Treatment of cancer with FGFR kinase inhibitors

Abstract

Provided herein are compositions and methods for the treatment of cancer. The compositions include an FGFR kinase inhibitor. Some embodiments include combination therapy featuring an FGFR kinase inhibitor and at least one cancer therapeutic agent.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Patent Application No. 63 / 287,456, filed December 8, 2021, which is incorporated by reference herein in its entirety. [Background technology]

[0002] Fibroblast growth factor receptors (FGFRs) are a subfamily of receptor tyrosine kinases (RTKs) that bind to protein members of the fibroblast growth factor family. Dysregulation of the fibroblast growth factor / FGF receptor network occurs frequently in tumors. It is therefore desirable that therapies targeting abnormal FGFR kinase activity can be used to treat cancer and other diseases. One such modulator of FGFR kinase is 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide. Summary of the Invention

[0003] One embodiment provides a method of treating cancer in a patient in need of such treatment. The method of treating cancer comprises administering 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, or a pharma- ceutical acceptable salt or solvate thereof, to the patient, the cancer being selected from the group consisting of bladder cancer, urinary bladder carcinoma, urothelial carcinoma, urothelial cancer, renal cell carcinoma, prostate cancer, double negative prostate, castration resistant prostate cancer, gastric carcinoma, gastric cancer, and the like. The cancer is selected from gastroesophageal junction adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, intrahepatic cholangiocarcinoma, pancreatic adenocarcinoma, pancreatic cancer, breast cancer, HER2(-) / ER(+) breast cancer, HER2(-) / ER(+) / PR(+) breast cancer, non-Hodgkin's lymphoma, acute myeloid leukemia, myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis, multiple myeloma, glioblastoma, glioma, astrocytoma, anaplastic astrocytoma, medulloblastoma, oligodendroglioma, anaplastic oligodendroglioma, meningioma, lung cancer, or non-small cell lung cancer. Another embodiment provides a method wherein the cancer is characterized by having an oncogenic FGFR mutation. Another embodiment provides a method wherein the cancer is characterized by having an oncogenic FGFR2 mutation. Another embodiment provides a method wherein the cancer is characterized by having an oncogenic FGFR3 mutation. [Brief description of the drawings]

[0004] [Figure 1A] FIG. 1 shows the antitumor activity of Compound 1 in a xenograft model derived from the RT-112 FGFR3-driven human cancer cell line. [Figure 1B] FIG. 1 shows the antitumor activity of Compound 1 in a xenograft model derived from the RT-112 FGFR3-driven human cancer cell line. [Figure 1C]FIG. 1 shows the antitumor activity of Compound 1 in a xenograft model derived from the RT-112 FGFR3-driven human cancer cell line. [Figure 2A] FIG. 1 shows the antitumor activity of Compound 1 in a xenograft model derived from the SNU-16 FGFR2-driven human cancer cell line. [Figure 2B] FIG. 1 shows the antitumor activity of Compound 1 in a xenograft model derived from the SNU-16 FGFR2-driven human cancer cell line. [Figure 2C] FIG. 1 shows the antitumor activity of Compound 1 in a xenograft model derived from the SNU-16 FGFR2-driven human cancer cell line. [Diagram 3] A flow chart of the BOIN study design is provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the specific purposes identified herein.

[0006] Specific Terms As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, a reference to "the cell" includes a reference to one or more cells (or cells) and equivalents thereof known to those of skill in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of the ranges and specific embodiments within the ranges are intended to be included. The term "about" when referring to a numerical value or numerical range means that the numerical value or numerical range referred to is approximate within experimental variation (or within statistical experimental error), and thus the numerical value or numerical range may vary, in some cases, between 1% and 15% of the stated numerical value or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude certain other embodiments, such as embodiments of any composition of matter, composition, method, or process described herein that "consist of" or "consist essentially of" the recited features.

[0007] As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated below.

[0008] "Pharmaceutically acceptable salt" includes both acid and base addition salts.The pharmaceutically acceptable salt of the heterocyclic FGFR kinase inhibitor described herein is intended to include any pharmaceutically suitable salt form.Preferred pharmaceutically acceptable salt of the compound described herein is pharmaceutically acceptable acid addition salt and pharmaceutically acceptable base addition salt.

[0009] "Pharmaceutically acceptable acid addition salts" refer to salts which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic monocarboxylic acids, aliphatic dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic sulfonic acids, aromatic sulfonic acids, etc., including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate, gluconate and galacturonate (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared in some embodiments by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those of ordinary skill in the art.

[0010] "Pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness and properties of the free acid and is not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts are formed in some embodiments with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2 dimethylaminoethanol, 2 diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0011] "Pharmaceutically acceptable solvate" refers to a substance composition that is a solvent addition form. In some embodiments, the solvate contains either a stoichiometric or non-stoichiometric amount of a solvent and is formed during the preparation process using a pharma-ceutically acceptable solvent such as water, ethanol, etc. When the solvent is water, a hydrate is formed, and when the solvent is alcohol, an alcoholate is formed. The solvates of the compounds described herein are conveniently prepared or formed by the process described herein. The compounds provided herein optionally exist in the form of solvates as well as unsolvates.

[0012] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalian class, such as humans, non-human primates such as chimpanzees, other apes and monkeys; domestic animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0013] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably. These terms refer to an approach to obtain a beneficial or desired result, including, but not limited to, therapeutic benefit and / or prophylactic benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying disease being treated. Therapeutic benefit is also achieved by eradication or amelioration of one or more of the physiological symptoms associated with the underlying disease, such that an improvement is observed in the patient, even though the patient is still suffering from the underlying disease. For prophylactic benefit, in some embodiments, the composition is administered to a patient at risk of developing a particular disease, or to a patient who reports one or more of the physiological symptoms of a disease, even though the patient has not been diagnosed with the disease. As used herein, the term "treating" means, unless otherwise indicated, reversing, alleviating, inhibiting the progression, or preventing the disease or condition to which the term applies, or one or more symptoms of the disease or condition. In some embodiments, the term "treating" includes slowing or retarding the progression of the disease or disorder to which the term applies. Moreover, in some embodiments, the term "treat" refers to one or more complications resulting from the disease or disorder to which the term applies. As used herein, unless otherwise indicated, the term "treatment" refers to the act of treating, as "treat" is defined immediately above.

[0014] The term "tumor" or "cancer" as used herein refers to the proliferation of neoplastic cells, unless otherwise specified, and includes precancerous and cancerous cells and tissues. A tumor usually appears as a lesion or lump. As used herein, "treating" a tumor means that one or more symptoms of the disease, such as the tumor itself, the tumor's vascularization, or other parameters by which the disease is characterized, are alleviated, ameliorated, suppressed, placed in remission, or maintained in remission. "Treating" a tumor also means that one or more characteristics of the tumor may be eliminated, reduced, or prevented by treatment. Non-limiting examples of such characteristics include uncontrolled degradation of the basement membrane and proximal extracellular matrix, migration, division, and organization of endothelial cells into capillaries with new functions, and persistence of capillaries with such functions.

[0015] The terms "refractory" or "treatment resistant" indicate that a patient has never responded to treatment.

[0016] The terms "relapsed" or "relapsed after treatment" indicate that a patient initially responded to a previous treatment but has subsequently progressed due to acquired resistance and / or intolerance.

[0017] The terms "resistance to therapy" or "acquired resistance to therapy" refer to a patient who initially responded to a previous therapy, but whose disease progresses due to clinical or molecular resistance to the therapy. Acquired resistance can result from the emergence of resistance mutations in the molecular target of the therapy, or the development of physiological functions such as efflux pumps.

[0018] As used herein, the phrase "therapeutically effective amount" refers to an amount of a drug or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, or human that is desired by a researcher, veterinarian, medical doctor, or the like.

[0019] Other aspects, advantages and features of the present invention will become apparent from the following detailed description.

[0020] Fibroblast Growth Factor Receptor Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases that control diverse physiological and pathological processes ranging from embryonic development to tumorigenesis. FGFR family members (FGFR1, FGFR2, FGFR3, FGFR4) are transmembrane proteins that contain an extracellular ligand-binding domain and an intracellular tyrosine kinase domain. In the absence of fibroblast growth factor (FGF) ligands, unphosphorylated FGFR kinases remain in an inactive conformation. Binding of FGF ligands leads to receptor dimerization and autophosphorylation, followed by activation of downstream signaling pathways, such as rat sarcoma viral oncogene homolog / mitogen-activated protein kinase (RAS-MAPK), phosphatidylinositol 3 kinase / protein kinase B (PI3K-AKT), and phospholipase Cγ / protein kinase C (PLCγ-PKC) axis, which control cell proliferation, survival, and migration (Babina & Turner 2017, Katoh 2019).

[0021] Oncogenic FGFR gene mutations, observed in approximately 7% of all human cancers, typically manifest as activating point mutations, small intragenic deletions, genomic amplifications, or chromosomal rearrangements / fusions (Cerami et al. 2012; Gao et al. 2013; Helsten et al. 2016), leading to aberrant signaling and promoting tumorigenesis. As a result, dysregulated FGFR signaling promotes tumor cell proliferation, survival, and the development of drug resistance (Babina & Turner 2017; Katoh 2019). In particular, FGFR2 gene fusions and FGFR3 activating mutations are predicted to be responsible for 10–20% of cholangiocarcinomas and 20–35% of urothelial cancers, respectively (Katoh 2019; Krook et al. 2020). Consistently, pharmacological inhibition of FGFRs has demonstrated remarkable anti-proliferative and anti-tumor effects in preclinical models of FGFR-dependent human cancers, supporting the clinical development of FGFR inhibitors (Hall et al. 2016; Perera et al. 2017; Goyal et al. 2019; Liu et al. 2020; Sootome et al. 2020).

[0022] Three FGFR inhibitors, erdafitinib, pemigatinib, and infigratinib, have recently been approved by the US Food and Drug Administration for the treatment of patients with advanced or metastatic FGFR2- and FGFR3-driven cancers (Loriot et al. 2019; Abou-Alfa et al. 2020; Jayle et al. 2021; BALVERSA® Package Insert [PI], PEMAZYRE® PI, TRUSELTIQ® PI). The main limitation of the currently approved and clinically staged FGFR inhibitors is the emergence of secondary target gene mutations that limit the duration of response (Goyal et al. 2017; Goyal et al. 2019; Silverman et al. 2021; Varghese et al. 2021). Mutations in key gatekeeper residues in the FGFR kinase domain lead to steric hindrance within the adenosine triphosphate (ATP) binding pocket, inhibiting access of ATP-competitive FGFR inhibitors. Mutations in gatekeeper residues in each FGFR (FGFR1-V561, FGFR2-V565F (also known as FGFR2-V564F), FGFR3-V555M, FGFR4-V550L) have been demonstrated to confer resistance to reversible type I pan-FGFR inhibition (Dai et al. 2019). FGFR2 kinase domain single nucleotide mutations corresponding to known gatekeeper and activating mutations have been identified in patients who progressed on FGFR inhibitor treatment and have been demonstrated to constitute an acquired resistance mechanism in intrahepatic cholangiocarcinoma (Goyal et al. 2017, Goyal et al. 2019). Similar activating mutations in FGFR3 have been detected in patient samples and show resistance in preclinical models (Patani et al. 2016 ).

[0023] Heterocyclic FGFR Kinase Inhibitors The heterocyclic FGFR kinase inhibitors described herein refer to compound 1 having the following structure, chemical name 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide.

[0024] [ka]

[0025] Compound 1 is an irreversible small molecule FGFR kinase inhibitor. Throughout this disclosure, when a heterocyclic FGFR kinase inhibitor, or a pharma- ceutically acceptable salt or solvate thereof is mentioned, the reference is to Compound 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0026] Cancer and Treatment Methods In one embodiment, disclosed herein is a method of inhibiting FGFR kinase enzyme, comprising contacting the enzyme with compound 1, or a pharma- ceutically acceptable salt or solvate thereof, as disclosed herein. In a particular embodiment, disclosed herein is a method of treating cancer in an individual in need thereof, comprising administering to the individual an effective amount of a heterocyclic FGFR kinase inhibitor as described herein. In a particular embodiment, disclosed herein is a heterocyclic FGFR kinase inhibitor for use in treating cancer. In a particular embodiment, disclosed herein is a heterocyclic FGFR kinase inhibitor for use in preparing a medicament for treating cancer, as described herein.

[0027] One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof. One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable excipient. Another embodiment provides a method, wherein the cancer is characterized by an oncogenic FGFR mutation. Another embodiment provides a method, wherein the cancer is characterized by an oncogenic FGFR2 mutation. Another embodiment provides a method, wherein the cancer is characterized by an oncogenic FGFR3 mutation. Another embodiment provides a method, wherein the FGFR mutation is FGFR2[K660M], FGFR2[K659M], FGFR2[L618V], FGFR2[L617V], FGFR2[N550H], FGFR2[N549H], FGFR2[N550K], FGFR2[N549K], FGFR2[V565F], FGFR2[V564F], FGFR2[N550S / T], FGFR2[N549S / T], FGFR3[G697C], FGFR3[V555M], FGFR3[K650E], FGFR3[N540K / S], FGFR3[K650M], and FGFR1[V561M], or a combination thereof, The method is selected from the group consisting of:

[0028] Another embodiment provides a method, wherein the FGFR mutation is selected from at least one mutation disclosed in Table 1.

[0029] [Table 1-1]

[0030] [Table 1-2]

[0031] [Table 1-3]

[0032] Another embodiment provides a method, wherein the oncogenic FGFR mutation is an FGFR2 amplification, an FGFR2 fusion or rearrangement, an FGFR2 insertion-deletion mutation, an FGFR3 fusion or rearrangement, FGFR3-TACC3, or FGFR3-BAIAP2L1.

[0033] One embodiment provides a method of treating cancer, the cancer being bladder cancer, urinary bladder carcinoma, urothelial carcinoma, urothelial cancer, renal cell carcinoma, prostate cancer, double negative prostate, castration resistant prostate cancer, gastric carcinoma, gastric cancer. cancer), esophagogastric junction cancer, hepatocellular carcinoma, cholangiocarcinoma, intrahepatic cholangiocarcinoma, pancreatic adenocarcinoma, pancreatic cancer, breast cancer, HER2(-) / ER(+) breast cancer, HER2(-) / ER(+) / PR(+) breast cancer, non-Hodgkin's lymphoma, acute myeloid leukemia, myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis, multiple myeloma, glioblastoma, glioma, astrocytoma, anaplastic astrocytoma, medulloblastoma, oligodendroglioma, anaplastic oligodendroglioma, meningioma, lung cancer, or non-small cell lung cancer.

[0034] Another embodiment provides a method of treating cancer, where the tumor is characterized by the presence of at least one FGFR2 or FGFR3 gene mutation. Another embodiment provides a method of treating cancer, where the tumor is characterized by the presence of FGFR2 and FGFR3 gene mutations. Another embodiment provides a method of treating cancer, where the tumor is characterized by the presence of at least one FGFR1, FGFR2 or FGFR3 gene mutation. Another embodiment provides a method of treating cancer, where the tumor is characterized by the presence of any FGFR gene mutation. Another embodiment provides a method of treating cancer, where the patient is selected by an FGFR1, FGFR2 or FGFR3 gene mutation detected by an FDA approved test. Another embodiment provides a method of treating cancer, where the patient is selected by an FGFR2 or FGFR3 fusion or rearrangement detected by an FDA approved test. Another embodiment provides a method of treating cancer, where the patient is selected by an FGFR2 fusion or rearrangement detected by an FDA approved test. Another embodiment provides a method of treating cancer in which patients are selected for an FGFR3 fusion or rearrangement as detected by an FDA approved test.

[0035] One embodiment provides a method of treating cancer, wherein the cancer is selected from gastric carcinoma, gastric cancer, or gastroesophageal junction cancer.

[0036] One embodiment provides a method of treating cancer, wherein the cancer is selected from bladder cancer, urinary bladder carcinoma, urothelial carcinoma, or urothelial cancer. One embodiment provides a method of treating cancer, wherein the cancer is selected from cholangiocarcinoma, intrahepatic cholangiocarcinoma, pancreatic adenocarcinoma, pancreatic cancer. One embodiment provides a method of treating cancer, wherein the cancer is selected from gastric carcinoma, gastric cancer, or gastroesophageal junction cancer, and the patient is selected by FGFR2 or FGFR3 fusions or rearrangements detected by an FDA approved test.

[0037] One embodiment provides a method of treating cancer, wherein the cancer is selected from bladder cancer, urinary bladder carcinoma, urothelial carcinoma, or urothelial cancer, and the patient is selected by an FGFR2 or FGFR3 fusion or rearrangement detected by an FDA approved test. One embodiment provides a method of treating cancer, wherein the cancer is selected from cholangiocarcinoma, intrahepatic cholangiocarcinoma, pancreatic adenocarcinoma, pancreatic cancer, and the patient is selected by an FGFR2 or FGFR3 fusion or rearrangement detected by an FDA approved test. One embodiment provides a method of treating cancer, wherein the cancer is selected from prostate cancer, double negative prostate, or castration resistant prostate cancer. One embodiment provides a method of treating cancer, wherein the cancer is selected from breast cancer, HER2(-) / ER(+) breast cancer, or HER2(-) / ER(+) / PR(+) breast cancer. One embodiment provides a method of treating cancer, wherein the cancer is selected from non-Hodgkin's lymphoma. One embodiment provides a method of treating cancer, wherein the cancer is selected from acute myeloid leukemia. One embodiment provides a method of treating cancer, wherein the cancer is selected from multiple myeloma. One embodiment provides a method of treating cancer, wherein the cancer is selected from myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. One embodiment provides a method of treating cancer, wherein the cancer is selected from glioblastoma, glioma, astrocytoma, anaplastic astrocytoma, medulloblastoma, oligodendroglioma, anaplastic oligodendroglioma, or meningioma. One embodiment provides a method of treating cancer, wherein the cancer is selected from lung cancer, or non-small cell lung cancer. One embodiment provides a method of treating cancer, wherein the cancer is renal cell carcinoma. One embodiment provides a method of treating cancer, wherein the cancer is hepatocellular carcinoma.

[0038] One embodiment provides a method of treating cancer, wherein the cancer is bladder cancer. One embodiment provides a method of treating cancer, wherein the cancer is urinary bladder carcinoma. One embodiment provides a method of treating cancer, wherein the cancer is urothelial carcinoma. One embodiment provides a method of treating cancer, wherein the cancer is urothelial cancer. One embodiment provides a method of treating cancer, wherein the cancer is cholangiocarcinoma. One embodiment provides a method of treating cancer, wherein the cancer is intrahepatic cholangiocarcinoma.

[0039] One embodiment provides a method of treating cancer, where the cancer is bladder cancer and the patient is selected by an FGFR2 or FGFR3 fusion or rearrangement detected by an FDA approved test. One embodiment provides a method of treating cancer, where the cancer is urinary bladder carcinoma and the patient is selected by an FGFR2 or FGFR3 fusion or rearrangement detected by an FDA approved test. One embodiment provides a method of treating cancer, where the cancer is urothelial carcinoma and the patient is selected by an FGFR2 or FGFR3 fusion or rearrangement detected by an FDA approved test. One embodiment provides a method of treating cancer, where the cancer is urothelial cancer and the patient is selected by an FGFR2 or FGFR3 fusion or rearrangement detected by an FDA approved test. One embodiment provides a method of treating cancer, where the cancer is cholangiocarcinoma and the patient is selected by an FGFR2 or FGFR3 fusion or rearrangement detected by an FDA approved test. One embodiment provides a method of treating cancer, wherein the cancer is intrahepatic cholangiocarcinoma and the patient is selected by an FGFR2 or FGFR3 fusion or rearrangement detected by an FDA approved test.

[0040] Another embodiment provides a method, wherein the cancer is metastatic. Another embodiment provides a method, wherein the method is adjuvant therapy after surgical resection. Another embodiment provides a method, wherein the method is neoadjuvant therapy before surgical resection. Another embodiment provides a method, wherein the patient has relapsed after a previous treatment. Another embodiment provides a method, wherein the patient has acquired resistance to a previous treatment. Another embodiment provides a method, wherein the patient is treatment resistant. Another embodiment provides a method, wherein 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof, is orally administered. Another embodiment provides a method, wherein a composition comprising 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof, or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable excipient, is orally administered. Another embodiment provides a method, wherein the oral administration is every other day, once a day, twice a day, or three times a day.

[0041] One embodiment is a method of treating cancer in a patient in need thereof, comprising: (a) a composition comprising 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, or a pharma- ceutically acceptable salt or solvate thereof; and (b) at least one cancer therapeutic agent selected from an mTOR inhibitor, a MAPK / PI3K inhibitor, an immune checkpoint inhibitor, an EGFR kinase inhibitor or an EGFR kinase antibody, a HER2 kinase inhibitor, an estrogen receptor antagonist, an androgen receptor antagonist, a CDK kinase inhibitor, an ALK receptor tyrosine kinase inhibitor, a ROS receptor tyrosine kinase inhibitor, an NTRK receptor tyrosine kinase inhibitor, or a chemotherapy regimen; to a patient.

[0042] Another embodiment provides a method, wherein at least one cancer therapeutic is an mTOR inhibitor. Another embodiment provides a method, wherein the mTOR inhibitor is rapamycin. Another embodiment provides a method, wherein at least one cancer therapeutic is a MAPK / PI3K inhibitor. Another embodiment provides a method, wherein the MAPK / PI3K inhibitor is binimetinib or copanlisib. Another embodiment provides a method, wherein at least one cancer therapeutic is a HER2 kinase inhibitor. Another embodiment provides a method, wherein the HER2 inhibitor is lapatinib. Another embodiment provides a method, wherein at least one cancer therapeutic is an immune checkpoint inhibitor. Another embodiment provides a method, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. Another embodiment provides a method, wherein the CTLA-4 inhibitor is ipilimumab. Another embodiment provides a method, wherein the PD-1 inhibitor is spartalizumab, nivolumab, atezolizumab, pembrolizumab, or cemiplimab. Another embodiment provides a method, wherein the PD-L1 inhibitor is atezolizumab, avelumab, or durvalumab. Another embodiment provides a method, wherein the at least one cancer therapeutic is a CDK inhibitor. Another embodiment provides a method, wherein the CDK inhibitor is a CDK4 / 6 inhibitor. Another embodiment provides a method, wherein the CDK4 / 6 inhibitor is palbociclib, abemaciclib, or ribociclib. Another embodiment provides a method, wherein the at least one cancer therapeutic is an EGFR kinase inhibitor or an EGFR kinase antibody. Another embodiment provides a method, wherein the EGFR kinase inhibitor is nazartinib, gefitinib, erlotinib, afatinib, brigatinib, icotinib, neratinib, osimertinib, dacomitinib, or lapatinib. Another embodiment provides a method, wherein the EGFR antibody is cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab. Another embodiment provides a method, wherein the at least one cancer therapeutic is an estrogen receptor antagonist. Another embodiment provides a method, wherein the estrogen receptor antagonist is fulvestrant. Another embodiment provides a method, wherein the at least one cancer therapeutic is an androgen receptor antagonist.Another embodiment provides a method, wherein the androgen receptor antagonist is enzalutamide.Another embodiment provides a method, wherein at least one cancer therapeutic agent is selected from ALK receptor tyrosine kinase inhibitor, ROS receptor tyrosine kinase inhibitor, or NTRK receptor tyrosine kinase inhibitor.Another embodiment provides a method, wherein at least one cancer therapeutic agent is a chemotherapy regimen.Another embodiment provides a method, wherein the chemotherapy regimen is a cisplatin regimen, a gemcitabine regimen, or a FOLFOX regimen.

[0043] Pharmaceutical Compositions In certain embodiments, the heterocyclic FGFR kinase inhibitors described herein are administered as pure chemicals.In other embodiments, the heterocyclic FGFR kinase inhibitors described herein are combined with a pharma- ceutically suitable or acceptable carrier (also referred to herein as pharma- ceutically suitable or acceptable excipient, physiologically suitable or acceptable excipient, or physiologically suitable or acceptable carrier) that is selected based on the selected route of administration and standard pharmaceutical practice.

[0044] Provided herein are pharmaceutical compositions comprising a heterocyclic FGFR kinase inhibitor as described herein, or a stereoisomer, pharma- ceutically acceptable salt, hydrate or solvate thereof, together with one or more pharma- ceutical acceptable carriers. Carrier(s) (or excipient(s)) are acceptable or suitable if they are compatible with the other components of the composition and not deleterious to the recipient of the composition (i.e., the subject or patient).

[0045] One embodiment provides a method for preparing a pharmaceutical composition comprising mixing a heterocyclic FGFR kinase inhibitor described herein, or a stereoisomer, pharma- ceutically acceptable salt, hydrate or solvate thereof, and a pharma- ceutically acceptable carrier.

[0046] Provided herein is a method for orally administering pharmaceutical compositions.Suitable oral administration forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or other suitable materials that dissolve easily in the digestive tract.In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, etc. (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005))).

[0047] Provided herein is a method of administering pharmaceutical compositions by injection.In some embodiments, the heterocyclic FGFR kinase inhibitor described herein or its pharma-ceutically acceptable salt or solvate is formulated for administration by injection.In some examples, the injection formulation is an aqueous formulation.In some examples, the injection formulation is a non-aqueous formulation.In some examples, the injection formulation is an oily formulation such as sesame oil.

[0048] The dosage of the composition comprising the heterocyclic FGFR kinase inhibitors described herein, or stereoisomers, pharma- ceutically acceptable salts, hydrates or solvates thereof, varies depending on the condition of the subject or patient (e.g., human). In some embodiments, such factors include general health, age, and other factors. The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dosage and the appropriate duration and frequency of administration are determined by factors such as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dosage and treatment regimen provides a sufficient amount of the composition(s) to provide a therapeutic and / or prophylactic benefit (e.g., improved clinical outcomes such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced severity of symptoms). Optimal dosages are generally determined using experimental models and / or clinical trials. Optimal dosages depend on the patient's size, weight, or blood volume. EXAMPLES

[0049] These examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0050] Compound 1, a novel, next-generation, irreversible, small molecule pan-FGFR inhibitor, was structurally designed to inhibit clinically observed secondary mutations known to cause resistance to approved FGFR inhibitors. In this study, we evaluated the biochemical inhibitory activity of compound 1 against a panel of wild-type and mutant FGFR kinases, as well as its selectivity against the rest of the kinome.

[0051] Example 1: FGFR kinase inhibitory activity of compound 1 Compound 1 was tested in biochemical assays to assess activity against both wild-type and mutant FGFR kinase family members in multiple independent experiments. Mobility shift assays were performed across a panel of purified FGFR kinase enzymes. Table 2 shows the average inhibitory potency of compound 1 against the enzyme panel. Wild-type FGFR1, FGFR2, FGFR3, and FGFR4 had ICs of 3.90 nM, 5.25 nM, 9.70 nM, and 4.91 nM, respectively. 50 The kinase domain mutations at the gatekeeper residues FGFR1-V561M, FGFR2-V565F (also known as FGFR2-V5654F), and FGFR3-V555M had IC values ​​of 62.98 nM, 20.81 nM, and 24.27 nM, respectively. 50 The FGFR2-N550H (also known as FGFR2-N549H) molecular brake and FGFR3-K650M activating mutations had IC values ​​of 22.80 nM and 4.63 nM, respectively. 50 The values ​​were shown.

[0052] [Table 2]

[0053] The broad kinome selectivity of compound 1 was tested by mobility shift assay (MSA). Compound 1 at a concentration of 1 μM was screened against a panel of 321 kinases. Table 3 lists the kinases that showed more than 40% inhibition. In this panel, only two non-FGFR kinases showed more than 40% inhibition, including TNK1 at 89.5% and LOK (also known as serine threonine kinase 10 [STK10]) at 64.6%, respectively.

[0054] [Table 3]

[0055] conclusion In biochemical assays, compound 1 was a potent inhibitor of FGFR wild-type and mutant kinases. Furthermore, kinome screening in a broad panel of human kinases showed minimal activity against kinases outside the FGFR kinase family. These studies indicate that compound 1 is a potent inhibitor of FGFR family kinases and is selective across the human kinome.

[0056] Example 2: Compound 1 inhibits cell proliferation in cell culture The ability of compound 1 to inhibit cellular FGFR kinases was tested across a range of assay formats: NanoBRET target engagement, pharmacodynamic biomarker modulation, and tumor cell growth inhibition.

[0057] Cellular FGFR target engagement Intracellular target engagement was demonstrated in a proximity-based assay by measuring energy transfer from a bioluminescent protein donor (NanoLuc fusion) to a fluorescent probe (NanoBRET tracer) in HEK-293 cells. In the NanoBRET assay, the apparent affinity of compound 1 was measured by competitive displacement of a tracer that reversibly binds to the fusion protein in live cells. As shown in Table 4, compound 1 exhibited target engagement half maximal inhibitory concentrations (IC ) of 13.7 nM, 7.3 nM, 25.8 nM, and 24.1 nM in FGFR1, FGFR2, FGFR3, and FGFR4 wild-type proteins, respectively. 50 ) values ​​for FGFR2 mutations including K659M, L617V, N549H (also known as FGFR2-N550H), N549K, and V565F (also known as FGFR2-V564F). 50 The NanoBRET IC values ​​for the G697C and V555M FGFR3 mutations were 51.3 nM, 21.7 nM, 6.8 nM, 27.5 nM, and 13.4 nM, respectively. 50 The values ​​were 32.3 nM and 71.6 nM, respectively.

[0058] [Table 4]

[0059] Inhibition of pERK in FGFR-dysregulated human cancer cells Compound 1 demonstrated broad cellular activity across human FGFR mutant cancer models as determined by MAPK pathway inhibition read out by pharmacodynamic modulation of pERK biomarker 1 hour after dosing in multiple independent experiments, as shown in Table 5. In FGFR2 amplified SNU-16 and KATO-III human gastric cancer cells, pERK EC 50 The values ​​were 1.26 nM and 2.58 nM, respectively. pERK EC of bladder carcinoma cells carrying RT-112 and RT-4 FGFR3-TACC3 fusion 50 The values ​​were 3.02 nM and 2.77 nM, respectively. Mean pERK EC 50 The value was 2.68.

[0060] [Table 5]

[0061] Inhibition of FGFR2 autophosphorylation in FGFR2-amplified human cancer cells Compound 1 inhibition of the Tyr653 / 654 autophosphorylation site of FGFR2 was evaluated in two FGFR2-amplified human cancer cell lines in multiple independent experiments. Cellular activity was determined by modulation of FGFR2 phosphorylation 2 hours after inhibitor administration and measured with a Meso Scale Discovery assay specific for phosphorylated Tyr653 / 654, as shown in Table 6. Compound 1 showed a mean EC 50 The cellular pFGFR2 was inhibited at 100-fold.

[0062] [Table 6]

[0063] Inhibition of FGFR-dysregulated human cancer cell proliferation In multiple independent experiments, Compound 1 inhibition of cell proliferation was evaluated across a panel of human FGFR-dysregulated cancer models and measured by CellTiter-Glo (CTG) 5 days after administration of Compound 1. As shown in Table 7, the EC 50 The EC values ​​of FGFR3 fusion-expressing bladder carcinoma cell lines RT-112, RT-4, and SW-780 were 3.89 nM and 5.19 nM, respectively. 50 The values ​​were 4.14 nM, 5.96 nM, and 4.14 nM, respectively.

[0064] [Table 7]

[0065] conclusion Compound 1 demonstrated cellular target engagement of wild-type and mutant FGFR kinase family proteins, as well as cellular activity across a panel of FGFR2- and FGFR3-dysregulated human cancer cell models. Cellular target engagement of compound 1 was established in wild-type FGFR1, FGFR2, FGFR3, and FGFR4, as well as in FGFR2 and FGFR3 proteins containing known secondary kinase domain resistance mutations in gatekeeper and molecular brake residues. The EC of compound 1 for intrinsic FGFR inhibition in five human tumor cell lines tested was 1.25-fold higher than that of compound 1 in the control group. 50 Values ​​ranged from 1 to 6 nM. Taken together, these findings indicate that compound 1 potently inhibits human FGFR-driven cancer cell proliferation and FGFR signaling and binds to clinically relevant mutant FGFR proteins.

[0066] Example 3: Determination of antiproliferative activity in a xenograft model Compound 1, a novel, next-generation, irreversible, small molecule pan-FGFR inhibitor, inhibits clinically observed secondary mutations known to cause resistance to approved FGFR kinase inhibitors. Preclinical studies have demonstrated that compound 1 is potent against FGFR2 and FGFR3 gatekeeper (FGFR2-V565F (also known as FGFR2-V564F) and FGFR3-V555M, respectively), molecular brake (FGFR2-N550X (also known as FGFR2-N549X)), and activation loop (FGFR3-K650M) mutations, among others, with low nanomolar biochemical and cellular target engagement and half maximal inhibitory concentrations (IC 50 ) values. Therefore, compound 1 has the potential to address targeted resistance mutations in patients with FGFR-driven tumors who have progressed on first-generation FGFR inhibitors, as well as extend the duration of response in frontline treatment. Here, the biotolerability and antitumor activity of compound 1 were evaluated in xenograft models derived from FGFR2- and FGFR3-driven human cancer cell lines.

[0067] Study design The average tumor volume is approximately 200-250 mm 3 Once tumor volume reached 100 mg / kg / day, grouping and treatment were initiated. Mice were assigned to groups based on starting tumor volume and body weight, such that the mean values ​​of both parameters were balanced across treatment groups. Groups and treatments for evaluating the antitumor activity of compound 1 in FGFR-driven human cancers (RT-112 and SNU-16) are shown in Table 8.

[0068] [Table 8]

[0069] result I. Human RT-112 bladder transitional cell carcinoma xenograft model The antitumor activity of compound 1 was evaluated in a human RT-112 bladder transitional cell carcinoma xenograft model harboring an FGFR3-TACC3 fusion. Treatment with compound 1 (2, 5, or 15 mg / kg) resulted in tumors with a volume of approximately 200-250 mm 3 (The actual mean tumor volume for all groups was 264 mm 3 ) and continued once daily (QD) for 3 weeks.

[0070] Treatment of mice bearing RT-112 xenografts with Compound 1 PO and QD showed that the AUC last Values ​​ranged from 1,320 to 9,760 h*ng / mL. A dose-dependent tumor growth inhibition was observed with compound 1 versus control (vehicle-treated) tumors (Figure 1A). All doses tested were well tolerated, although some weight loss was observed in animals treated with 15 mg / kg (mean weight loss 5.4%, Figure 1B). In the 15 mg / kg cohort, three animals lost more than 10% of their body weight during treatment but had recovered by the end of the study.

[0071] Waterfall plots of individual tumor responses, defined as the change in tumor volume from baseline, and mean TGI by treatment group are shown in Figure 1C and Table 9, respectively. Statistically significant reductions in RT-112 tumor growth were achieved at all doses tested. Mean TGIs achieved at daily doses of 2 mg / kg, 5 mg / kg, and 15 mg / kg were 80%, 91%, and 99%, respectively (p<0.0001, Figure 1C and Table 9), with 4 of 9 mice (44%) each showing tumor regression in the latter two groups. Table 9 summarizes the results of FGFR3-driven bladder cancer (RT-112) xenograft tumor growth inhibition by compound 1.

[0072] [Table 9]

[0073] II. Human SNU-16 gastric cancer xenograft model We next evaluated the antitumor activity of compound 1 in human xenograft models exhibiting FGFR2 gene amplification and low levels of FGFR2 fusions, including FGFR2-PDHX. Xenografts derived from the SNU-16 gastric cancer cell line were similarly treated with compound 1 at 2 mg / kg, 5 mg / kg, or 15 mg / kg daily for 3 weeks. 3 Treatment was started when the actual mean TV for all groups was 262 mm 3 (It was.)

[0074] Treatment of mice bearing SNU-16 xenografts with Compound 1 PO and QD showed that the AUC last Values ​​are 1,090 to 9,760 h * Compound 1 was administered at a dose-dependent inhibition of SNU-16 tumor growth relative to control (vehicle-treated) tumors (Figure 2A). All doses and dosing schedules tested were well tolerated, as indicated by the lack of significant body weight changes in treated animals (Figure 2B).

[0075] Waterfall plots of individual tumor responses and mean TGI by treatment group are shown in Figure 2C and Table 10, respectively. Statistically significant reductions in SNU-16 tumor growth were achieved at all doses tested. Mean TGI achieved at daily doses of 2 mg / kg, 5 mg / kg and 15 mg / kg were 69%, 81% and 93%, respectively (p<0.0001, Figure 2, Table 10). Tumor regression was observed in one animal in the 15 mg / kg QD cohort. Table 10 summarizes the results of FGFR2-driven gastric cancer (SNU-16) xenograft tumor growth inhibition by compound 1.

[0076] [Table 10]

[0077] conclusion Dose-dependent inhibition of the growth of xenografts derived from FGFR2- and FGFR3-driven human cancer cell lines was observed with daily administration of compound 1 (2–15 mg / kg). RT-112 (FGFR3-TACC3 fusion positive) and SNU-16 (FGFR2 amplification and FGFR2-PDHX fusion positive) xenografts showed mean TGI of 80–99% and 69–93%, respectively (p<0.0001). Weight loss was observed at the highest dose of compound 1 (15 mg / kg) in the former model, but not in the latter model. Taken together, oral administration of compound 1 is generally well tolerated and efficacious in mouse xenograft models of FGFR-driven human cancer.

[0078] Example 4: Use of Compound 1 in Human Clinical Trials Title: A Phase 1 / 1b, Open-Label, Multicenter, Two-Part Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Compound 1 in Participants with Advanced Tumors with FGFR1, FGFR2, and / or FGFR3 Genetic Mutations Investigational drug: Compound 1 Trial Phase: Phase 1 / 1b Indications: Advanced tumors with FGFR1, FGFR2, and / or FGFR3 gene mutations

[0079] overview The study is a first-in-human (FIH), two-part, open-label, multicenter, dose-escalation, and dose-expansion study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of compound 1, a next-generation irreversible small molecule pan-fibroblast growth factor receptor (FGFR) inhibitor. Additionally, the study will determine the recommended phase 2 dose (RP2D) of compound 1 for further clinical development and evaluate the objective response to treatment with compound 1 in participants with advanced tumors harboring relevant FGFR1, FGFR2, and / or FGFR3 genetic alterations.

[0080] Test Purpose The primary objective of Part A, the dose escalation portion of the study, is to determine the safety and tolerability of oral administration of Compound 1, including dose-limiting toxicities (DLTs), in participants with advanced tumors harboring FGFR1, FGFR2, and / or FGFR3 genetic alterations, and to identify the maximum tolerated dose (MTD) and / or RP2D of Compound 1 for further clinical development.

[0081] The primary objective of Part B, the dose-expansion portion of the study, is to evaluate preliminary evidence of antitumor activity of Compound 1 in participants with advanced tumors (including intrahepatic cholangiocarcinoma [ICC], urothelial carcinoma [UC], and other solid tumors, as appropriate) harboring FGFR1, FGFR2, and / or FGFR3 genetic alterations.

[0082] A secondary objective is to characterize the PK of Compound 1.

[0083] Exploratory objectives include further characterization of the exposure-response relationship and potential metabolites of Compound 1 with respect to efficacy and safety, evaluation of target PD modulation by Compound 1, and evaluation of potential biomarkers of response / resistance to Compound 1 in blood samples and / or tumor biopsies.

[0084] Study design The study will be conducted in two parts: Part A is dose escalation, and Part B is dose expansion. Part A aims to evaluate the safety, tolerability, PK, and PD of Compound 1 and to determine the MTD of a once-daily (QD) dosing schedule in participants with advanced tumors with FGFR1, FGFR2, and / or FGFR3 genetic mutations using a modified Bayesian optimal interval (BOIN) design. Once the MTD and / or biologically active dose (e.g., RP2D of Compound 1 for further clinical development) have been determined in Part A, the dose expansion part (Part B) of the study can be initiated. Part A will consist of up to approximately 45 participants, and Part B will consist of approximately 75 participants, including at least three cohorts with advanced tumors with FGFR1, FGFR2, and / or FGFR3 genetic mutations (i.e., ICC, UC, and all other advanced tumors). Part B may use different dosing schedules based on the clinical and PK data from Part A, but will be limited to those with less dosing intensity than the daily dosing schedule for 28 days. The DLT evaluation period is 28 days.

[0085] Administration of Compound 1 to participants in Parts A and B may continue until evidence of disease progression, intolerance to study drug, unacceptable toxicity, initiation of new systemic cancer therapy, withdrawal of consent, investigator / sponsor decision, or death.

[0086] Part A (dose escalation): Part A will follow a modified BOIN dose escalation scheme to identify the MTD and / or RP2D of compound 1 in participants with advanced tumors harboring FGFR1, FGFR2, and / or FGFR3 genetic alterations. The target DLT rate for the MTD will be defined as 30% of participants experiencing a DLT at a dose level during the 28-day DLT evaluation period.

[0087] In Part A, participants with advanced tumors harboring FGFR2 and / or FGFR3 gene mutations will be included, provided they meet all protocol-defined eligibility requirements.

[0088] Participants with advanced tumors harboring FGFR1, FGFR2, and / or FGFR3 genetic alterations will receive compound 1 orally QD over 28-day treatment cycles. Alternative dosing schedules may be included depending on study data and recommended by the Dosage Review Committee (DRC).

[0089] The study will start with a cohort size of 3. The starting dose, dose level 1 (DL1), will be 5 mg by comparing the DLT rate observed at the current dose level with fixed pre-specified dose escalation boundary values ​​of 0.197 (λe) and 0.298 (λd) (see Table 11). Provisional Compound 1 dose levels for dose escalation in Part A. It can also be decided to escalate, deescalate, eliminate, or maintain the current dose based on the number of DLTs observed relative to the number of participants treated at the current dose level (Table 2). "Exclusion" means excluding the current dose and any doses above it from the study because they are too toxic, preventing future patients from being treated at these dose levels. Once the lowest dose is excluded, the study will be stopped without choosing an MTD.

[0090] [Table 11] *Dose escalation step size is capped at 100%. The number of participants enrolled in a cohort depends on whether DLT occurs during that treatment cohort. Maximum cohort size is 9.

[0091] [Table 12]

[0092] Dose escalation will continue to the next higher dose until the planned sample size (n=30) is reached or the maximum cohort size (n=9) is reached according to the modified BOIN decision rules outlined in Table 12 and Figure 3. Tentative Compound 1 dose levels are shown in Table 11. Intermediate doses may be recommended if necessary.

[0093] A dose review committee (DRC), consisting of the investigators and representatives of the sponsor, will review the available safety, PK, and PD data before initiating enrollment at the next dose level. The specific step size may be determined by referring to the modified BOIN design recommendations and, in some cases, by adding additional supplemental Bayesian models. The dose escalation and deescalation rules described above also apply to intermediate dose levels where testing will be conducted. The DRC will determine the MTD and / or RP2D of compound 1 for further clinical development once sufficient safety, efficacy, and PK / PD data are available.

[0094] Part A of the study will allow within-participant dose escalation and backfilling at the sponsor's discretion.

[0095] Part B (dose expansion): Part B evaluates the antitumor activity of Compound 1 in the following cohorts (approximately 25 patients / cohort) at the recommended dose of Compound 1 for cohort expansion as determined in Part A: Cohort 1: Participants with advanced ICC and FGFR2 mutations Cohort 2: Participants with advanced UC and FGFR2 and / or FGFR3 gene mutations Cohort 3: Participants with advanced tumors (other than ICC or UC) with FGFR1, FGFR2, and / or FGFR3 gene mutations

[0096] Enrollment of participants into the three dose expansion cohorts may occur simultaneously, but not in Part A. As a guideline, a table of allowed gene variants is provided.

[0097] For cohorts 1 and 2, a Simon two-stage optimal design is planned.

[0098] Enrollment of participants with a variety of tumor types harboring FGFR2 and / or FGFR3 gene alterations will be monitored over the course of the study in Cohort 3. Enrollment of certain tumor types may be limited to ensure broad representation of a variety of advanced tumors in this cohort.

[0099] Study Evaluation Items Primary endpoint Safety endpoints included: Incidence of dose-limiting toxicities (DLTs) Incidence of adverse events (AEs), including treatment-related adverse events (TEAEs) and treatment-related adverse events (TRAEs) Clinically significant changes in vital signs, physical examination, 12-lead electrocardiogram (ECG), and laboratory tests

[0100] Efficacy is measured by: Objective response rate (ORR), defined as the proportion of partial responses (PR) plus complete responses (CR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Disease control rate (DCR) Duration of response (DOR) Progression-free survival (PFS)

[0101] Secondary endpoints PK parameters for Compound 1 include maximum plasma concentration (C max ), C max Arrival time (t max ), and area under the plasma concentration-time curve (AUC). exploratory Compound 1 exposure and safety and exposure and efficacy relationships ·Overall survival (OS) Stable period Characterization of potential metabolites of compound 1 in plasma and urine · In the expansion cohort (Part B), quality of life PROs may be incorporated (e.g., 5Q-ED-5L). Molecular and / or genetic analysis of biomarkers including, but not limited to, phosphorus levels, FGF23 levels, genomic analysis, gene expression profiling (GEP), and FGFR pathway modulation in blood and / or tumor biopsy samples to evaluate pharmacodynamic relationships and characterize potential resistance mechanisms.

[0102] Sample size Part A (dose escalation): Part A of the study will enroll up to approximately 45 participants. Approximately 30 of the 45 participants will be enrolled according to a modified BOIN design. Up to 15 additional participants may be enrolled as backfill to further characterize the MTD and / or RP2D. Part B (dose expansion):

[0103] Approximately 75 participants will be enrolled in Part B of the study, which will include the following cohorts (approximately 25 participants / cohort): Cohort 1: Participants with advanced ICC and FGFR2 mutations Cohort 2: Participants with advanced UC and FGFR2 and / or FGFR3 gene mutations Cohort 3: Participants with advanced tumors (other than ICC or UC) with FGFR1, FGFR2 and / or FGFR3 gene mutations

[0104] Overview of Participant Eligibility Criteria Adult participants (age 18 years or older, or age of majority in the local jurisdiction) with a histologically or cytologically confirmed diagnosis of advanced malignancy are eligible for the study. Part A dose escalation will enroll participants with any type of advanced tumor with FGFR1, FGFR2 and / or FGFR3 gene mutations. Part B dose expansion will enroll participants with advanced ICC with FGFR2 gene mutations, advanced UC with FGFR2 and / or FGFR3 gene mutations, or advanced tumors (other than ICC or UC) with FGFR1, FGFR2 and / or FGFR3 gene mutations. Participants must have previously received standard therapy (including agents approved in the local jurisdiction) appropriate for their tumor type and stage, or, in the opinion of the investigator, be unable to tolerate or unlikely to derive clinically meaningful benefit from standard therapy. Participants with history and / or current evidence of non-tumor related alterations in calcium-phosphorus homeostasis, history and / or current evidence of clinically significant ectopic mineralization / calcification, or history and / or current evidence of clinically significant retinal damage will be excluded from participation in the study.

[0105] Enrollment will be limited to participants with advanced tumors with FGFR1, FGFR2, and / or FGFR3 genetic alterations, as confirmed by prior genomic analysis of tumor tissue or ctDNA performed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory (within the United States) or in accordance with local regulatory requirements (other countries). After consenting, participants will provide a medical history, undergo screening safety tests, and ensure all eligibility requirements for the study are met. Participants will provide archived tumor tissue specimens (formalin-fixed paraffin-embedded [FFPE] specimens) taken within the past 5 years (if available) and will undergo a mandatory pretreatment tumor biopsy, if medically feasible.

[0106] Test location / location The study will be conducted worldwide at approximately 10 locations for Part A and approximately 30 locations for Part B.

[0107] Test period The estimated duration of the study is approximately four years.

[0108] Duration of treatment Participants will receive Compound 1 in 28-day cycles until evidence of disease progression, intolerance to study drug, unacceptable toxicity, initiation of new systemic cancer therapy, withdrawal of consent, investigator's decision, sponsor's decision, or death.

[0109] Statistical considerations Part A of the study will use a modified BOIN design with a target DLT rate of 25% at the MTD. Upon completion of dose escalation in Part A, isotonic regression analysis will be performed to identify the MTD and / or RP2D of compound 1 for further clinical development. A summary of DLTs observed across all dose levels will be provided along with a summary of AEs and serious adverse events (SAEs).

[0110] Safety analyses, including analyses of all AEs, clinical laboratory values, and vital signs, will include all participants who received at least one dose of Compound 1 in both Parts A and B of the study.

[0111] Efficacy analyses will focus on participants enrolled in Part B. However, participants receiving the same dose as in Part B may be included in appropriate disease cohorts as sensitivity analyses. For ORR endpoints, Clopper-Pearson 95% confidence intervals (CIs) will be provided. DOR will be calculated in responders (CR and PR). PFS, OS, and duration of SD will be analyzed using the Kaplan-Meier method with graphical representation of Kaplan-Meier curves.

Claims

1. 1. A pharmaceutical composition comprising 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer in a patient in need thereof, said method comprising administering to said patient 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt or solvate thereof.

2. 1. A pharmaceutical composition comprising 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, for use in a method of treating cancer in a patient in need thereof, said method comprising administering said pharmaceutical composition to said patient.

3. 1. A pharmaceutical composition comprising 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer in a patient in need thereof, said method comprising: (a) a composition comprising 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt or solvate thereof; and (b) at least one cancer therapeutic agent selected from the group consisting of an mTOR inhibitor, a MAPK / PI3K inhibitor, an immune checkpoint inhibitor, an EGFR kinase inhibitor or an EGFR kinase antibody, a HER2 kinase inhibitor, an estrogen receptor antagonist, an androgen receptor antagonist, a CDK kinase inhibitor, an ALK receptor tyrosine kinase inhibitor, a ROS receptor tyrosine kinase inhibitor, an NTRK receptor tyrosine kinase inhibitor, or a chemotherapy regimen; to said patient.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the cancer is characterized by the presence of at least one oncogenic FGFR1, FGFR2 or FGFR3 gene mutation.

5. Oncogenic FGFR mutations include: FGFR2 [K660M], FGFR2 [K659M], FGFR2 [L618V], FGFR2 [L617V], FGFR2[N550H], FGFR2[N549H], FGFR2 [N550K], FGFR2 [N549K], FGFR2 [V565F], FGFR2[V564F], FGFR2 [N550S / T], FGFR2[N549S / T], FGFR3 [G697C], FGFR3 [V555M], FGFR3 [K650E], FGFR3[N540K / S], FGFR3[K650M], and FGFR1[V561M], or a combination thereof; 5. The pharmaceutical composition of claim 4, selected from the group consisting of:

6. The pharmaceutical composition according to claim 4, wherein the oncogenic FGFR mutation is FGFR2 amplification, FGFR3-TACC3, or FGFR3-BAIAP2L1.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cancer has wild-type FGFR2 or FGFR3.

8. The pharmaceutical composition of any one of claims 1 to 3, wherein the patient is selected by an FGFR2 or FGFR3 fusion or rearrangement as detected by an FDA approved test.

9. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cancer is a solid tumor.

10. The cancers include bladder cancer, urinary bladder cancer, urothelial carcinoma, and urothelial carcinoma. cancer), renal cell carcinoma, prostate cancer, double-negative prostate, castration-resistant prostate cancer, gastric carcinoma, gastric cancer The pharmaceutical composition of any one of claims 1 to 3, wherein the cancer is selected from the group consisting of esophago-gastric junction cancer, hepatocellular carcinoma, cholangiocarcinoma, intrahepatic cholangiocarcinoma, pancreatic adenocarcinoma, pancreatic cancer, breast cancer, HER2(-) / ER(+) breast cancer, HER2(-) / ER(+) / PR(+) breast cancer, non-Hodgkin's lymphoma, acute myeloid leukemia, myeloproliferative neoplasm, polycythemia vera, essential thrombocythemia, primary myelofibrosis, multiple myeloma, glioblastoma, glioma, astrocytoma, anaplastic astrocytoma, medulloblastoma, oligodendroglioma, anaplastic oligodendroglioma, meningioma, lung cancer, and non-small cell lung cancer.

11. 11. The pharmaceutical composition of claim 10, wherein the cancer is selected from bladder cancer, urinary bladder carcinoma, urothelial carcinoma, urothelial cancer, bile duct cancer, or intrahepatic cholangiocarcinoma.

12. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cancer is metastatic.

13. The pharmaceutical composition according to any one of claims 1 to 3, wherein the method is an adjuvant therapy after surgical resection.

14. The pharmaceutical composition according to any one of claims 1 to 3, wherein the method is a neoadjuvant therapy before surgical resection.

15. The pharmaceutical composition of any one of claims 1 to 3, wherein the patient has relapsed after a previous treatment.

16. The pharmaceutical composition according to any one of claims 1 to 3, wherein the patient has acquired resistance to a previous treatment.

17. The pharmaceutical composition according to any one of claims 1 to 3, wherein the patient is treatment-resistant.

18. 4. The pharmaceutical composition of claim 3, wherein the at least one cancer therapeutic agent is an immune checkpoint inhibitor.

19. The pharmaceutical composition of claim 18, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.

20. 20. The pharmaceutical composition of claim 19, wherein the CTLA-4 inhibitor is ipilimumab.

21. 20. The pharmaceutical composition of claim 19, wherein the PD-1 inhibitor is spartalizumab, nivolumab, pembrolizumab, or cemiplimumab.

22. 20. The pharmaceutical composition of claim 19, wherein the PD-L1 inhibitor is atezolizumab, avelumab, or durvalumab.

23. 4. The pharmaceutical composition of claim 3, wherein the at least one cancer therapeutic agent is a CDK inhibitor.

24. 24. The pharmaceutical composition of claim 23, wherein the CDK inhibitor is a CDK4 / 6 inhibitor.

25. 25. The pharmaceutical composition of claim 24, wherein the CDK4 / 6 inhibitor is palbociclib, abemaciclib, or ribociclib.

26. 4. The pharmaceutical composition of claim 3, wherein the at least one cancer therapeutic agent is an EGFR kinase inhibitor or an EGFR kinase antibody.

27. 27. The pharmaceutical composition of claim 26, wherein the EGFR kinase inhibitor is nazartinib, gefitinib, erlotinib, afatinib, brigatinib, icotinib, neratinib, osimertinib, dacomitinib, or lapatinib.

28. 27. The pharmaceutical composition of claim 26, wherein the EGFR antibody is cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab.

29. 4. The pharmaceutical composition of claim 3, wherein the at least one cancer therapeutic agent is an mTOR inhibitor.

30. 30. The pharmaceutical composition of claim 29, wherein the mTOR inhibitor is rapamycin.

31. 4. The pharmaceutical composition of claim 3, wherein the at least one cancer therapeutic agent is a MAPK / PI3K inhibitor.

32. 32. The pharmaceutical composition of claim 31, wherein the MAPK / PI3K inhibitor is binimetinib or copanlisib.

33. 4. The pharmaceutical composition of claim 3, wherein the at least one cancer therapeutic agent is a HER2 kinase inhibitor.

34. 34. The pharmaceutical composition of claim 33, wherein the HER2 inhibitor is lapatinib.

35. 4. The pharmaceutical composition of claim 3, wherein the at least one cancer therapeutic agent is an estrogen receptor antagonist.

36. 36. The pharmaceutical composition of claim 35, wherein the estrogen receptor antagonist is fulvestrant.

37. 4. The pharmaceutical composition of claim 3, wherein the at least one cancer therapeutic agent is an androgen receptor antagonist.

38. 38. The pharmaceutical composition of claim 37, wherein the androgen receptor antagonist is enzalutamide.

39. 4. The pharmaceutical composition of claim 3, wherein the at least one cancer therapeutic agent is selected from an ALK receptor tyrosine kinase inhibitor, a ROS receptor tyrosine kinase inhibitor, or an NTRK receptor tyrosine kinase inhibitor.

40. 4. The pharmaceutical composition of claim 3, wherein the at least one cancer therapeutic agent is a chemotherapy regimen.

41. 41. The pharmaceutical composition of claim 40, wherein the chemotherapy regimen comprises platinum-based chemotherapy.

42. 42. The pharmaceutical composition of claim 41, wherein the platinum-based chemotherapy is oxaliplatin, cisplatin, or carboplatin.

43. 41. The pharmaceutical composition of claim 40, wherein the chemotherapy regimen comprises a gemcitabine regimen.

44. 41. The pharmaceutical composition of claim 40, wherein the chemotherapy regimen comprises a FOLFOX regimen.

45. 45. The pharmaceutical composition of claim 44, wherein the FOLFOX regimen comprises folinic acid.

46. 45. The pharmaceutical composition of claim 44, wherein the FOLFOX regimen comprises 5-fluorouracil.

47. 45. The pharmaceutical composition of claim 44, wherein the FOLFOX regimen comprises folinic acid and folinic acid.

48. The pharmaceutical composition according to any one of claims 1 to 3, wherein the 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-4,6-difluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt or solvate thereof, is administered orally.

49. 49. The pharmaceutical composition of claim 48, wherein oral administration occurs every other day, once a day, twice a day, or three times a day.

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