine-4,6-diamine A mixture of 4-(4-ethylpiperazin-1-yl)-aniline (1 g, 4.88 mmol), (6-chloro-pyrimidin-4-yl)-methyl-amine (1. 81 g, 12.68 mmol, 1.3 eq.), and 4 N HCl in dioxane (15 mL) is heated in a sealed tube to 150 °C for 5 hours. The reaction mixture is concentrated and diluted with dichloromethane (DCM) and saturated aqueous sodium bicarbonate. The aqueous layer is separated with DCM and extracted. The organic phase is washed with brine, dried (sodium sulfate), filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH, 93:7). 81 g, 12.68 mmol, 1.3 eq.), and 4 N HCl in dioxane (15 mL) is heated in a sealed tube to 150 °C for 5 hours. The reaction mixture is concentrated and diluted with dichloromethane (DCM) and saturated aqueous sodium bicarbonate. The aqueous layer is separated with DCM and extracted. The organic phase is washed with brine, dried (sodium sulfate), filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH, 93:7). 81 g, 12.68 mmol, 1.3 eq.), and 4 N HCl in dioxane (15 mL) is heated in a sealed tube to 150 °C for 5 hours. The reaction mixture is concentrated and diluted with dichloromethane (DCM) and saturated aqueous sodium bicarbonate. The aqueous layer is separated with DCM and extracted. The organic phase is washed with brine, dried (sodium sulfate), filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH, 93:7). 81 g, 12.68 mmol, 1.3 eq.), and 4 N HCl in dioxane (15 mL) is heated in a sealed tube to 150 °C for 5 hours. The reaction mixture is concentrated and diluted with dichloromethane (DCM) and saturated aqueous sodium bicarbonate. The aqueous layer is separated with DCM and extracted. The organic phase is washed with brine, dried (sodium sulfate), filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH, 93:7). 81 g, 12.68 mmol, 1.3 eq.), and 4 N HCl in dioxane (15 mL) is heated in a sealed tube to 150 °C for 5 hours. The reaction mixture is concentrated and diluted with dichloromethane (DCM) and saturated aqueous sodium bicarbonate. The aqueous layer is separated with DCM and extracted. The organic phase is washed with brine, dried (sodium sulfate), filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH, 93:7). 81 g, 12.68 mmol, 1.3 eq.), and 4 N HCl in dioxane (15 mL) is heated in a sealed tube to 150 °C for 5 hours. The reaction mixture is concentrated and diluted with dichloromethane (DCM) and saturated aqueous sodium bicarbonate. The aqueous layer is separated with DCM and extracted. The organic phase is washed with brine, dried (sodium sulfate), filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH, 93:7). 81 g, 12.68 mmol, 1.3 eq.), and 4 N HCl in dioxane (15 mL) is heated in a sealed tube to 150 °C for 5 hours. The reaction mixture is concentrated and diluted with dichloromethane (DCM) and saturated aqueous sodium bicarbonate. The aqueous layer is separated with DCM and extracted. The organic phase is washed with brine, dried (sodium sulfate), filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH, 93:7). Purify it, then triturate in diethyl ether to obtain the titled compound as a white solid: ESI-MS: 313.2 [MH] ; t + ; t R = 1.10 min (gradient J); TLC C: R f = 0.21 (DCM / MeOH, 93:7).

[0121] Step B: Synthesis of 4-(4-ethylpiperazin-1-yl)-aniline A suspension of 1-ethyl-4-(4-nitro-phenyl)-piperazine ( 6.2 g, 26.35 mmol) and Raney nickel (2 g) in MeOH (120 mL) is stirred at RT for 7 h under a hydrogen atmosphere . The reaction mixture is filtered through a pad of Celite, concentrated, and 5.3 g of the titled compound is obtained as a purple solid: ESI-MS: 206.1 [MH] ; T + ; T LC: R f = 0.15 (DCM / MeOH + 1% NH3 aq , 9:1).

[0122] Step C: Synthesis of 1-ethyl-4-(4-nitro-phenyl)-piperazine A mixture of 1-bromo-4-nitrobenzene (6 g, 29.7 mmol) and 1-ethylpiperazine (7.6 mL, 59.4 mmol, 2 eq.) is heated to 80 °C for 15 h . After cooling to RT, the reaction mixture is diluted with water and DCM / MeOH, 9:1 . The aqueous layer is separated and extracted with DCM / MeOH, 9:1. The organic phase is washed with brine , dried (sodium sulfate), filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH + 1% NH3 , 9:1) to obtain 6.2 g of the titled compound as a yellow solid: ESI-MS: 236.0 [MH] aq ; t ; t + ; t R = 2.35 minutes (purity: 100%, gradient J); TLC: R f = 0.50 (DCM / MeO H + 1% NH3 aq 9:1).

[0123] Step D: Synthesis of (6-chloro-pyrimidin-4-yl)-methyl-amine This substance was prepared by modifying the procedure disclosed in the literature (J. Appl. Che m. 1955, 5, 358): To a suspension of commercially available 4,6 -dichloropyrimidine (20 g, 131.6 mmol, 1.0 eq.) in isopropanol (60 mL), while maintaining the internal temperature from rising above 50 °C, add 33% methylamine in ethanol (40.1 mL, 328.9 mmo l, 2.5 eq.). After the addition is complete, stir the reaction mixture at room temperature for 1 hour. Next, add water (50 mL) and cool the resulting suspension to 5 °C in an ice bath. Filter the precipitated product and wash it with cold isopropanol / water 2:1 (45 mL ) and water. Dry the collected substance under vacuum at 45 °C overnight to obtain the title compound as a colorless powder: t = 3.57 minutes (purity: >99%, gradient A), ESI-MS: R = 3.57 min (purity: >99%, gradient A), ESI-MS: 144.3 / 146.2 [MH] + .

[0124] Step E: Synthesis of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-4 -(4-ethyl-piperazin-1-yl)-phenylamino}-pyrimidin-4-yl }-1-methyl-urea The title compound was prepared by reacting 2,6-dichloro-3,5-dimethoxyphenyl-isocyanate (1 .25 eq.) with N-4-(4-ethyl-piperazin-1-yl)-phenyl in toluene -N'-Methyl-pyrimidine-4,6-diamine (2.39 g, 7.7 mmol, 1 eq.) was added to a solution and the reaction mixture was stirred for 1.5 hours while refluxing to prepare. The crude product was purified by silica gel column chromatography (DCM / MeOH + 1% NH3 a q , 95:5) to give the title compound as a white solid: ESI- MS: 560.0 / 561.9 [MH] + ; t R = 3.54 min (purity: 100%, gradient J ); TLC: R f = 0.28 (DCM / MeOH + 1% NH3 aq , 95:5). Analysis: C 26 H 31 N7O3Cl2, calculated C, 55.72%; H, 5.57%; N, 17. 49%; O, 8.56%; Cl, 12.65%. Found C, 55.96%: H, 5.8 4%; N, 17.17%; O, 8.46%; Cl, 12.57%.

[0125] Example 2: Synthesis of the monophosphate form A (BGJ398) of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-4- (4-ethyl-piperazin-1-yl)-phenylamino}-pyrimidin-4-yl} -1-methyl-urea To a round-bottom flask was added 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6 -4-(4-ethylpiperazin-1-yl)phenylamino}-pyrimidin-4-yl )-1-methyl-urea (134 g, 240 mmol) and isopropanol (IPA) ( 2000 mL). The suspension was stirred and heated to 50 °C, and a solution of phosphoric acid (73.5 g, 750 mmol) in water (2000 mL) was added thereto separately. The mixture was stirred at 3 ​Stirred at 60 °C for 0 minutes and filtered through a polypropylene pad. The pad was washed with warm IP A / water (1:1, 200 mL), and the filtrates were combined. To this clear solution, I PA (6000 mL) was added, and the mixture was stirred under reflux for 20 minutes and then slowly cooled to room temperature (25 °C) and stirred for 24 hours. The white salt product was collected by filtration, washed with IPA (2 × 500 mL), and dried in an oven at 60 °C under reduced pressure for 2 days to afford anhydrous crystalline monophosphate (110 g). Yield 70%. Purity by HPLC > 98% . Analysis: C H 26 H 34 N7O7Cl2P, calculated C, 47.42%; H, 5.20%; N, 14.89%; O, 17.01%; C1, 10.77%; P. 4.70%. Found C, 47.40%; H, 5.11%: N, 14.71%; O, 17.18%: Cl, 10 .73%; P 4.87%.

[0126] Example 3: Manufacturing process for infliximab pharmaceutical formulations at 25 mg, 100 mg, and 125 mg dosages The manufacturing process for the following examples is outlined for all the exemplified dosages in the following. The relevant amounts for the components are provided in the formulations of Examples 3.1, 3.2, and 3.3 below . For the components, the corresponding amounts are provided in the formulations of Examples 3.1, 3.2, and 3.3 below .

[0127] Manufacture of pharmaceutical formulations Cellulose MK-GR, lactose (powder), infliximab, cellulose HPM 603, and crosslinked polyvinylpyrrolidone (PVP-XL) were placed into a vertical wet high-shear granulator (e.g TK Fiedler (bottom-driven, 65 L) with an approximately 45 - 50% granulator fill Add in volume order, and then add the five components. Set the impeller to 60 - 270 rpm, preferably or 150 rpm; set the chopper to 600 - 3000 rpm, preferably 150 0 rpm, and mix for about 5 minutes to obtain a dried formulation.

[0128] Add purified water as the granulation liquid at a rate of about 385 g / min for 7 minutes (add water until about 2.7 kg) and set the spray pressure to 1.5 bar (set the impeller to 60 - 270 rpm, preferably or 150 rpm; set the chopper to 600 - 3000 rpm, preferably 150 0 rpm), and add. Knead the resulting granulation mixture for about 3 minutes (set the impeller to 60 - 270 rpm, preferably 150 rpm; set the chopper to 600 - 30 00 rpm, preferably 1500 rpm). Pass the kneaded granulation mass through a 3.0 mm sieve using a Comil at 90 - 600 rp m. This process step is not essential and may be omitted, but preferably this process step is carried out.

[0129] The granules are dried in a fluidized bed dryer, such as a Glatt GPCG 15 / 30 or equivalent, at an inlet temperature of 55 - 65 °C, preferably 6 0 °C, a product temperature of about 30 - 40 °C, and an inlet volume of 300 - 1200 m / h to reach a dry endpoint of ≤ 2.2%. 3 / h of the intake volume and dry.

[0130] The dried granules are sieved at 800 - 1000 μm in a Comil. The resulting dried and sieved granules are also referred to herein as the inner phase as well.

[0131] ​The excipients PVP XL and Aerosil 200 of the outer phase are sieved at approximately 900 - 1000 μm in a Comil at approximately 50 - 150 rp m, and then combined with the inner phase in a suitable container (e.g., a bin blender, turbula, or equivalent) at approximately 4 - 2 5 rpm, preferably 17 rpm for about 5 minutes (filling 33 - 66% of the powder).

[0132] The solid is blended in a diffusion mixer (tumbler) or bin blender (e.g., Bohle PM400, Turbula, or equivalent) at approximately 17 rpm for about 3 minutes and smoothed by adding magnesium stearate sieved at 500 rpm as an additional outer phase excipient, obtaining a final formulation that can be used immediately for capsule filling.

[0133] Manufacture of Capsules The final formulation is then filled into hard gelatin capsules (HGC) of size 0, 1, or 3 without pre - pressure at a encapsulation rate of 10,00 0 - 100,000 caps / hour using a capsule filling device having a dosing plate principle or a dosing tube (e.g., Hoefliger&Karg GKF330, Bosch GKF1500, Zanasi12 E.Zanasi40 E). The weight of the capsules is inspected and the capsules are dust - removed.

[0134] Example 3.1

Table 1

[0135] Example 3.2

Table 2

[0136] Example 3.3 [Table 3]

[0137] Example 4: Oral Infigratinib (BIF) in Adult Patients with Advanced or Metastatic Bile Duct Cancer GJ398) Test Purpose and rationale This study validated the efficacy of the target-selective pan-FGFR inhibitor BGJ398 in genetically selected Overall response rate when administered as a single agent to selected patients with advanced or metastatic cholangiocarcinoma Designed to be evaluated through estimation.

[0138] Molecular characterization of these tumors at baseline and progression will identify promising treatment options. This will allow for a better understanding of the mechanisms of resistance, both primary and acquired, as well as the mechanisms of resistance.

[0139] Main purpose RECIST v1.1 (Eisenhauer et al., 2009) The patients were randomly assigned to receive either FGFR2 gene fusions or FGFR2-associated gliomas, as measured by overall response assessed by central review of patient images. In patients with advanced or metastatic cholangiocarcinoma, especially those with translocations or other FGFR genetic alterations To evaluate the efficacy of single agent BGJ398 in

[0140] Secondary Objectives Overall response as determined by the investigator; by investigator and RECIST Progression-free survival, best overall response, disease progression as assessed by central radiological review according to v1.1 to further demonstrate the efficacy of single-agent BGJ398 as measured by control and overall survival. Evaluate to.

[0141] Characterize the safety and tolerability of agent BGJ398 by the type, frequency, and severity of adverse events (AE) and serious adverse events (SAE).

[0142] Determine the specific trough levels and 2-hour or 4-hour plasma concentrations of BGJ398 and its metabolites.

[0143] Characterize the pharmacokinetic profiles for doses of 25 mg and 100 mg.

[0144] Study Design This is a multicenter, open-label, single-arm, Phase II study to evaluate the antitumor activity of BGJ398 in patients with advanced or metastatic cholangiocarcinoma with FGFR genetic alterations. Oral BGJ398 at 125 mg is administered once daily for the first 3 weeks (21 days) of each 28-day cycle. The starting dose of 125 mg may be decreased to 100 mg, 75 mg, or 50 mg. Treatment is continued from day 1 of cycle 1 until disease progression, unacceptable toxicity, withdrawal of informed consent, or death. Patients are evaluated for antitumor response by radiography every 8 weeks using the RECIST v1.1 criteria until disease progression or discontinuation of the study.

[0145] Patient Population Patients with histologically or cytologically confirmed advanced or metastatic cholangiocarcinoma with FGFR2 gene fusion or translocation or other FGFR genetic alterations, with evidence of radiographic progression after treatment with a therapy containing cisplatin and gemcitabine for advanced disease or a therapy containing gemcitabine for patients considered intolerant to cisplatin. ​​​​​​​​​​​​Register human patients. Register approximately 160 or fewer adult patients over 18 years old, both male and female. The three cohorts of patients include the following study groups: · Cohort 1: Approximately 120 patients, 108 with FGFR2 gene fusions or translocations and 12 with other FGFR genetic changes. · Cohort 2: Approximately 20 patients with FGFR genetic changes other than FGFR2 gene fusions or translocations. · Cohort 3: Approximately 20 or fewer patients with FGFR2 gene fusions or translocations who have previously received an FGFR inhibitor.

[0146] Main inclusion criteria Patients with cholangiocarcinoma histologically or cytologically confirmed at the time of diagnosis. Patients with cancer of the gallbladder or the ampulla of Vater are not eligible.

[0147] Documentation of determination by the local or central testing agency for the following FGFR gene changes: · Cohort 1: FGFR2 gene fusion or translocation. · Cohort 2: One of the following: (a) FGFR1 fusion or translocation, (b) FGFR 3 fusion or translocation, or (c) activating mutations known and shown in Table 4 to be FGFR1 / 2 / 3 mutations.

[0148]

Table 4

[0149] Patients have previously received at least one treatment containing gemcitabine with or without cisplatin for advanced or metastatic disease. Patients have subsequently Must have evidence of disease progression or previous treatment discontinued due to toxicity In cases where measurable or evaluable disease evidence is being continuously taken.

[0150] ECOG Performance Status ≤ 1 (patients with an ECOG Performance Status of 2 may be considered individually). The ECOG Performance Status is determined as shown in Table 5. as shown in Table 5.

[0151]

Table 5

[0152] Cohort 3 only: Documented history of prior treatment with FGFR inhibitors other than BGJ398 / infigratinib.

[0153] Major exclusion criteria Previous treatment or current treatment with a MEK inhibitor (all cohorts), BGJ398 / infigratinib (all cohorts), or a selective FGFR inhibitor (cohorts 1 and 2 only).

[0154] Evidence of corneal or retinal disorders / keratopathies, including but not limited to bullous / band keratopathy, corneal abrasions, inflammation / ulcers, keratoconjunctivitis, confirmed by ophthalmological examination.

[0155] History and / or current evidence of extensive tissue calcification, including but not limited to soft tissue, kidney, intestine, myocardium, vasculature, and lung, excluding lymph node calcification, mild pulmonary parenchymal calcification, and asymptomatic coronary artery calcification.

[0156] ​​​​​​Gastrointestinal (GI) dysfunction or GI diseases (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection) that may significantly alter the absorption of oral BGJ398.

[0157] Changes in calcium / phosphate homeostasis due to endocrine factors, e.g., parathyroid disorders, history of parathyroidectomy surgery, evidence of tumor lysis, tumoral calcinosis, etc. are present currently.

[0158] Receiving concurrent treatment with drugs that are known potent inhibitors or inducers of CYP3A4. Drugs that increase serum phosphorus and / or calcium concentrations are excluded. Patients are not permitted to receive enzyme-inducing antiepileptic drugs.

[0159] Cohort 3 only: The presence of the V564F mutation in the FGFR2 gene is known.

[0160] Assessment of efficacy Antitumor response and survival according to RECIST v1.1.

[0161] Assessment of safety Reporting of adverse events (AEs) and changes from baseline in clinical laboratory parameters, vital signs, ophthalmologic assessments, and cardiac imaging.

[0162] Other assessments Pharmacokinetic assessment: Blood samples are collected for the measurement of plasma concentrations of BGJ398 and its metabolites.

[0163] Biomarker assessment: Analysis of next-generation DNA sequencing data from tumor samples at baseline and after the onset of disease progression (whenever available) to assess cancer ​​To investigate the mechanism of resistance to treatment, archival tumor samples or newly obtained tumor samples are collected.

[0164] For cell-free DNA analysis to investigate the genetic changes, clinical response, and correlation with the development of resistance in the tumor tissue at baseline, blood samples are collected at screening and throughout the trial.

[0165] Data Analysis To enable the analysis of a sufficient number of patients, data from the sites participating in this trial protocol are combined. The data are summarized for demographic and baseline characteristics, observations and measurements for efficacy and safety, and all relevant PK and PD measurements. Categorical data are presented as frequencies and percentages. For continuous data, the mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum values are provided.

[0166] Results Prior to starting the trial treatment, patient 5010004 had been treated with oral erdafitinib. Treatment with erdafitinib was discontinued approximately 2 months later due to disease progression by radiography. That is, the best response of the patient was disease progression.

[0167] Patient 5010004 then started the trial treatment approximately 2 months after the discontinuation of treatment with erdafitinib. During treatment with infigratinib, the patient's response was determined by follow-up examinations conducted by the local trial investigator according to RECIST v1.1. The patient had stable disease in the first 3 It was decided. The trial treatment was discontinued due to disease progression approximately 5 months later. The outline of the trial is shown in Table 6.

[0168]

Table 6

[0169] Example 5: FGFR3 mutant Vex-MR086M established in nude mice Evaluation of the antitumor activity of infigratinib and erdafitinib used as single agents in a patient-derived ureteral cancer xenograft model in vivo Purpose To determine the antitumor activity of infigratinib used as a single agent compared with erdafitinib, a FGRF1-4 tyrosine kinase inhibitor, in a FGFR3 mutant VEx-MR086M patient-derived ureteral cancer xenograft model developed in immunodeficient female mice.

[0170] Human tumor xenograft model The Vex-MR086M1 human tumor xenograft model was obtained from metastatic lesions of a patient whose bladder cancer progressed under treatment with erdafitinib after the initial effect (Table 7). The patient's tumor and patient-derived xenograft (PDX) have the FGFR3 mutation (S249C). The PD X model was developed based on treatment with 15 mg / kg of erdafitinib (Ca rbosynth (registered trademark)) administered continuously for 5 days per week.

[0171]

Table 7

[0172] Animals and breeding conditions Female non-inbred thymus-deficient (nu / nu) mice (HSD: thymus-deficient nude Foxn1) weighing 18 - 25 grams (ENVIGO, Gannat, France) were allocated to adapt at least 6 days prior in an animal facility where feed and water were freely available (Table 8). deficient nude Foxn1 nu )(ENVIGO, Gannat, France) were allocated to adapt at least 6 days prior in an animal facility where feed and water were freely available in an animal facility where feed and water were freely available (Table 8).

[0173]

Table 8

[0174] Housing of animals Mice were housed in groups of a maximum of 7 during the acclimation period and a maximum of 6 during the experimental phase. Mice were housed in individual ventilated cages (IVC) made of polysulfone (PSU) plastic with a sterilized and dust-free corncob bedding (mm 213W×362D×185H, Allentown, USA with a sterilized and dust-free corncob bedding (mm 213W×362D×185H, Allentown, USA ). Feed and water were sterilized. Animals were housed under a light-dark cycle (14-hour artificial light cycle) and controlled room temperature and humidity. Environmental conditions were monitored and data were stored in the Central Animal House Archives ). Feed and water were sterilized. Animals were housed under a light-dark cycle (14-hour artificial light cycle) and controlled room temperature and humidity. Environmental conditions were monitored and data were stored in the Central Animal House Archives ). Feed and water were sterilized. Animals were housed under a light-dark cycle (14-hour artificial light cycle) and controlled room temperature and humidity. Environmental conditions were monitored and data were stored in the Central Animal House Archives ).

[0175] Supply of feed and water Drinking water was provided ad libitum. Each mouse was given a complete pellet diet (150-SP-25, SAFE) daily throughout the test ). Analytical certificates for the animals' feed and water were stored on the CERFE site ).

[0176] Identification of animals All animals were weighed before each experiment and identified by a unique pattern of ear punching and numbering. Each cage was identified by a paper tag indicating the following: cage identification by a unique pattern of ear punching and numbering. Each cage was identified by a paper tag indicating the following: cage ​Number, mouse strain and number, tumor code, date of experiment.

[0177] Test compound and formulation The preparation of INFIGLATINIB and the INFIGLATINIB solvent (50% 50 mM acetate buffer + 50% PEG300 pH 4.6) for the treatment of the solvent group was prepared in two steps.

[0178] First step, preparation of 50 mM acetate buffer at pH 4.6 + / - 0.05: Weighed the required amount of sodium acetate trihydrate and dissolved it in sterile deionized water. Next, glacial acetic acid (1 L to 1.5 ml) was added to the solution, and the pH was adjusted to 4.6 + / - 0. 5 with 1 N HCl. Sterile deionized water was used to make up the final volume.

[0179] Second step, preparation of 50% 50 mM acetate buffer + 50% PEG300 pH 4.6 solvent : The 50 mM acetate buffer at pH 4.6 was mixed with PEG300 (ratio 1:1, v / v) with magnetic stirring for at least 1 minute.

[0180] The stock solution was stored at +4 °C in a light-protected cabinet for 1 month. Aliquots were prepared weekly for treatment.

[0181] The dosing solutions of INFIGLATINIB (BGJ398) at 3 and 5 mg / ml free base (3.51 and 5.85 mg / ml salt form respectively) were prepared by weighing the required amount of INFIGLATINIB, taking into account a salt form / free base ratio of 1.17, and then adding the INFIGLATINIB solvent (50% 50 mM acetate buffer + 50% PEG300 pH 4.6) with magnetic stirring until completely dissolved (at least 15 minutes). The preparations were stored at +4 °C in a light-protected cabinet for 7 days. ​

[0182] HP-β-CD (Kleptose) 20% in sterilized deionized water (for erdafitinib preparation was prepared by dissolving the required amount of HP-β-CD in the required amount of sterilized deionized water while stirring magnetically The stock solution was stored at +4 °C for 1 month in a light-shielded cabinet .

[0183] The dosing solution of 1.5 mg / ml erdafitinib was prepared by weighing the required amount of erdafitinib by weight and then adding 20% HP-β-CD while stirring magnetically until completely dissolved . The preparation was stored at +4 °C for 7 days in a light-shielded cabinet

[0184] Induction of tumor xenograft model Tumors of the same passage were subcutaneously transplanted into 3 - 24 mice (donor mice, passage (n - 1)) . When these tumors reached 1470 - 1688 mm 3 , the donor mice were sacrificed by cervical dislocation with a pestle, and the tumors were aseptically excised and dissected. After removing the necrotic parts, the tumors were cut into fragments of approximately 20 mm 3 in volume and transferred into the culture medium before transplantation

[0185] Fifty-nine mice were anesthetized with 100 mg / kg ketamine hydrochloride and 10 mg / kg xylazine , and then the skin was disinfected (aseptized) with chlorhexidine solution, and an incision was made at the height between the scapulae , and 20 mm 3 tumor fragments were placed in the subcutaneous tissue. The skin was closed with clips

[0186] All mice with the same experiment were transplanted on the same day

[0187] Treatment stage In the test, between 62.5 and 196 mm 3 28 mice with proliferative tumors (P9.1.1 / 0) established by VEx-MR086M1 were assigned to each treatment group according to their tumor volumes so that the mean and median tumor volumes were uniform (Table 9). Treatments were randomly assigned to cages housing up to five mice and initiated 36 days after tumor implantation (47% incorporation rate). The test ended 21 days after the start of treatment (Table 9). Treatments were randomly assigned to cages housing up to five mice and initiated 36 days after tumor implantation (47% incorporation rate). The test ended 21 days after the start of treatment . .

[0188]

Table 9

[0189] Tumor measurements and animal observations Tumor volume was evaluated by measuring the vertical tumor diameter three times a week during the treatment period with calipers . All animals were weighed at the same time as tumor size measurements. Relative body weight loss (RBW loss ) was considered a treatment side effect . Mice were observed daily for appearance, behavior, and clinical changes . All signs of illness were recorded for each animal along with any changes in behavior or response to treatment .

[0190] Test design A total of four groups were used as summarized in Table 10. Each group initially included seven mice . In Group 1, the vehicle was administered orally at 10 ml / kg per day for 21 days (D0 - D21) . In Group 2, erdafitinib was administered orally at 15 mg / kg (10 ml / kg ) per day for 21 days (D0 - D21) In Groups 3 and 4, infliximab was administered orally once daily for 21 days (D0 - D21) at 30 and 50 mg / kg (10 ml / kg), respectively. All treatment doses were adjusted according to body weight at the time of dosing. All treatment doses were adjusted according to body weight at the time of dosing.

[0191]

Table 10

[0192] Measures to be taken if weight loss or adverse phenomena occur During the treatment period, any general changes in behavior or clinical signs were notified to the sponsor of the clinical trial as soon as possible (within 24 hours on weekdays - within 48 hours on weekends). During the treatment period, any general changes in behavior or clinical signs were notified to the sponsor of the clinical trial as soon as possible (within 24 hours on weekdays - within 48 hours on weekends).

[0193] In the following cases, according to tumor volume: - Weight loss ≥ 15% (tumor volume ≤ 1100 mm3) or - Weight loss ≥ 10% (tumor volume > 1100 mm 3 3), the sponsor of the clinical trial was notified immediately (within 24 hours on weekdays - within 48 hours on weekends).

[0194] Next, the following measures were taken: - Treatment of the relevant animal was stopped; when weight loss was < 10%, treatment was restarted. - DietGel Recovery® was given to the entire group, weight loss was observed, and the body weight of the relevant animals was measured daily until weight loss was < 10%; additional administration of DietGel Recovery® was stopped when weight loss was < 10%. - DietGel Recovery® was given to the entire group, weight loss was observed, and the body weight of the relevant animals was measured daily until weight loss was < 10%; additional administration of DietGel Recovery® was stopped when weight loss was < 10%. - DietGel Recovery® was given to the entire group, weight loss was observed, and the body weight of the relevant animals was measured daily until weight loss was < 10%; additional administration of DietGel Recovery® was stopped when weight loss was < 10%. - DietGel Recovery® was given to the entire group, weight loss was observed, and the body weight of the relevant animals was measured daily until weight loss was < 10%; additional administration of DietGel Recovery® was stopped when weight loss was < 10%. - DietGel Recovery® was given to the entire group, weight loss was observed, and the body weight of the relevant animals was measured daily until weight loss was < 10%; additional administration of DietGel Recovery® was stopped when weight loss was < 10%.

[0195] Criteria for ethical euthanasia Each animal was immediately euthanized if any one of the following conditions was met: - General changes in behavior or clinical signs - Tumor volume ≥ 1764 mm 3 - Immediate intervention required weight loss (BWL) · Tumor ≤ 1100 mm 3 Mouse having: BWL ≥ 20% at any point compared to the weight on the day of registration BWL ≥ 15% maintained for 48 hours compared to the weight on the day of registration (2 days or 3 consecutive measurements). · Tumor > 1100 mm 3 Mouse having: BWL ≥ 15% at any point compared to the weight on the day of registration BWL ≥ 10% maintained for 48 hours compared to the weight on the day of registration (2 days or 3 consecutive measurements).

[0196] Endpoint / End of test Only mice that reached the ethical sacrifice criteria were sacrificed at the appropriate time. The entire experimental group was ended at the end of the experimental period .

[0197] The endpoints of the experiment were as follows: - 3-week treatment phase.

[0198] Tumor sampling When the tumor reached 500 - 847 mm 3 4 tumors were collected from spare mice for FFPE and RNA - la ter (registered trademark).

[0199] For each compound and each dose, fresh tumor samples were collected from all mice in each group at the end of the test or at the time of ethical sacrifice (excluding weekends) for FFPE and RNA Late r (56 samples: 28 FFPE and 28 RNA later).

[0200] Tumor sampling for FFPE Half of the tumor was processed for FFPE: The tumor was fixed in 10% formalin for 24 hours, transferred into 70% ethanol, and then sent to Althisia for paraffin embedding (i.e., 28 + 4 FFPE tumor samples). The exact sampling time, formalin fixation, and storage period in ethanol were recorded for each tumor sampling. The storage period of the tumor in 70% ethanol did not exceed two weeks.

[0201] When the size of the tumor sample did not fit into one standard tissue diagnosis cassette, the whole was divided and embedded in paraffin. When the tumor was too large, two cassettes were made. The samples were dehydrated and impregnated in paraffin of Peloris (Leica) according to the Althisia procedure described below:

[0202] - Immersed 7 times in ethanol of different concentrations and temperatures

[0203] - Immersed 3 times in xylene of different concentrations and temperatures - Immersed 3 times in paraffin at 65 °C in a vacuum atmosphere. After treatment, the samples were embedded in paraffin blocks (Diawax paraffin).

[0204] The time out of the dehydration cycle was recorded.

[0205]

[0206] Tumor RNA Sampling Half of the tumor for RNA: The tumor was cut into fragments of 4 × 4 × 1 mm, transferred into RNA later®, stored at 4 °C for 24 hours, then RNA later® was removed, and the samples were transferred to -80 °C for storage.

[0206] ​​The exact sampling time was noted for each sample (i.e. 28+4RNA later(registered trademark) sample).

[0207] Data analysis - data processing All raw data must be recorded, stored and compiled in a suitable format linked to a numbered register. The data were processed using a computer system. Day 0 was considered the day of enrollment. Study days were numbered consecutively according to this definition. The treatment period began on day 0. Records were expressed as mean ± standard error of the mean (m ± sem). Relative body weight (RBW) was calculated by dividing body weight by weight at the start of treatment. , is calculated for each measurement. Individual percent body weight loss (%BWL) = 100 - (BWx / BW0 x 100), BW x is the BW on any day during treatment and BW0 is the BW on the day of enrollment. Average percent weight loss (%BWL) = 100 - (average BWx / average BW0 x 100) , BWx is the average BW on any day during treatment, and BW0 is the average BW on the day of enrollment. It is. Mean relative body weight curves were generated by plotting mean RBW against time for each experimental group. Delta relative body weight (the relative body weight of the treatment group compared to the control group) was obtained by The mean body weight (relative to the weight of the control) was used for statistical analysis. formula TV(mm 3 ) = [length (mm) x width (mm) 2 ] / 2 is used, and the length and width are These are the longest and shortest diameters of the tumor, respectively. Tumor growth curves are shown in mm versus time for each experimental group. 3 Plot the mean tumor volume at Delta tumor volume (relative tumor volume of treated compared to control group) The relative tumor volume of the treatment group was used for statistical analysis. The individual tumor growth delay (TGD) was calculated as the time in days required for each individual tumor to reach 3 to 5 times its initial tumor volume. The median growth delay / group was calculated and reported in the table. The tumor growth delay index (TGDI) was calculated as the median growth delay in the treatment group divided by the median growth delay in the control group. The percentage ratio between the average tumor volume (T) of the treatment group and the average tumor volume (C) of the control group was calculated. The tumor growth rate was evaluated by the formula DT / T0, where DT is the difference in tumor volume (TV) between the day under consideration and the day of enrollment, and T0 is the average TV at D0. Thus, DT / T0 < 0 means that the TV at Dxx has decreased compared to the average TV at D0, and DT / T0 > 0 means that the TV at Dxx has increased compared to the average TV at D0. T0 < 0 The results were expressed as a percentage in the table ([DT / T0] × 100), where Dxx is the day when the control group ends. Regarding a classification similar to RECIST based on tumor volume measurements, the inventors previously defined tumors outside the range of 20% > [DT / T0] × 100 > -30% as progressing or regressing, respectively. 1 Statistical analysis was performed for each measurement by the Mann-Whitney non-parametric comparison test. Each treatment group was compared with the control group.

[0208] Results - Tolerance Data, Clinical Observation In this study, the body weight of the mice was measured three times a week during the experimental period. In Group 1, 10 ml / kg was administered daily via the oral route for 21 days (D0 - D21). The solvent used had good tolerance. The average weight loss was 3.1% on D13, and the maximum individual weight loss was 10.1% on D11. No related prominent symptoms were reported during the experimental period. In Group 2, erdafitinib administered orally at 15 mg / kg (1 0 ml / kg) daily for 21 days (D0 - D21) was well tolerated in all mice except one. There was no average weight loss, and the maximum individual weight loss was 10.6% on D17 (p < 0.05 from D11 to D18). Due to the BWL of mouse #16 on D17 > 15%, DietGel Recovery (registered trademark) was administered to the entire group on D17. No related prominent symptoms were reported during the experimental period. In Group 3, infliximab administered orally at 30 mg / kg (1 0 ml / kg) daily for 21 days (D0 - D21) was well tolerated. The average weight loss was 2.1% on D21, and the maximum individual weight loss was 8.6% on D18. All mice had depressions in the height of the sternum from D13 to D21 (the end of the test). A strain-specific modifier for the characteristic of having a depression in the height of the sternum could not be ruled out. No other clinical symptoms were reported. In Group 4, infliximab administered orally at 50 mg / kg (1 0 ml / kg) daily for 21 days (D0 - D21) showed tolerance. The average weight loss was 10. 3%, and the maximum individual weight loss was 19.8% on D18. The relative weights of the infliximab-treated mice in this group showed no significant difference compared to the solvent control group at each time point. For mouse #53 from D6 to D8 (due to 3 consecutive days of BWL > 15%, on D8 ​​​For mice #67 at D18 - D21 and mice #21 at D18 and D21 with BWL>15%, DietGel Recovery® was given to the entire group. Treatment was interrupted from D6 to D8 (for mouse #53) and from D18 to D20 (for mice #67 and #21). All mice had depressions in the height of the sternum from D11 or D13 to D21 (end of the study). It is not possible to rule out strain - specific modifiers for the characteristic of having a depression in the height of the sternum. No other clinical symptoms were reported. For the characteristic of having a depression in the height of the sternum, it is not possible to rule out strain - specific modifiers. No other clinical symptoms were reported. For the characteristic of having a depression in the height of the sternum, it is not possible to rule out strain - specific modifiers. No other clinical symptoms were reported. For the characteristic of having a depression in the height of the sternum, it is not possible to rule out strain - specific modifiers. No other clinical symptoms were reported. For the characteristic of having a depression in the height of the sternum, it is not possible to rule out strain - specific modifiers. No other clinical symptoms were reported. For the characteristic of having a depression in the height of the sternum, it is not possible to rule out strain - specific modifiers. No other clinical symptoms were reported. For the characteristic of having a depression in the height of the sternum, it is not possible to rule out strain - specific modifiers. No other clinical symptoms were reported.

[0209] Antitumor Efficacy Data Tumor growth curves (average tumor volume over a period of time) are illustrated in Figure 1. The T / C percentage values for each treatment group are shown in Table 11 and illustrated in Figure 2. Statistical analysis is shown in Table 12. Tumor growth curves (average tumor volume over a period of time) are illustrated in Figure 1. The T / C percentage values for each treatment group are shown in Table 11 and illustrated in Figure 2. Statistical analysis is shown in Table 12. In this study, the body weights of the mice were measured three times a week during the experimental period. In Group 2, erdafitinib administered orally at 15 mg / kg (10 ml / kg) daily for 21 days (D0 - D21) induced a statistically significant inhibition of tumor growth compared to the control group (p < 0.05 from D11 to D15; TGDI = 1.71; best T / C = 48.37% at D15, and ΔT / T0 = 465.31% at D18 (end of the control group)). In Group 2, erdafitinib administered orally at 15 mg / kg (10 ml / kg) daily for 21 days (D0 - D21) induced a statistically significant inhibition of tumor growth compared to the control group (p < 0.05 from D11 to D15; TGDI = 1.71; best T / C = 48.37% at D15, and ΔT / T0 = 465.31% at D18 (end of the control group)). In Group 2, erdafitinib administered orally at 15 mg / kg (10 ml / kg) daily for 21 days (D0 - D21) induced a statistically significant inhibition of tumor growth compared to the control group (p < 0.05 from D11 to D15; TGDI = 1.71; best T / C = 48.37% at D15, and ΔT / T0 = 465.31% at D18 (end of the control group)). In Group 2, erdafitinib administered orally at 15 mg / kg (10 ml / kg) daily for 21 days (D0 - D21) induced a statistically significant inhibition of tumor growth compared to the control group (p < 0.05 from D11 to D15; TGDI = 1.71; best T / C = 48.37% at D15, and ΔT / T0 = 465.31% at D18 (end of the control group)). In Group 2, erdafitinib administered orally at 15 mg / kg (10 ml / kg) daily for 21 days (D0 - D21) induced a statistically significant inhibition of tumor growth compared to the control group (p < 0.05 from D11 to D15; TGDI = 1.71; best T / C = 48.37% at D15, and ΔT / T0 = 465.31% at D18 (end of the control group)). In Group 3, infliximab administered orally at 30 mg / kg (10 ml / kg) daily for 21 days (D0 - D21) induced a statistically significant inhibition of tumor growth compared to the control group (p < 0.05 at D6, p < 0.01 from D8 to D18; TGDi>2.06, best T / C% = 14.81% at D15, and ΔT / T0 = D In Group 3, infliximab administered orally at 30 mg / kg (10 ml / kg) daily for 21 days (D0 - D21) induced a statistically significant inhibition of tumor growth compared to the control group (p < 0.05 at D6, p < 0.01 from D8 to D18; TGDi>2.06, best T / C% = 14.81% at D15, and ΔT / T0 = D In Group 3, infliximab administered orally at 30 mg / kg (10 ml / kg) daily for 21 days (D0 - D21) induced a statistically significant inhibition of tumor growth compared to the control group (p < 0.05 at D6, p < 0.01 from D8 to D18; TGDi>2.06, best T / C% = 14.81% at D15, and ΔT / T0 = D In Group 3, infliximab administered orally at 30 mg / kg (10 ml / kg) daily for 21 days (D0 - D21) induced a statistically significant inhibition of tumor growth compared to the control group (p < 0.05 at D6, p < 0.01 from D8 to D18; TGDi>2.06, best T / C% = 14.81% at D15, and ΔT / T0 = D 18 (end of control group) of 77.83%). Infliximab at 30 mg / kg showed higher tumor growth inhibition than erdafitinib at 15 mg / kg (p < 0.05 from D11 to D21). The average tumor volume of infliximab-treated tumors was 3.2-fold lower than that of erdafitinib-treated tumors at D18 (end of the erdafitinib treatment group). In group 4, infliximab administered orally daily at 50 mg / kg (1 0 ml / kg) for 21 days (D0 - D21) induced statistically significant tumor growth inhibition compared to the control group (p < 0.05 at D6, p < 0.01 from D8 to D18 ; TGDi > 2.06, best T / C% = 13.13% at D15, and ΔT / T0 = D 18 (end of control group) of 44.04%). Infliximab at 50 mg / kg showed higher tumor growth inhibition than erdafitinib at 15 mg / kg (p < 0.05 from D11 to D21). The average tumor volume of infliximab-treated tumors was 3.8-fold lower than that of erdafitinib-treated tumors at D18 (end of the erdafitinib treatment group).

[0210] Based on body weight data and clinical observations, all compounds used as monotherapy showed tolerance. However, infliximab induced slight progressive BWL at the highest dose of 50 mg / kg, and one mouse was sacrificed due to BWL > 15% within 48 hours.

[0211] Erdafitinib monotherapy at 15 mg / kg, qdx21 showed slight anti-tumor activity. Infliximab monotherapy at 30 and 50 mg / kg, qdx21 was statistically significantly​​​​ showed tumor growth inhibition. In the Vex-MR086M1 model, infigratinib demonstrated statistically significant antitumor activity compared to erdafitinib.

[0212]

Table 11

[0213]

Table 12

[0214] Example 6: FGFR3 mutant UREx-MR205 established in nude mice Evaluation of the antitumor activity of infigratinib and erdafitinib used as single agents in a 7PD-AR patient-derived ureteral cancer xenograft model in vivo Objective To determine the antitumor activity of the QED Therapeutics investigational compound infigratinib, an ATP-competitive FGFR1-3 tyrosine kinase inhibitor, used as a single agent and compared to the FGRF1-4 tyrosine kinase inhibitor erdafitinib (Erda) in the FGFR3 mutant UREx-MR205 7PD-AR patient-derived ureteral cancer xenograft model developed in immunodeficient female mice. -AR patient-derived ureteral cancer xenograft model, and compared to the FGRF1-4 tyrosine kinase inhibitor erdafitinib (Erda). eutics investigational compound infigratinib, an ATP-competitive FGFR1-3 tyrosine kinase inhibitor. eutics investigational compound infigratinib, an ATP-competitive FGFR1-3 tyrosine kinase inhibitor inhibitor, in the FGFR3 mutant UREx-MR205 7PD-AR patient-derived ureteral cancer xenograft model developed in immunodeficient female mice.

[0215] Human tumor xenograft model The UREx-MR205 7PD-AR model was established from metastatic lesions of a patient with urothelial carcinoma after progression under treatment with Erda. The prior treatment history before Erda is unknown, but is thought to have included surgery and, moreover, non-targeted chemotherapy. The patient's tumor had an FGFR 3 mutation, FGFR3 S249C (serine at amino acid 249 mutated to cysteine 3 mutation, FGFR3 S249C (serine at amino acid 249 mutated to cysteine carries a [mutation] that results in constitutive activation of the FGFR3 receptor, which is a known oncogenic mutation in the extracellular immunoglobulin-like domain. Erdafitinib has shown clinical efficacy in patients with FGFR3 S249C mutant urothelial carcinoma (Pal SK, Cancer Discovery, 2018). This is a known oncogenic mutation in the extracellular immunoglobulin-like domain of the FGFR3 receptor. Erdafitinib has shown clinical efficacy in patients with FGFR3 S249C mutant urothelial carcinoma (Pal SK, Cancer Discovery, 2018).

[0216] [Table 13]

[0217] Animals and housing conditions Non-inbred athymic (nu / nu) female mice (HSD: Nude Foxn1nu) weighing 18 - 25 grams (ENVIGO, Gannat, France) were acclimatized in an animal facility with free access to food and water at least 6 days prior to the procedure (Table 14). This is a known oncogenic mutation in the extracellular immunoglobulin-like domain of the FGFR3 receptor. Erdafitinib were assigned to adapt (Table 14) in an animal facility where food and water could be freely ingested at least 6 days before the procedure with little manipulation (Table 14).

[0218] [Table 14]

[0219] Housing of animals Mice were housed in groups of up to 7 during the acclimation period and up to 6 during the experimental phase. Mice were housed in individually ventilated cages (IVC) made of polysulfone (PSU) plastic (mm 213W × 362D × 185H, Allentown, USA ) with a sterile and dust-free corncob bedding. Food and water were sterilized. Animals were housed under a 14-hour light / dark cycle (artificial light day cycle) and controlled room temperature and humidity. Environmental conditions were monitored and data were stored in the Central Animal House Archives . and the data was stored in the Central Animal House Archives . It should be noted that the original text seems to have some unclear or potentially incorrect parts (such as the [mutation] placeholder in the first line of the translation). If possible, it would be beneficial to have the complete and accurate original text for a more precise translation.

[0220] Supply of food and water Drinking water was given freely. Each mouse was given a complete pellet diet ( 150-SP-25, SAFE) daily throughout the experiment. Certificates of analysis for animal feed and water were kept on the CERFE site.

[0221] Identification of animals All animals were weighed before each experiment and identified by a unique pattern of ear punching numbering system.

[0222] Each cage was identified by paper tags indicating the following: cage number, mouse strain and number, tumor code, date of experiment.

[0223] Test compound and formulation The preparation of infliximab and the infliximab solvent (50% 50 mM acetate buffer + 50% PEG300 pH 4.6) for the treatment of the solvent group were prepared in two steps.

[0224] First step, preparation of 50 mM acetate buffer at pH 4.6 + / - 0.05: Weighed the required amount of sodium acetate trihydrate and dissolved it in sterile deionized water. Next, added glacial acetic acid (1 ml per 1 L) to the solution and adjusted the pH to 4.6 + / - 0. 5 with 1 N HCl. Sterile deionized water was used to make up the final volume.

[0225] Second step, preparation of 50% 50 mM acetate buffer + 50% PEG300 pH 4.6 solvent : The 50 mM acetate buffer at pH 4.6 was mixed with PEG300 (ratio 1:1, v / v) with magnetic stirring for at least 1 minute.

[0226] The stock solution was stored at +4°C in a light-proof cabinet for one month. Aliquots were Made every week.

[0227] 3 and 5 mg / ml free base (3.51 and 5.85 mg / ml salt form, respectively) The dosage solution of nigratinib (BGJ398) is designed to have a salt form / free base ratio of 1.17. Weigh out the required amount of infigratinib, taking into consideration the amount of infigratinib needed, then place on a magnetic plate until completely dissolved. With vigorous stirring (at least 15 min), infiltrate the infigratinib solvent (50% 50 mM acetic acid The preparation was prepared by adding 50% PEG300 (pH 4.6) to the solution. They were stored in a cabinet at +4° C. for 7 days.

[0228] HP-β-CD (Kleptose) 20% (Erdaftinib preparation) in sterile deionized water Add the required amount of HP-β-CD (for preparation) to the required amount of sterile deionized water with magnetic stirring. The stock solution was stored at +4°C in a light-proof cabinet for one month. .

[0229] The 1.5mg / ml Erdafitinib dosage solution is the required amount of Erdafitinib by weight. Then add 20% HP-β-CD with magnetic stirring until completely dissolved. The preparation was stored at +4° C. in a light-proof cabinet for 7 days.

[0230] Induction of tumor xenograft models Tumors of the same passage were subcutaneously implanted in 3 to 24 mice (donor mice, passage (n-1)). These tumors ranged from 1372 to 1568 mm 3 When the donor mouse reached the target tissue, it was removed by cervical dissection. The mice were sacrificed by mortar and the tumors were aseptically excised and dissected. After removing the necrotic parts, the tumors was cut into fragments with a volume of approximately 20 mm 3 and transferred into the culture medium before transplantation.

[0231] Forty-four mice were anesthetized with 100 mg / kg ketamine hydrochloride and 10 mg / kg xylazine, and then the skin was disinfected with chlorhexidine solution, and an incision was made at the height of the interscapular region, and 20 mm 3 tumor fragments were placed in the subcutaneous tissue. The skin was closed with clips.

[0232] All mice with the same experiment were transplanted on the same day.

[0233] Treatment stage In the test, 32 mice with proliferative tumors (P9.1.1 / 0) established by UREx-MR2057PD-A 3 R between 62.5 and 171.15 mm were assigned to each treatment group according to their tumor volumes so that the average and median tumor volumes were uniform (Table 15). The treatment was randomly assigned to boxes accommodating up to 5 mice and started 9 days after tumor transplantation (75% incorporation rate). The test ended 21 days after the start of treatment.

[0234]

Table 15

[0235] Tumor measurement and animal observation results Tumor volume was evaluated by measuring the vertical tumor diameter three times a week with calipers during the treatment period. All animals were weighed at the same time as the tumor size was measured. Relative body weight loss (RBW loss) was considered a side effect of the treatment. ​​​​The mice were observed daily for appearance, behavior, and clinical changes. All signs of illness were recorded for each animal, along with any changes in behavior or response to treatment.

[0236] Test Design A total of 4 groups were used as summarized in Table 16. Each group initially included 8 mice. In Group 1, the solvent was administered orally at 10 ml / kg daily for 21 days (D0 - D21). In Group 2, erdafitinib was administered orally at 15 mg / kg (10 ml / kg) daily for 21 days (D0 - D21). In Groups 3 and 4, infliximab was administered orally at 30 and 50 mg / kg (10 ml / kg) daily for 21 days (D0 - D21), respectively. All treatment doses were adjusted according to body weight at the time of dosing.

[0237]

Table 16

[0238] Measures to be taken in case of weight loss or adverse phenomena During the treatment period, any general changes in behavior or clinical signs were notified to the trial sponsor as soon as possible (within 24 hours on weekdays - within 48 hours on weekends).

[0239] In the following cases, based on tumor volume: - Weight loss ≥ 15% (tumor volume ≤ 1100 mm 3 ) or - Weight loss ≥ 10% (tumor volume > 1100 mm 3 ), the trial sponsor was notified immediately (within 24 hours on weekdays - within 48 hours on weekends).

[0240] ​​​​​​ Next, the following measures were taken: - Treatment for the animal was stopped; treatment was resumed when the weight loss reached < 10%. - DietGel Recovery (registered trademark) was administered to the entire group, and weight loss was observed while the weight of the corresponding animals was measured daily until the weight loss reached < 10%; the addition of DietGel Recovery (registered trademark) was stopped when the weight loss reached < 10%.

[0241] Criteria for ethical euthanasia Each animal was immediately euthanized if it met one of the following conditions: - General changes in behavior or clinical signs - Tumor volume ≧ 1764 mm 3 - Immediate intervention required weight loss (BWL) · Mice with tumors ≦ 1100 mm 3 : BWL ≧ 20% at any point compared to the weight on the registration day BWL ≧ 15% maintained for 48 hours compared to the weight on the registration day (2 days or 3 consecutive measurements). · Mice with tumors > 1100 mm 3 : BWL ≧ 15% at any point compared to the weight on the registration day ○ BWL ≧ 10% maintained for 48 hours compared to the weight on the registration day (2 days or 3 consecutive measurements).

[0242] Endpoint / end of the test Only mice that reached the ethical euthanasia criteria were euthanized at an appropriate time. The entire experimental group was ended at the end of the experimental period . The endpoint of the experiment was set as follows: - A 3-week treatment phase.

[0243] ​​Tumor Sampling Once the tumor reached 500 - 726 mm 3 five tumors were collected from the pre - mice for FFPE and RNA - later® (registered trademark).

[0244] For each compound and each dose, fresh tumor samples were collected from all mice in each group at the end of the study or at the time of ethical sacrifice (excluding weekends) for FFPE and RNA later® (64 samples: 32 FFPE and 32 RNA later).

[0245] Tumor Sampling for FFPE Half of the tumor was processed for FFPE: the tumor was fixed in 10% formalin for 24 hours, transferred to 70% ethanol, and then sent to Althisia for paraffin embedding (i.e., 32 + 5 FFPE tumor samples). The exact sampling time, formalin fixation, and storage period in ethanol were recorded for each tumor sampling . The storage period of the tumor in 70% ethanol did not exceed 2 weeks . If the size of the tumor sample did not fit into one standard tissue diagnosis cassette the whole was divided and embedded in paraffin. If the tumor was too large, two cassettes were made . The samples were dehydrated according to the Althisia procedure described below and impregnated in paraffin from Peloris (Leica): - Immersed 7 times in ethanol of different concentrations and temperatures - Immersed 3 times in xylene of different concentrations and temperatures - Immersed 3 times in paraffin at 65 °C in a vacuum atmosphere . After treatment, the samples were embedded in paraffin blocks (Diawax paraffin). ​The time out of the dehydration cycle was recorded.

[0246] Tumor RNA sampling For RNA, half of the tumor:tumor was cut into 4×4×1 mm fragments and transferred into RNAlater r, stored at 4°C for 24 hours, then RNAlater was removed, and the samples were transferred to -80°C for storage in tubes. The exact sampling time was noted for each sample (i.e., 32+5 RNA later sample).

[0247] Data analysis - data processing All raw data were recorded, stored, and processed by a computer system in an appropriate format linked to a numbered register. Day 0 was considered the day of incorporation. The experimental days were subsequently numbered according to this definition. The treatment period started on day 0. Records were presented as mean ± standard error of the mean (m±sem). Relative body weight (RBW) was calculated for each measurement by dividing the weight by the weight at the start of treatment. Individual percent body weight loss (%BWL)=100 - (BWx / BW0×100), where BW x is the BW on any day during treatment and BW0 is the BW on the day of incorporation. Mean percent body weight loss (%BWL)=100 - (mean BWx / mean BW0×100) where BWx is the mean BW on any day during treatment and BW0 is the mean BW on the day of incorporation. The mean relative body weight curve was obtained for each experimental group by plotting the mean RBW against time. Delta relative body weight (the relative body weight of the treatment group compared to the relative body weight of the control group) was used for statistical analysis.

[0248] The formula for TV (mm 3 ) = [length (mm) × width (mm) 2 / 2 is used, and the length and width are the longest and shortest diameters of the tumor, respectively. The tumor growth curve was obtained by plotting the mean tumor volume in mm 3 against time for each experimental group. The delta tumor volume (relative tumor volume of the treatment group compared to the relative tumor volume of the control group) was used for statistical analysis. The individual tumor growth delay (TGD) was calculated as the time in days required for an individual tumor to reach 3 - 5 times its initial tumor volume. The median growth delay / group was calculated and reported in the table. The tumor growth delay index (TGDI) was calculated as the median growth delay in the treatment group divided by the median growth delay in the control group. The percentage ratio between the mean tumor volume (T) of the treatment group and the mean tumor volume (C) of the control group was calculated. The tumor growth rate was evaluated by the formula [Ty / Tx] - 1, where Ty is the mean tumor volume on the day under consideration and Tx is the mean TV of DX. "-1" is used for comparison with the day of registration. Therefore, when [Ty / Tx] - 1 < 1, it means that the TV of DY has decreased compared to the mean TV of DX, and when [Ty / Tx] - 1 > 1, it means that the TV of DY has increased compared to the mean TV of DX. The results were expressed as percentages in the table.

[0249]

[0250] Statistical analysis was performed for each measurement by the Mann - Whitney non - parametric comparison test. Each treatment group was compared with the control group.

[0251] Results - Tolerance data, clinical observations In this study, the body weights of the mice were measured three times a week during the experimental period. In Group 1, a solvent was administered orally at 10 ml / kg daily for 21 days (D0 - D21). The solvent had good tolerance, with no maximum mean body weight loss and a maximum individual body weight loss of 1.2% on D3. No related prominent symptoms were reported during the experimental period. In Group 2, erdafitinib was administered orally at 15 mg / kg (10 ml / kg) daily for 21 days (D0 - D21). The erdafitinib had good tolerance, with no maximum mean body weight loss and a maximum individual body weight loss of 4.9% on D3. No related prominent symptoms were reported during the experimental period. In Group 3, infliximab was administered orally at 30 mg / kg (10 ml / kg) daily for 21 days (D0 - D21). The infliximab had good tolerance, with no mean body weight loss and a maximum individual body weight loss of 3.5% on D3. All mice had a depression in the height of the sternum from D15 to D21 (end of the study). It cannot be ruled out that there is a strain - specific modifier for the characteristic of having a depression in the height of the sternum. No other clinical symptoms were reported. In Group 4, infliximab was administered orally at 50 mg / kg (10 ml / kg) daily for 21 days (D0 - D21). The infliximab showed tolerance, with a mean body weight loss of 6.6% and a maximum individual body weight loss of 17.8% on D21 (p < 0.001 from D17 to D19). Due to the BWL of mouse #32 being > 15% on D19, DietGel Recovery (registered trademark) was given to the entire group, and the treatment was interrupted from D19 to D21. The infliximab had good tolerance, with no mean body weight loss and a maximum individual body weight loss of 3.5% on D3. All mice had a depression in the height of the sternum from D15 to D21 (end of the study). It cannot be ruled out that there is a strain - specific modifier for the characteristic of having a depression in the height of the sternum. No other clinical symptoms were reported. In Group 4, infliximab was administered orally at 50 mg / kg (10 ml / kg) daily for 21 days (D0 - D21). The infliximab showed tolerance, with a mean body weight loss of 6.6% and a maximum individual body weight loss of 17.8% on D21 (p < 0.001 from D17 to D19). Due to the BWL of mouse #32 being > 15% on D19, DietGel Recovery (registered trademark) was given to the entire group, and the treatment was interrupted from D19 to D21. The infliximab had good tolerance, with no mean body weight loss and a maximum individual body weight loss of 3.5% on D3. All mice had a depression in the height of the sternum from D15 to D21 (end of the study). It cannot be ruled out that there is a strain - specific modifier for the characteristic of having a depression in the height of the sternum. No other clinical symptoms were reported. In Group 4, infliximab was administered orally at 50 mg / kg (10 ml / kg) daily for 21 days (D0 - D21). The infliximab showed tolerance, with a mean body weight loss of 6.6% and a maximum individual body weight loss of 17.8% on D21 (p < 0.001 from D17 to D19). Due to the BWL of mouse #32 being > 15% on D19, DietGel Recovery (registered trademark) was given to the entire group, and the treatment was interrupted from D19 to D21. The infliximab had good tolerance, with no mean body weight loss and a maximum individual body weight loss of 3.5% on D3. All mice had a depression in the height of the sternum from D15 to D21 (end of the study). It cannot be ruled out that there is a strain - specific modifier for the characteristic of having a depression in the height of the sternum. No other clinical symptoms were reported. The infliximab showed tolerance, with a mean body weight loss of 6.6% and a maximum individual body weight loss of 17.8% on D21 (p < 0.001 from D17 to D19). Due to the BWL of mouse #32 being > 15% on D19, DietGel Recovery (registered trademark) was given to the entire group, and the treatment was interrupted from D19 to D21. The infliximab had good tolerance, with no mean body weight loss and a maximum individual body weight loss of 3.5% on D3. All mice had a depression in the height of the sternum from D15 to D21 (end of the study). It cannot be ruled out that there is a strain - specific modifier for the characteristic of having a depression in the height of the sternum. No other clinical symptoms were reported. The infliximab showed tolerance, with a mean body weight loss of 6.6% and a maximum individual body weight loss of 17.8% on D21 (p < 0.001 from D17 to D19). Due to the BWL of mouse #32 being > 15% on D19, DietGel Recovery (registered trademark) was given to the entire group, and the treatment was interrupted from D19 to D21. All mice were maintained with a sternal depression from D15 to D21 (end of study). The presence of a sternal depression as a strain-specific modifier was ruled out. No other clinical symptoms were reported.

[0252] Results – Antitumor Efficacy Data Tumor growth curves (mean tumor volume over time) are depicted in Figure 3. For each treatment group, The T / C percentage values are shown in Table 17 and illustrated in Figure 4. Statistical analysis is shown in Table 18. In this study, mice were weighed three times a week for the duration of the experiment. In group 2, 15 mg / kg (1 Erdafitinib administered at a dose of 0.0 ml / kg did not show any statistically significant effect compared to the control group. No statistically significant tumor growth inhibition was demonstrated (TGDI=1.01; best T / C=D 87.71% for 3 and ΔT / T0=1450.67% for D17 (end of group). In group 3, 30 mg / kg (1 Infigratinib administered at a dose of 0.0 ml / kg was statistically significantly lower than the control group. induced significant tumor growth inhibition (p<0.05 from D7 to D12, p<0.05 from D14 to D17) p<0.01 for D19 and p<0.001 for D20; TGDi=1.20, best T / C% = 51.66% of D19, and ΔT / T0 = 909 of D19 (end of control group) .42%). In group 4, 50 mg / kg (1 Infigratinib administered at a dose of 0.0 ml / kg was statistically significantly lower than the control group. It induced significant tumor growth inhibition (p<0.05 on D5, p<0.01 from D7 to D12). 、and from D14 to D19, p < 0.001; TGDi = 1.79, best T / C% = 37.38% of D19, and ΔT / T0 = 650. of D19 (end of control group). 26%). 50 mg / kg of infliximab showed higher tumor growth inhibition than 30 mg / kg (from D10 to D21, p < 0.05).

[0253] Based on body weight data and clinical observations, all compounds used as monotherapy showed tolerance. However, infliximab, at the highest dose of 50 mg / kg, induced a statistically significant but mild progressive BWL. Single-agent erdafitinib at 15 mg / kg, qdx21 showed no anti-tumor activity. Infliximab at 30 and 50 mg / kg, qdx21 administered as monotherapy demonstrated statistically significant, dose-dependent tumor growth inhibition (p < 0.05 from D10 to D21 between infliximab dosed at 30 and 50 mg / kg).

[0254]

Table 17

[0255]

Table 18

[0256] Incorporation by reference This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are hereby incorporated by reference into this specification. In the event of any conflict between any of the incorporated references and this specification of the Any particular embodiment of the present disclosure within the enclosure may be expressly excluded from any one or more of the claims. Since such embodiments are considered to be known to those skilled in the art, they may be excluded even if not expressly described herein as being excluded. Any particular embodiment of the present disclosure can be excluded from any claim regardless of whether or not it relates to the existence of the prior art and for any reason. Equivalents The present invention may be exemplified in other specific forms without departing from its spirit or essential characteristics. Therefore, the foregoing embodiments are not intended to limit the present invention described herein, but should be regarded as illustrative in all respects. The scope of the present invention is thus indicated by the appended claims rather than the foregoing description, and all changes within the meaning and range equivalent to the claims are intended to be embraced by the claims. Any particular embodiment of the present disclosure within the enclosure may be expressly excluded from any one or more of the claims. Since such embodiments are considered to be known to those skilled in the art, they may be excluded even if not expressly described herein as being excluded. Any particular embodiment of the present disclosure can be excluded from any claim regardless of whether or not it relates to the existence of the prior art and for any reason. Equivalents The present invention may be exemplified in other specific forms without departing from its spirit or essential characteristics. Therefore, the foregoing embodiments are not intended to limit the present invention described herein, but should be regarded as illustrative in all respects. The scope of the present invention is thus indicated by the appended claims rather than the foregoing description, and all changes within the meaning and range equivalent to the claims are intended to be embraced by the claims. Any particular embodiment of the present disclosure within the enclosure may be expressly excluded from any one or more of the claims. Since such embodiments are considered to be known to those skilled in the art, they may be excluded even if not expressly described herein as being excluded. Any particular embodiment of the present disclosure can be excluded from any claim regardless of whether or not it relates to the existence of the prior art and for any reason. Equivalents The present invention may be exemplified in other specific forms without departing from its spirit or essential characteristics. Therefore, the foregoing embodiments are not intended to limit the present invention described herein, but should be regarded as illustrative in all respects. The scope of the present invention is thus indicated by the appended claims rather than the foregoing description, and all changes within the meaning and range equivalent to the claims are intended to be embraced by the claims. Any particular embodiment of the present disclosure within the enclosure may be expressly excluded from any one or more of the claims. Since such embodiments are considered to be known to those skilled in the art, they may be excluded even if not expressly described herein as being excluded. Any particular embodiment of the present disclosure can be excluded from any claim regardless of whether or not it relates to the existence of the prior art and for any reason. Equivalents

Claims

Claim 1 A method for treating progressive or metastatic cholangiocarcinoma in a patient in need thereof, comprising administering an effective amount of infigratinib or a pharmaceutically acceptable salt thereof, wherein the patient has progression of cholangiocarcinoma after a previous administration of other therapies.

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