Methods for treating solid tumors with activating FGFR3 gene alterations

Abstract

The present disclosure provides methods of treating cancers harboring activating FGFR3 genetic alterations by administering a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) disclosed herein.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 373,933, filed August 30, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure is directed to methods of treating cancer using FGFR3 inhibitors. [Background technology]

[0003] The fibroblast growth factor (FGF) family of receptor tyrosine kinases consists of four highly conserved membrane-associated proteins (FGFR1, FGFR2, FGFR3, and FGFR4) that function to regulate cell growth, differentiation, and homeostasis. The structure of FGFRs contains an extracellular domain, a transmembrane domain, and an intracellular tyrosine kinase domain. The activity of the intracellular kinase domain is regulated by the interaction of the extracellular domain with members of the FGF family of ligands. Twenty-two FGF family members have been identified, of which 18 are secreted and act as ligands for FGFRs. While most of these FGFs act locally in a paracrine manner to affect adjacent cells, three FGFs (FGF19, FGF21, and FGF23) circulate in the blood and act endocrinely to regulate FGFRs in distant tissues. When activated, these receptors stimulate multiple cellular pathways, including proliferation. See Xie Y, Su N, Yang J et al., FGF / FGFR signaling in health and disease. Signal Transduct Target Ther. 2020;5(1):181.

[0004] The four FGFRs are structurally homologous but have specific physiological roles depending on their tissue expression and ligand interactions. The functions of these receptors are often redundant and overlapping, including roles in embryogenesis, tissue homeostasis, tissue repair, apoptosis, and cell migration. See Yue S, Li Y, Chen X, et al., FGFR-TKI resistance in cancer: current status and perspectives. J Hematol Oncol. 2021;14:23. Germline mutations in these receptors can be associated with genetic disorders (e.g., point mutations in FGFR3 can cause achondroplasia, the most common form of short stature in humans).

[0005] In the FGFR family of receptors, oncogenic alterations that act as constitutive activators can occur in the ligand-binding and transmembrane domains, as well as directly in the intracellular kinase domain. Similarly, in addition to mutations, oncogenes can arise in FGFRs through gene rearrangements and amplifications. Activating mutations, fusions, or amplifications initiate multiple intracellular pathways, such as the mitogen-activated protein kinase pathway and the phosphoinositide 3-kinase pathway, that are common with other oncogenes. See Facchinetti F, Hollebecque A, Baleda R, et al., Facts and new hopes on selective FGFR inhibitors in solid tumors. Clin Cancer Res. 2020;26(4):764-74. Using next-generation sequencing (NGS), it has been shown that 7.1% of cancers harbor some form of FGFR alteration, with gene amplification being the most common (66%), followed by activating mutations (26%). The most common cancers showing mutations appear to be urothelial carcinoma (32%), breast cancer (18%), endometrial cancer (13%), lung cancer (13%), and ovarian cancer (9%). See Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing. Clin Cancer Res. 2016;22(1):259-67.

[0006] Urothelial carcinoma (URC) is a leading cause of morbidity and mortality worldwide, with over 420,000 new cases and over 165,000 deaths annually. FGFR3 alterations are found in up to 80% of non-muscle-invasive bladder cancers and up to 15-20% of muscle-invasive tumors. The most common FGFR3 alteration is the S249C mutation found in the ligand-binding domain, followed by the Y375C mutation in the transmembrane domain; these two mutations account for approximately 80% of FGFR3 mutations in bladder cancer.

[0007] Currently approved and late-stage pan-FGFR inhibitors are susceptible to acquired resistance mutations in the gatekeeper site of the FGFR3 protein. These same pan-FGFR inhibitors are limited by significant toxicity associated with inhibiting off-target receptor tyrosine kinases, including other isoforms of the FGFR family. This off-target activity limits dosing and, theoretically, provides additional opportunities for acquired resistance due to frequent interruptions and dose reductions.

[0008] Therefore, there is a need for methods of treating cancers with activating FGFR3 genetic alterations using isoform-selective FGFR3 inhibitors.

[0009] The compounds of formula (I) are highly selective inhibitors of FGFR3 that are being developed for the treatment of FGFR3-driven cancers. The compounds of formula (I) have the following structure:

[0010] [ka]

[0011] A description of the synthesis and activity of compounds of formula (I), as well as pharmaceutical salts of compounds of formula (I) and pharmaceutical compositions that may contain compounds of formula (I) (and / or salts thereof), can be found in WO 2022 / 147246, which is incorporated herein by reference. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] International Publication No. 2022 / 147246 [Non-patent literature]

[0013] [Non-Patent Document 1] Xie Y, Su N, Yang J, et al. FGF / FGFR signaling in health and disease. Signal Transduct Target Ther. 2020;5(1):181 [Non-patent document 2] Yue S, Li Y, Chen X, et al. FGFR-TKI resistance in cancer: current status and perspectives. J Hematol Oncol. 2021;14:23 [Non-patent document 3] Facchinetti F, Hollebecque A, Bahleda R, et al. Facts and new hopes on selective FGFR inhibitors in solid tumors. Clin Cancer Res. 2020;26(4):764~74 [Non-patent document 4] Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing. Clin Cancer Res. 2016;22(1):259~67 [Non-Patent Document 5] US Food and Drug Administration. Drug Development and Drug Interactions. Table of Substrates, Inhibitors and Inducers [Non-patent document 6] Eisenhauser EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228~47 Summary of the Invention [Means for solving the problem]

[0014] The present disclosure fulfills the need for a method of treating cancer harboring an activating FGFR3 genetic alteration using an isoform-selective FGFR3 inhibitor by providing a method of treating cancer in a patient, the method comprising administering to the patient a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer harbors an activating FGFR3 genetic alteration. [Brief explanation of the drawings]

[0015] [Figure 1] Figure 1 shows a schematic diagram of the study design. Abbreviations: FGFR3 = fibroblast growth factor receptor 3, FGFRi = fibroblast growth factor receptor inhibitor, MTD = maximum tolerated dose, mUC = locally advanced / metastatic urothelial carcinoma, RP2D = recommended phase 2 dose. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present disclosure may be more fully understood by reference to the following description, including the following definitions and examples. Certain features of the disclosed methods that are described herein in the context of separate embodiments may also be provided in combination in a single embodiment. Alternatively, various features of the disclosed methods that are described in the context of a single embodiment for brevity of description may also be provided separately or in any subcombination.

[0017] With regard to the use of substantially all plural and / or singular terms in this specification, those skilled in the art can convert from plural to singular and / or from singular to plural as required by the context and / or application. Various singular / plural permutations may be expressly stated herein for clarity of explanation. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0018] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid, such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, for example, formic acid, acetic acid, benzenesulfonic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example, an alkali metal salt such as an ammonium salt, a sodium salt, or a potassium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, a salt of an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and the like, and a salt with an amino acid such as arginine and lysine. Particularly preferred salts of the compound of formula (I) are described in WO 2022 / 147246.

[0019] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. Additionally, in any compound described herein having one or more double bonds that produce geometric isomers that can be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof. It is understood that in any compound described herein having one or more chiral centers, all possible diastereomers are also contemplated. It is understood that in any compound described herein, all tautomers are contemplated. It is also understood that in any compound described herein, all isotopes of the atoms involved are contemplated. For example, any example of hydrogen may include hydrogen-1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium), or other isotopes; any example of carbon may include carbon-12, carbon-13, carbon-14, or other isotopes; any example of oxygen may include oxygen-16, oxygen-17, oxygen-18, or other isotopes; any example of fluorine may include one or more of fluorine-18, fluorine-19, or other isotopes; and any example of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.

[0020] A "pharmaceutically acceptable excipient" refers to a substance, e.g., an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a compound of formula (I), that is compatible with a compound of formula (I), non-toxic, biologically tolerated, and otherwise biologically suitable for administration to a subject.

[0021] As used herein, "subject," "host," "patient," "participant," and "individual" are used interchangeably and shall be given their ordinary meaning, and shall also refer to organisms that have FGFR proteins. This includes mammals, such as humans, non-human primates, ungulates, dogs, cats, horses, mice, rats, etc. The term "mammal" includes both human and non-human mammals.

[0022] The terms "treatment," "treating," "treating," and the like shall be given their ordinary meaning and, as used herein, shall also include a general reference to obtaining a desired pharmacological and / or physiological effect. This effect may be prophylactic, in that it completely or partially prevents a disease or its symptoms, and / or therapeutic, in that it partially or completely stabilizes or cures the disease and / or adverse effects caused by the disease. "Treatment," as used herein, shall be given its ordinary meaning and shall also encompass any treatment of disease in mammals, particularly humans, including (a) preventing a disease or condition from occurring in a subject believed to be predisposed to the disease or condition but not yet diagnosed as having the disease or condition, (b) inhibiting a disease symptom, e.g., halting its development, and / or (c) alleviating a disease symptom, e.g., causing the disappearance of the disease or condition.

[0023] The term "administering," when used in the context of administering a therapeutic agent to a patient, refers to introducing the therapeutic agent into the patient's body. For example, the therapeutic agent may be introduced into the patient's body orally, nasally, subcutaneously, intravenously, intravesically, intramuscularly, transdermally, vaginally, rectally, or any combination thereof.

[0024] The terms "cancer," "neoplasm," and "tumor" are used interchangeably herein and shall be given their ordinary meaning, and shall also refer to cells that exhibit relatively autonomous growth and, as a result, exhibit an abnormal growth phenotype characterized by a significant loss of control of cell proliferation. Generally, cells of interest for detection or treatment in this application include precursor, pre-cancerous (e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells.

[0025] As used herein, "activating FGFR3 gene alteration" refers to a mutation or rearrangement of the FGFR3 gene compared to the wild-type FGFR3 gene such that an FGFR3 gene having an activating FGFR3 gene alteration encodes an FGFR kinase having greater FGFR3 kinase activity than the FGFR kinase encoded by the wild-type FGFR3 gene.

[0026] In some aspects, the present disclosure is directed to a method of treating cancer in a patient, comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0027] In some aspects, the present disclosure is directed to a method of treating cancer in a patient, comprising administering to the patient a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the cancer has an activating FGFR3 genetic alteration.

[0028] In some embodiments, the cancer is urothelial cancer, breast cancer, endometrial cancer, lung cancer, ovarian cancer, or bladder cancer.

[0029] In some embodiments, the cancer is urothelial carcinoma.

[0030] In other embodiments, the cancer is urothelial carcinoma.

[0031] In some other embodiments, the cancer is breast cancer.

[0032] In other embodiments, the cancer is endometrial cancer.

[0033] In other embodiments, the cancer is lung cancer.

[0034] In other embodiments, the cancer is ovarian cancer.

[0035] In other embodiments, the cancer is bladder cancer.

[0036] In some embodiments, the cancer is non-muscle invasive bladder cancer (NMIBC).

[0037] In other embodiments, the cancer is a locally advanced solid tumor.

[0038] In other embodiments, the cancer is a metastatic solid tumor.

[0039] In some embodiments of the disclosed methods, the cancer has an activating FGFR3 gene alteration.

[0040] In some embodiments, the activating FGFR3 gene change is mutation.In this context, the term " mutation " refers to the change in FGFR3 gene that causes the encoded FGFR3 kinase to have different amino acid sequence from wild-type FGFR3 kinase.The method for identifying FGFR3 mutation is known in the art.

[0041] In some embodiments, the mutation is: FGFR3 p.S84L, FGFR3 p.G380R, FGFR3 p.R621H, FGFR3 p.R248C, FGFR3 p.G380E, FGFR3 p.K650E, FGFR3 p.S249C, FGFR3 p.A391V, FGFR3 p.K650M, FGFR3 p.P250R, FGFR3 p.A391E, FGFR3 p.K650T, FGFR3 p.T264M, FGFR3 p.M528I, FGFR3 p.K650N, FGFR3 p.G370C, FGFR3 p.N540D, FGFR3 p.R669Q, FGFR3 p.S371C, FGFR3 p.N540S, FGFR3 p.G697C, FGFR3 p.Y373C, or FGFR3 p.N540K Any one or more of the following.

[0042] In other embodiments, the mutation is: FGFR3 p.V553M, FGFR3 p.V555M, or FGFR3 p.V555L Any one or more of the following.

[0043] In other embodiments, the activating FGFR3 gene alteration is a fusion gene mutation. As used in this context, a "fusion" is a gene that results from the joining of two previously independent genes.

[0044] In some embodiments, the fusion comprises the complete FGFR3 kinase domain and Breakpoints in intron 17 or exon 18 of FGFR3 and known partner genes (e.g., TACC3, BAIAP2L1), A breakpoint in intron 17 or exon 18 of FGFR3 and an in-frame novel partner gene, or Breakpoints in intron 17 or exon 18 of FGFR3 and intragenic regions or out-of-frame partner genes and FGFR3 rearrangement accompanied by

[0045] In some embodiments of the methods of the present disclosure, the patient is administered a compound of formula (I).

[0046] In other embodiments of the disclosed methods, the patient is administered a pharmaceutically acceptable salt of a compound of formula (I).

[0047] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is hydrochloride, besylate, maleate, tosylate, sulfate, 2-hydroxyethanesulfonate, ethanesulfonate (esylate), mesylate, dimesylate, R-camsylate, S-camsylate, or hydrobromide.

[0048] In some embodiments of the disclosed methods, the patient is administered a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) (based on Formula (I)) in an amount of 10 mg to 120 mg per day, such as, for example, 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, or 120 mg / day. In other embodiments of the disclosed methods, the patient is administered a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) (based on Formula (I)) in an amount of 10 mg to 200 mg per day, e.g., 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg 100mg / day, 90mg / day, 95mg / day, 100mg / day, 105mg / day, 110mg / day, 115mg / day, 120mg / day, 125mg / day, 130mg / day, 135mg / day, 140mg / day, 145mg / day, 150mg / day, 155mg / day, 160mg / day, 165mg / day, 170mg / day, 175mg / day, 180mg / day, 185mg / day, 190mg / day, 195mg / day, or 200mg / day. When the compound of formula (I) is administered as a pharmaceutically acceptable salt, the amount of the salt administered is based on the compound of formula (I). That is, the amount of the salt administered is the amount containing the specified amount of the free base of formula (I).

[0049] In some embodiments of the disclosed methods, the patient is administered a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) (based on formula (I)) in an amount of 10 mg per day.

[0050] In some embodiments of the disclosed methods, the patient is administered a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) (based on formula (I)) in an amount of 20 mg per day.

[0051] In some embodiments of the disclosed methods, the patient is administered a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) (based on formula (I)) in an amount of 40 mg per day.

[0052] In some embodiments of the disclosed methods, the patient is administered a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) (based on formula (I)) in an amount of 60 mg per day.

[0053] In some embodiments of the disclosed methods, the patient is administered a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) (based on formula (I)) in an amount of 75 mg per day.

[0054] In some embodiments of the disclosed methods, the patient is administered a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) (based on formula (I)) in an amount of 80 mg per day.

[0055] In some embodiments of the disclosed methods, the patient is administered a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) (based on formula (I)) in an amount of 90 mg per day.

[0056] In some embodiments of the disclosed methods, the patient is administered a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) (based on formula (I)) in an amount of 120 mg per day.

[0057] In some embodiments of the methods of the present disclosure, the daily dose of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) (based on formula (I)) is administered in a single dose.

[0058] In some embodiments of the methods of the present disclosure, the daily dose of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) (based on formula (I)) is administered in multiple doses, each of the multiple doses containing a fraction of the daily dose.

[0059] In some embodiments, the daily dose of a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) (based on Formula (I)) is administered in two doses, each of the two doses containing a fraction of the daily dose.

[0060] In some embodiments, the daily dose of a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) (based on Formula (I)) is administered in two doses, each of the two doses containing one-half of the daily dose.

[0061] In the methods of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) may be administered by any suitable route of administration, such as, for example, oral, nasal, subcutaneous, intravenous, intravesical, intramuscular, transdermal, vaginal, rectal, or any combination thereof.

[0062] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) is administered orally.

[0063] In the methods of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) can be administered in any suitable pharmaceutical dosage form. Suitable dosage forms include, but are not limited to, capsules, tablets, powders, suspensions, liquids, etc. Pharmaceutical dosage forms are typically formulated to provide a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) as an active ingredient. In some embodiments, the pharmaceutical dosage form also contains one or more pharmaceutically acceptable excipients.

[0064] In some embodiments of the present disclosure, the compound of Formula (I) or a pharmaceutically acceptable salt of the compound of Formula (I) is administered for at least 28 days. In some aspects, the administration is at least once daily. In some aspects, the administration is once daily.

[0065] In other embodiments of the present disclosure, the compound of Formula (I) or a pharmaceutically acceptable salt of the compound of Formula (I) is administered for 28 days. In some embodiments, the administration is at least once daily. In some embodiments, the administration is once daily.

[0066] In some embodiments, the disclosed methods comprise administering a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) together with an additional therapy.

[0067] In some embodiments, the additional therapy comprises one or more of radiation therapy, chemotherapy, and surgical treatment (eg, at least partial removal of a tumor).

[0068] In some embodiments, the additional therapy is chemotherapy, ie, the administration of one or more additional therapeutic agents.

[0069] In some embodiments, the additional therapeutic agent is a checkpoint inhibitor.

[0070] In some embodiments, the checkpoint inhibitor is a PD-1 / PD-L1 inhibitor such as, for example, one or more of pembrolizumab, nivolumab, avelumab, durvalumab, atezolizumab, cemiplimab, dostallimab, JTX-4014, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012 (MGA012), AMP-224, or AMP-514 (MEDI0680).

[0071] In other embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor such as, for example, one or more of ipilimumab, tremelimumab, or AGEN-1884.

[0072] In some embodiments, the additional therapeutic agent is an antibody-drug conjugate such as, for example, enfortumab vedotin, sacituzumab govitecan, dicitamab vedotin, or Vic-trastuzumab duocarmazine (SYD985).

[0073] In other embodiments, the additional therapeutic agent is cisplatin, carboplatin, gemcitabine, docetaxel, paclitaxel, vinflunine, methotrexate, vinblastine, mitomycin, valrubicin, or doxorubicin.

[0074] In some embodiments, the additional therapeutic agent is a MEK inhibitor such as, for example, trametinib, cobimetinib, or binimetinib.

[0075] In some embodiments, the additional therapeutic agent is a PARP inhibitor such as, for example, olaparib, veliparib, niraparib, rucaparib, or talazoparib.

[0076] In some embodiments, the additional therapeutic agent is a HER2 inhibitor such as, for example, lapatinib, afatinib, AZD8931, AST-1306, AEE-788, canertinib (CI-1033), CP724, CP714, CUDC-101, TAK-285, AC-480 (BMS-599626), dacomitinib (PF299804 PF299) (dacomitinib), or pelitinib (EKB-569).

[0077] In some embodiments, the additional therapeutic agent is an SHP2 inhibitor such as, for example, TNO-155 or RMC-4630.

[0078] In some embodiments, the additional therapeutic agent is an antibody.

[0079] In some embodiments, the antibody is a HER2 antibody, such as one or more of trastuzumab or pertuzumab.

[0080] In some embodiments, the antibody is a bispecific antibody, such as one or more of MM-111 or ertumaxomab.

[0081] In some embodiments, the additional therapy is a biological immunotherapy such as, for example, intravesical BCG (Bacillus Calmette-Guerin).

[0082] In embodiments of the disclosed methods that include administering a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) in combination with an additional therapy, the compound of formula (I) (or salt thereof) is administered before, during, or after the administration or administration of the additional therapy.

[0083] In embodiments of the disclosed methods in which the additional therapy is chemotherapy, the chemotherapeutic agent can be administered by any suitable route of administration, such as, for example, oral, nasal, subcutaneous, intravenous, intravesical, intramuscular, transdermal, vaginal, rectal, or any combination thereof.

[0084] In some embodiments, a compound of formula (I) (or a salt thereof) is administered prior to the administration or application of an additional therapy.

[0085] In some embodiments, the compound of formula (I) (or salt thereof) is administered during the administration or application of an additional therapy.

[0086] In some embodiments, the compound of formula (I) (or salt thereof) is administered after the administration or application of an additional therapy.

[0087] In some embodiments of the methods of the present disclosure, the cancer exhibits a complete response (CR) or partial response (PR) to administration of the compound of Formula (I) or a pharmaceutically acceptable salt of the compound of Formula (I), as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0088] In some embodiments, the cancer exhibits a complete response (CR) to administration of a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0089] In other embodiments, the cancer exhibits a partial response (PR) to administration of a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0090] The present disclosure is also directed to the following aspects:

[0091] Embodiment 1. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (I):

[0092] [ka]

[0093] or a pharmaceutically acceptable salt thereof.

[0094] Embodiment 2. The method of embodiment 1, wherein the cancer has an activating FGFR3 genetic alteration.

[0095] Aspect 3. The method of Aspect 1 or 2, wherein the cancer is urothelial cancer, breast cancer, endometrial cancer, lung cancer, ovarian cancer, or bladder cancer.

[0096] Embodiment 4. The method of embodiment 3, wherein the cancer is urothelial carcinoma.

[0097] Embodiment 5 The method of embodiment 3, wherein the cancer is urothelial carcinoma.

[0098] Embodiment 6 The method of embodiment 3, wherein the cancer is breast cancer.

[0099] Embodiment 7 The method of embodiment 3, wherein the cancer is endometrial cancer.

[0100] Embodiment 8 The method of embodiment 3, wherein the cancer is lung cancer.

[0101] Embodiment 9 The method of embodiment 3, wherein the cancer is ovarian cancer.

[0102] Embodiment 10 The method of embodiment 3, wherein the cancer is bladder cancer.

[0103] Embodiment 11 The method of any one of embodiments 1 to 10, wherein the cancer is a locally advanced solid tumor.

[0104] Embodiment 12 The method of any one of embodiments 1 to 11, wherein the cancer is a metastatic solid tumor.

[0105] Embodiment 13 The method of any one of embodiments 2 to 12, wherein the activating FGFR3 genetic alteration is a mutation.

[0106] Aspect 14. The mutation is: FGFR3 p.S84L, FGFR3 p.G380R, FGFR3 p.R621H, FGFR3 p.R248C, FGFR3 p.G380E, FGFR3 p.K650E, FGFR3 p.S249C, FGFR3 p.A391V, FGFR3 p.K650M, FGFR3 p.P250R, FGFR3 p.A391E, FGFR3 p.K650T, FGFR3 p.T264M, FGFR3 p.M528I, FGFR3 p.K650N, FGFR3 p.G370C, FGFR3 p.N540D, FGFR3 p.R669Q, FGFR3 p.S371C, FGFR3 p.N540S, FGFR3 p.G697C, FGFR3 p.Y373C, or FGFR3 p.N540K 14. The method of embodiment 13, wherein the method is or comprises one or more of:

[0107] Aspect 15. The mutation is: FGFR3 p.V553M, FGFR3 p.V555M, or FGFR3 p.V555L 14. The method of embodiment 13, wherein the method is or comprises one or more of:

[0108] Embodiment 16 The method of any one of embodiments 2 to 12, wherein the activating FGFR3 gene alteration is a fusion.

[0109] Embodiment 17. The fusion comprises a complete FGFR3 kinase domain, Breakpoints in intron 17 or exon 18 of FGFR3 and known partner genes (e.g., TACC3, BAIAP2L1), A breakpoint in intron 17 or exon 18 of FGFR3 and an in-frame novel partner gene, or Breakpoints in intron 17 or exon 18 of FGFR3 and intragenic regions or out-of-frame partner genes and

[0110] Embodiment 18 The method of any one of embodiments 1 to 17, wherein the patient is administered a compound of formula (I).

[0111] Embodiment 19 The method of any one of embodiments 1 to 17, wherein the patient is administered a pharmaceutically acceptable salt of a compound of Formula (I).

[0112] Aspect 20 The method of Aspect 19, wherein the pharmaceutically acceptable salt of the compound of Formula (I) is a besylate salt.

[0113] Aspect 21. The method of any one of Aspects 1 to 20, wherein the patient is administered a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) (based on Formula (I)) in an amount of 10 mg to 120 mg per day.

[0114] Aspect 22. The method of Aspect 21, wherein the patient is administered a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) (based on Formula (I)) in an amount of 10 mg per day.

[0115] Aspect 23. The method of Aspect 21, wherein the patient is administered a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) (based on Formula (I)) in an amount of 20 mg per day.

[0116] Aspect 24. The method of Aspect 21, wherein the patient is administered a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) (based on Formula (I)) in an amount of 40 mg per day.

[0117] Aspect 25. The method of Aspect 21, wherein the patient is administered a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) (based on Formula (I)) in an amount of 60 mg per day.

[0118] Aspect 26. The method of Aspect 21, wherein the patient is administered a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) (based on Formula (I)) in an amount of 90 mg per day.

[0119] Aspect 27. The method of Aspect 21, wherein the patient is administered a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) (based on Formula (I)) in an amount of 120 mg per day.

[0120] Aspect 28 The method of any one of Aspects 21 to 27, wherein the compound of Formula (I) or a pharmaceutically acceptable salt of the compound of Formula (I) is administered orally.

[0121] Aspect 29 The method of any one of Aspects 1 to 28, wherein the compound of Formula (I) or a pharmaceutically acceptable salt of the compound of Formula (I) is administered for at least 28 days.

[0122] Aspect 30 The method of Aspect 29, wherein the compound of Formula (I) or a pharmaceutically acceptable salt of the compound of Formula (I) is administered for 28 days.

[0123] Aspect 31 The method of any one of aspects 1 to 30, wherein the cancer exhibits a complete response (CR) or partial response (PR) to administration of a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I), as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0124] Aspect 32 The method of Aspect 31, wherein the cancer exhibits a complete response (CR) to administration of the compound of Formula (I) or a pharmaceutically acceptable salt of the compound of Formula (I), as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0125] Aspect 33 The method of Aspect 31 or 32, wherein the cancer exhibits a partial response (PR) to administration of the compound of Formula (I) or a pharmaceutically acceptable salt of the compound of Formula (I), as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0126] The examples provided below further describe and illustrate the disclosed methods. It should be understood that the scope of the present invention is in no way limited by the scope of the following examples. [Example]

[0127] [Table 1A]

[0128] [Table 1B]

[0129] [Table 1C]

[0130] [Table 1D]

[0131] Study title: A multicenter, open-label, phase 1 / 2 study of formula (I) in advanced urothelial carcinoma and other solid tumors with activating FGFR3 gene alterations the purpose: Main purpose: To determine the optimal and maximum tolerated dose (MTD) of Formula (I) and the recommended Phase 2 dose (RP2D) in participants with advanced solid tumors (Phase 1, Parts A and B) To evaluate the preliminary antitumor activity of RP2D Formula (I) in a selected tumor expansion cohort of participants with activating fibroblast growth factor receptor (FGFR) 3 gene alterations (Phase 2) Secondary Objectives: To characterize the safety and tolerability of Formula (I) in participants with advanced cancer (Phase 1, Parts A and B, and Phase 2) To conduct preliminary characterization of the pharmacokinetics (PK) and pharmacodynamics in participants treated with Formula (I) (Phase 1, Parts A and B, and Phase 2) To characterize the objective response rate (ORR) in participants with activating FGFR3 gene alterations (Phase 1, Part B) Characterize duration of response (DOR) (Phase 1, Part B, and Phase 2) To characterize disease control rates (DCR) beyond 12 weeks (Phase 1, Part B, and Phase 2) Characterize time to response (TTR) (Phase 1, Part B, and Phase 2) To characterize progression-free survival (PFS) in participants treated with Formula (I) in specific tumor expansion cohorts (Phase 2 Cohorts 1 and 2 only) Exploratory purpose: To identify potential biomarkers of FGFR binding / inhibition, toxicity, tumor response, and resistance to Formula (I) in blood, urine, and tissues. To evaluate the concordance between tissue and confirmatory clinical trial assay (CTA) results for the detection of FGFR3 gene alterations in participants with locally advanced / metastatic urothelial carcinoma To estimate overall survival (OS) in cohorts 1 and 2 of phase 2

[0132] Study design: This study is a Phase 1 / 2 open-label, international, multicenter, dose-escalation / dose-expansion study of Formula (I) conducted in several parts.

[0133] Phase 1, Part A: Dose Escalation Participants with any advanced solid tumor for which no approved standard therapy exists are eligible for enrollment, regardless of FGFR3 mutation status. The Formula (I) starting dose in Part A is 10 mg daily (DL1), with a dose escalation schema as follows: DL1: 10mg per day DL2: 20mg per day ·DL3: 40mg per day DL4: 60mg per day ·DL5: 90mg per day ·DL6: 120mg per day

[0134] This study will use an i3+3 design with a target toxicity rate of 0.3 (0.25-0.35) at the MTD. Each dose level (DL) will be evaluated through a dose-limiting toxicity (DLT) evaluation period (cycle 1 [28 days]), after which the next DL will be enrolled. Depending on the number of participants and the number of DLTs observed, decisions will be made to escalate to a higher dose or, if DL6, continue enrollment at the highest dose (E), maintain the same dose (S), reduce to the next lower dose (D), or reduce to the next lower dose and never repeat the current dose (DU).

[0135] DL1 and DL2 will be accelerated, with toxicity monitored in one participant during the DLT assessment period. Any treatment-related adverse event (TRAE) of Grade 2 or higher will constitute a DLT for DL1 and DL2. If no Grade 2 or higher TRAEs occur in DL1, the next participant will be enrolled in DL2. Similarly, if no Grade 2 or higher TRAEs occur in DL2, the next cohort dose will be escalated (i.e., enrolled in DL3). If additional participants are enrolled in either DL1 or DL2 because of this more stringent DLT definition, the study will switch to an i3+3 design, and all subsequent dose escalation decisions will use the same DLT definition as for DL3 and above (i.e., no longer use Grade 2 or higher TRAEs as the definition of a DLT).

[0136] DL3 and above will enroll a minimum of 3 participants per DL. These cohorts may enroll 1-3 additional participants at a time if required by DLT provisions. Dose escalation will continue up to DL6 and until the MTD is determined or approximately 30 participants are enrolled in Part A.

[0137] Phase 1, Part B: Dose Expansion If DL3 passes dose escalation, a dose expansion cohort will begin enrolling in parallel to further explore pharmacodynamics and biomarkers in FGFR3-mutant cancers. Enrollment will be limited to participants with advanced / metastatic solid tumors harboring FGFR3-activating genetic alterations appropriate for FGFR-directed therapy. Participants in the dose expansion will undergo additional analyses of biomarker and pharmacodynamic endpoints, including, but not limited to, on-treatment and post-progression assessment of ctDNA, serial blood biomarker analysis, and skin biopsies to assess FGFR target inhibition.

[0138] Eligible FGFR3 gene mutations and fusions are defined as follows:

[0139] Eligible FGFR3 gene mutations are listed in the table below.

[0140] [Table 2]

[0141] competent fibroblast growth factor receptor 3 fusion FGFR3 rearrangement with the complete FGFR3 kinase domain and: Breakpoints in intron 17 or exon 18 of FGFR3 and known partner genes (e.g., TACC3, BAIAP2L1). Breakpoints in intron 17 or exon 18 of FGFR3 and in-frame novel partner genes. Breakpoints in intron 17 or exon 18 of FGFR3 and intragenic regions or out-of-frame partner genes.

[0142] Secondary fibroblast growth factor receptor 3 mutations responsible for acquired resistance to current-generation fibroblast growth factor receptor inhibitors: FGFR3 p.V553M FGFR3 p.V555M FGFR3 p.V555L

[0143] Part B also utilizes an i3+3 design, but dose escalation is not applied. Cohorts can continue to expand based on the toxicity probability attributable to participants observed in both Part A and Part B for that DL. Because Part A escalates doses in parallel from DL4 to DL6, DLTs observed in Part B may necessitate interrupting or halting enrollment in Part A. Depending on the number of participants and the number of DLTs observed, a decision may be made to continue Part B expansion (E), continue Part B expansion but halt enrollment in Part A (S), or halt expansion for that DL and discontinue Part A (D or DU). Cohort expansion continues if the toxicity probability is ≤0.35 across DLs including data from both Part A and Part B. If Part B causes an interruption of enrollment in Part A, enrollment to a higher dose in Part A will resume if the toxicity rate decreases to <0.25 during Part B dose expansion and ongoing monitoring.

[0144] If the MTD is determined in Part A, up to 10 additional participants with locally advanced / metastatic FGFR3 mutation-positive urothelial carcinoma who have not received a prior FGFR inhibitor will be enrolled in Part B at the MTD. This cohort will evaluate the PK of the tablet formulation used in the Phase 2 portion of the study. PK and AEs will be reviewed by the SRC for 3-5 participants to ensure there are no safety concerns, after which enrollment in this expansion cohort will be completed.

[0145] Intra-participant dose escalation determination - Phase 1, Parts A and B Intra-participant dose escalation will be permitted for participants in these cohorts under the following circumstances: During dose escalation (Part A), higher doses were reached and were thought to be tolerated. The participant does not have a TRAE greater than Grade 1 while taking Formula (I). If any participant experiences Grade 3 or higher treatment-related toxicity at a given DL, intraparticipant dose escalation will not be permitted at that DL. The higher doses in the study in enrollment or completion cohorts are believed to be safe and may be more effective than the current dose in treating participants' tumors. Participants have completed at least two cycles of study medication and have had at least one post-baseline tumor imaging assessment.

[0146] Participants with evidence of progressive disease (PD) as defined by RECIST v1.1 will continue to receive study drug if they would benefit from continuing the study drug. The following criteria must be met to provide assurance that participants are not being exposed to unreasonable risk: - Absence of symptoms and signs of clinically significant disease progression. -No decline in ECOG PS or Karnofsky Performance Status (KPS). There is no symptomatic rapid disease progression (e.g., symptomatic pleural effusion, spinal cord compression, etc.) requiring urgent medical intervention.

[0147] At the time of radiographic progression, participants will be asked to consent again and provided with details of all approved therapies and potential clinical benefits that may be withheld in order to continue receiving Formula (I).

[0148] The dose will be increased by no more than 50% of the previous dose from DL3 onwards, and intermediate doses may be explored. The MTD is the highest DL at which no more than 35% of participants have AEs that meet the criteria for DLT. Participants may be replaced if they do not receive at least 75% of the planned dose during the DLT assessment period for reasons other than TRAEs, or if they discontinue the study during the DLT assessment period for reasons other than DLT.

[0149] Dose Escalation Decision - Phase 1, Parts A and B Generally, dose escalation or expansion is performed according to i3+3.

[0150] If any of the participant / study stopping criteria are met in a dose cohort, further enrollment into that cohort will not occur until all safety data from participants at that dose has been reviewed. If the decision not to start a new cohort is made before all planned previous cohorts are completed, it will not be considered an early termination of the study. After review of the safety data, one of the following recommendations will be made: · The study continues as planned (i.e., no significant safety concerns exist) or with appropriate changes to the study to address emerging safety risks. Continue the study, but at a dose between the current dose and the next planned dose, or between the current dose and the next lower dose. Continue the study but expand either the current cohort or higher / lower dose cohorts by an appropriate number of participants for a more detailed safety evaluation. ·Finish the study.

[0151] Definition of dose-limiting toxicity For an AE to be a DLT, the AE must be causally related to Formula (I) (not all related AEs are considered DLTs). A DLT is defined as any of the following occurring during the first cycle of DL and considered related to Formula (I): The Common Terminology Criteria for Adverse Events (CTCAE) v5.0 will be used to evaluate toxicity / AEs. Hematologic dose-limiting toxicity Absolute neutrophil count (ANC) <500 / mm for more than 7 days 3 Febrile neutropenia (ANC < 1,000 / mm 3 and a single episode of body temperature of 38.3°C or a temperature of 38.0°C sustained for more than 1 hour), or grade 3 neutropenia lasting for more than 7 days with or without drug intervention ·Platelets<25,000 / mm 3 Grade 3 or greater thrombocytopenia associated with grade 3 bleeding Non-hematologic dose-limiting toxicity Grade 3 or 4 non-hematologic toxicities, including nausea and vomiting refractory to antiemetics. The following are not considered DLTs: Grade 3 nausea or vomiting lasting less than 48 hours. Grade 3 fatigue for less than 1 week. Grade 3 or greater electrolyte abnormalities (excluding hyperphosphatemia) lasting 72 hours or less are clinically uncomplicated and resolve spontaneously or respond to conventional medical intervention. Grade 3 or greater elevation of amylase or lipase not associated with symptoms or clinical findings of pancreatitis. Grade 3 hyperphosphatemia (severe or medically significant, but not immediately life-threatening; requiring hospitalization or prolonged hospitalization) is considered a DLT, regardless of whether it resolves with the use of phosphate binders. High's Law: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × upper limit of normal (ULN), and Total bilirubin >2×ULN, and Alkaline phosphatase <2×ULN, and o There is no other reason for liver damage. Any AST or ALT elevation greater than 8xULN regardless of duration, and an AST or ALT assessment of 5-8xULN that persists for more than 2 weeks - all regardless of the presence or absence of liver metastases ·Delay in administration of study drug for more than 14 days due to an AE. Any death not clearly attributable to an underlying disease or external cause.

[0152] Various dose-limiting toxicities If unexpected drug-related toxicity is observed more frequently, the toxicity may be declared a DLT for the remainder of the study.

[0153] Any toxicity considered to be related to Formula (I) that warrants withholding the drug for more than 7 days during the DLT evaluation period. Such toxicity may be Grade 1 or Grade 2 toxicity (e.g., prolonged fatigue or loss of appetite) that interferes with activities of daily living and may require administration interruption / dose reduction to ensure participant compliance. Examples may include Grade 2 nail loss or Grade 3 paronychia that has not improved after 4 weeks of supportive treatment.

[0154] For certain toxicities, such as laboratory assessments without clear clinical correlation (e.g., increased lipase without clinical signs of pancreatitis; or Grade 2 hyperphosphatemia that does not resolve to Grade 1 or less within 7 days of treatment with phosphate binders and dietary adjustment), a decision will be made as to whether the AE should be evaluated as a DLT requiring a dose reduction.

[0155] The initial dosing cohorts (DL1 and DL2) utilize a more stringent definition of DLT than DL3 and above, with any TRAE of Grade 2 or higher constituting a DLT for DL1 and DL2. If DL1 or DL2 is expanded due to this more stringent DLT definition, subsequent dose escalation decisions will be made using the same DLT definition used for DL3 and above (i.e., no longer using a TRAE of Grade 2 or higher as the definition of a DLT).

[0156] Results from dose escalation and dose expansion cohorts will be analyzed for safety and for potential relationships between dose, PK, biomarkers of target binding, and preliminary anti-tumor activity of Formula (I). The RP2D will be selected using the entire Phase 1 data.

[0157] Phase 2: Cohort Expansion Once the MTD is determined and the RP2D is selected, participants will be enrolled in Phase 2 expansion cohorts to further characterize preliminary efficacy, safety, and tolerability in the following cohorts: 1. Participants with locally advanced / metastatic urothelial carcinoma previously treated with an FGFR inhibitor who currently have a defined FGFR3 resistance mutation to any FGFR inhibitor: Participants must have received prior approved therapy, including platinum-based chemotherapy, immune checkpoint inhibitors, and antibody-drug conjugates, unless the participant cannot tolerate any of these approved agents or the participant refuses any / all of these therapies. Participants with urothelial carcinoma will be screened and evaluated for eligible resistance mutations using a CTA that assesses somatic mutations in plasma-derived ctDNA. Participants with eligible genetic alterations based on a local test that is licensed / approved or validated by the Clinical Laboratory Improvement Act (CLIA) (or local equivalent) can be enrolled, and samples must be submitted for central testing using a CTA. Confirmation prior to initiating Formula (I) is not required for these participants. ● Participants who discontinued a prior FGFR inhibitor due to toxicity may be eligible if they have evidence of activating FGFR3 alterations and known FGFR3 acquired resistance mutations in a CTA or on-site test that is licensed / approved or validated by CLIA (or local equivalent). 2. Participants with locally advanced / metastatic urothelial carcinoma harboring activating FGFR3 gene alterations who have not previously received an FGFR inhibitor. Participants must have received prior approved therapy, including platinum-based chemotherapy, immune checkpoint inhibitors, and antibody-drug conjugates, unless the participant cannot tolerate any of these approved agents or the participant refuses any / all of these therapies. Participants with urothelial carcinoma will be screened and evaluated for eligible activating mutations and rearrangements using a CTA. Participants with eligible genetic alterations based on a licensed / approved or CLIA (or local equivalent) validated local test may be enrolled, and specimens must be submitted for central testing using a CTA. Confirmation prior to initiating Formula (I) is not required for these participants. 3. Participants with any locally advanced / metastatic solid tumor with an activating FGFR3 genetic alteration who have not previously received an FGFR inhibitor. Participants must have received prior approved therapy, unless the participant cannot tolerate the approved medication or the participant refuses any / all of these therapies. Participants will be enrolled based on the results of an FDA-cleared / cleared companion diagnostic (CDx) or CLIA (or local equivalent) validated on-site test performed in an accredited laboratory. Blood specimens must be submitted to a central laboratory for analysis using a CTA. No confirmation is required before initiating Formula (I) for these participants. With medical monitor approval, participants who have progressed on a prior FGFR inhibitor may be enrolled if they have an activating FGFR3 alteration and a known FGFR3 acquired resistance mutation as determined by a CTA or a licensed / approved or CLIA (or local equivalent) validated local test.

[0158] In Phase 2, approximately 110 participants will be enrolled in each of Cohorts 1 and 2. A Simon two-stage design will be used for enrollment. In the first stage, 39 participants will be recruited, and if there are six or fewer responders, enrollment in that cohort will be stopped due to futility. Otherwise, 71 additional participants will be recruited for a total of 110 participants. Response is defined as CR or PR by RECIST v1.1 at any time during therapy; in Cohort 1, a clinical benefit (extended SD for 6 months or more during therapy) will be considered a response.

[0159] Cohort 3 will be exploratory, with approximately 40 participants enrolled in a single phase.

[0160] Research stop criteria The study may be terminated at any time if the incidence and severity of AEs suggest that the risk-benefit ratio for the participant is no longer appropriate for continuation in the study. Examples include, but are not limited to, severe hepatotoxicity without an underlying cause or unexplained participant death not attributable to disease progression or external causes.

[0161] Research period All enrolled participants will receive Formula (I) daily until disease progression, death, unacceptable toxicity, withdrawal of consent for treatment by the participant, withdrawal from the study, or termination of the study, whichever occurs first. Planned sample size and treatment groups: In Phase 1, the total number of participants enrolled will depend on the number of titration and dose-expansion cohorts evaluated. A maximum of 50 participants may be enrolled in Part A and Part B combined (maximum of 30 participants in Part A and maximum of 20 participants in Part B). In Phase 2, approximately 110 participants will be enrolled in each of Cohorts 1 and 2. A Simon two-stage design will be used for enrollment. In the first stage, 39 participants will be recruited; if there are six or fewer responders, enrollment in that cohort will be stopped due to futility. Otherwise, 71 additional participants will be recruited for a total of 110 participants. If 23 or more responses are observed among the 110 participants, the null hypothesis will be rejected. This design yields a 5% one-sided type I error rate and 80% power to detect a true response rate of 25%. Response is defined as a complete response (CR) or partial response (PR) by RECIST v1.1 at any time during therapy; in Cohort 1, a clinical benefit (extended stable disease [SD] for 6 or more months during therapy) is considered a response. Cohort 3 will be exploratory, with approximately 40 participants enrolled in a single phase. Target population: Phase 1, Part A: Participants with any advanced solid tumor who have exhausted all standard treatment options. Phase 1, Part B: Participants with locally advanced / metastatic solid tumors and FGFR3 activating genetic alterations who may be suitable for FGFR3-targeted therapy. The expansion at the MTD will enroll up to 10 participants with locally advanced / metastatic urothelial carcinoma with FGFR3 activating genetic alterations who have not previously received an FGFR inhibitor. Phase 2, Cohort 1: Participants with locally advanced / metastatic urothelial carcinoma previously treated with an FGFR inhibitor who now have a defined FGFR3 resistance mutation. Phase 2, Cohort 2: Participants with locally advanced / metastatic urothelial carcinoma harboring a defined activating FGFR3 gene alteration who have not previously received an FGFR inhibitor. Phase 2, Cohort 3: Participants with any locally advanced / metastatic solid tumor with a defined activating FGFR3 genetic alteration who have not previously received an FGFR inhibitor. Eligibility criteria: Phase 1, Part A Inclusion Criteria 1. Male and female participants who are 18 years of age or older on the day they sign the Informed Consent Form (ICF). 2. Life expectancy >12 weeks. 3. Able to understand and sign the ICF and comply with study procedures. 4. ECOG PS ≤ 1. 5. Participants with any histologically confirmed advanced solid tumor who have exhausted standard treatment options. 6. Capsules can be swallowed. 7. Disease evaluable by RECIST v1.1. 8. Adequate organ and bone marrow function as demonstrated by: a. Absolute neutrophil count (ANC) ≥ 1500 / mm 3 . b. Platelet count ≥75,000 / mm 3 . c. International normalized ratio (INR) ≤ 1.5 × upper limit of normal (ULN). i. Participants treated with anticoagulants (e.g., warfarin or heparin) will be admitted provided there is no prior evidence of underlying abnormalities in these parameters. Careful monitoring with at least weekly assessments will be performed until the INR is stable based on pre-dose measurements as defined by the local standard of care. d. Total bilirubin ≤ 1.5 x ULN. Documented evidence of Gilbert syndrome is acceptable even if the total bilirubin is mildly elevated (< 6 mg / dL). e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for participants with hepatic complications of cancer). f. Serum albumin >2g / dL. Glomerular filtration rate (GFR) ≥ 60 mL / min / 1.73 m, measured directly via 24-hour urine collection or calculated using the Cockcroft-Gault equation 2 . 9. Participants and their partners must use contraception and other reproductive control measures for this study as follows: a. Female participants who are not of childbearing potential (i.e., surgically sterile by hysterectomy and / or bilateral oophorectomy, or chemically sterile, or amenorrhea for 12 months or more in the absence of chemotherapy, antiestrogens, or ovarian suppression) do not need to undergo a pregnancy test. 10. Female participants of childbearing potential must have a documented negative pregnancy test result within 7 days prior to starting Formula (I). a. Female participants of childbearing potential and all male participants must agree to use highly effective contraception from before study entry until up to 120 days after the final dose of Formula (I). 11. Have a negative test result for coronavirus disease 2019 (COVID-19) by either a polymerase chain reaction (PCR)-based test within 48 hours prior to starting Formula (I) or a rapid antigen test within 24 hours prior to starting Formula (I) and meet COVID-19 vaccination requirements per local regulations (if any). Participants who test positive for COVID-19 infection at screening and meet all other study eligibility criteria may be screened again after normalization of test results and clinical recovery. Phase 1, Part B Inclusion Criteria 1. Male and female participants who are 18 years of age or older on the date they sign the ICF. 2. Life expectancy >12 weeks. 3. Able to understand and sign the ICF and comply with study procedures. 4. ECOG PS ≤ 1. 5. Participants with any histologically confirmed advanced solid tumor who have exhausted standard treatment options. a. The tumor must have a qualifying FGFR3 gene mutation or fusion diagnosed by any licensed / approved or CLIA (or local equivalent) validated on-site test performed in an accredited laboratory. b. The specimen must be submitted for analysis using a CTA, but the CTA results do not need to be available before commencing formula (I). c. Many prior therapies, including previous FGFR inhibitors, are permitted. d. Up to 10 participants at the MTD with metastatic urothelial carcinoma with a qualifying FGFR3 genetic alteration identified by CTA or any licensed / approved CLIA (or local equivalent) validated on-site test who have not received a prior FGFR inhibitor. 6. Capsules can be swallowed. 7. At least one measurable lesion by RECIST v1.1. 8. Adequate organ and bone marrow function as demonstrated by: ANC≧1500 / mm 3 . b. Platelet count ≥75,000 / mm 3 . c. INR ≤ 1.5 × ULN. i. Participants treated with anticoagulants (e.g., warfarin or heparin) will be admitted provided there is no prior evidence of underlying abnormalities in these parameters. Careful monitoring with at least weekly assessments will be performed until the INR is stable based on pre-dose measurements as defined by the local standard of care. d. Total bilirubin ≤ 1.5 x ULN. Documented evidence of Gilbert syndrome is acceptable even if the total bilirubin is mildly elevated (< 6 mg / dL). e. ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN for participants with hepatic complications of cancer). f. Serum albumin >2g / dL. GFR ≥ 45 mL / min / 1.73 m as measured directly via 24-hour urine collection or calculated using the Cockcroft-Gault formula 2 . 9. Participants and their partners must use contraception and other reproductive control measures for this study as follows: a. Female participants who are not of childbearing potential (i.e., surgically sterile by hysterectomy and / or bilateral oophorectomy, or chemically sterile, or amenorrhea for 12 months or more in the absence of chemotherapy, antiestrogens, or ovarian suppression) do not need to undergo a pregnancy test. Female participants of childbearing potential must have a documented negative pregnancy test result within 7 days prior to starting Formula (I). b. Female participants of childbearing potential and all male participants must agree to use highly effective contraception from before study participation until up to 120 days after the final dose of Formula (I). 10. Have a negative COVID-19 test result by either a PCR-based test within 48 hours prior to starting Formula (I) or a rapid antigen test within 24 hours prior to starting Formula (I) and meet COVID-19 vaccination requirements per local regulations (if any). Participants who test positive for COVID-19 infection at screening and meet all other study eligibility criteria may be screened again after normalization of test results and clinical recovery. Phase 2 inclusion criteria 1. Male and female participants who are 12 years of age or older on the date they sign the ICF. 2. Life expectancy >12 weeks. 3. Able to understand and willing to sign the ICF. For participants under 18 years of age (or equivalent in each country), a parent / legal guardian who can understand and sign the informed consent form, and a child who can understand and sign the assent document. 4. ECOG PS 0-2. For participants aged 12-17 years, KPS > 70. 5. Participants must have histologically confirmed locally advanced / metastatic tumors that fit into one of the following categories: a. Urothelial carcinoma with a qualifying FGFR3 gene mutation or rearrangement that has progressed on a prior FGFR inhibitor and in which resistance mutations or other kinase domain mutations likely to respond to Formula (I) are present, as identified using a CTA, or an FDA-cleared / approved CDx, or a CLIA (or local equivalent)-validated on-site test performed in an accredited laboratory. b. Patients with urothelial carcinoma harboring a qualifying FGFR3 gene mutation or rearrangement identified by a central CTA, or FDA-cleared / approved CDx, or CLIA (or local equivalent)-validated on-site test performed in an accredited laboratory who have not received a prior FGFR inhibitor. c. Any solid tumor with a qualifying FGFR3 gene mutation or rearrangement identified via licensed / approved or CLIA (or local equivalent) validated on-site testing in an accredited laboratory. i. With medical monitor approval, participants who have progressed on a prior FGFR inhibitor may be enrolled if they have a documented FGFR3 resistance mutation or other kinase domain mutation for which Formula (I) is likely to be active based on preclinical studies. 6. Capsules can be swallowed. 7. At least one measurable lesion by RECIST v1.1. 8. Adequate organ and bone marrow function as demonstrated by: ANC≧1500 / mm 3 . b. Platelet count ≥75,000 / mm 3 . c. INR ≤ 1.5 × ULN. i. Participants treated with anticoagulants (e.g., warfarin or heparin) will be admitted provided there is no prior evidence of underlying abnormalities in these parameters. Careful monitoring with at least weekly assessments will be performed until the INR is stable based on pre-dose measurements as defined by the local standard of care. d. Total bilirubin ≤ 1.5 x ULN. Documented evidence of Gilbert syndrome is acceptable even if the total bilirubin is mildly elevated (< 6 mg / dL). e. ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN for participants with hepatic complications of cancer). f. Serum albumin >2g / dL. GFR ≥ 45 mL / min / 1.73 m as measured directly via 24-hour urine collection or calculated using the Cockcroft-Gault formula 2 . 9. Participants and their partners must use contraception and other reproductive control measures for this study as follows: a. Female participants who are not of childbearing potential (i.e., surgically sterile by hysterectomy and / or bilateral oophorectomy, or chemically sterile, or amenorrhea for 12 months or more in the absence of chemotherapy, antiestrogens, or ovarian suppression) do not need to undergo a pregnancy test. 10. Female participants of childbearing potential must have a documented negative pregnancy test result within 7 days prior to starting Formula (I). a. Female participants of childbearing potential and all male participants must agree to use highly effective contraception from before study participation until up to 120 days after the final dose of Formula (I). 11. Have a negative COVID-19 test result by either a PCR-based test within 48 hours prior to starting Formula (I) or a rapid antigen test within 24 hours prior to starting Formula (I) and meet COVID-19 vaccination requirements per local regulations (if any). Participants who test positive for COVID-19 infection at screening and meet all other study eligibility criteria may be screened again after normalization of test results and clinical recovery. Study exclusion criteria 1. Participant received chemotherapy, targeted therapy, immunotherapy, or investigational therapy within 2 weeks or 5 half-lives (6 weeks for nitrosoureas and mitomycin) prior to the first dose of study drug. 2. The participant has not recovered from reversible toxicities of prior anticancer therapy (excluding clinically non-significant toxicities, including but not limited to alopecia, skin discoloration, or grade 1 neuropathy). 3. Underwent major surgery within 4 weeks prior to enrollment. 4. Any reason that may materially impair the participant's ability to comply with study procedures or increase the participant's risk. Examples include poorly controlled diabetes (glycosylated hemoglobin [HbA1c] >8%) and ongoing active infection requiring intravenous (IV) antibiotics. 5. Women who are pregnant, nursing, or planning to become pregnant within 120 days of the last dose of Formula (I), and men who plan to father a child while enrolled in this study or within 120 days of the last dose of Formula (I). 6. Impaired wound healing, defined as skin / pressure ulcers, chronic leg ulcers, known gastric ulcers, or non-healing cuts. 7. Serum phosphorus levels above the ULN during screening (within 14 days of treatment and before Cycle 1, Day 1) that remain above the ULN despite medical management with phosphorus binders. 8. Any ocular condition likely to increase the risk of ocular toxicity, including: a. History or current evidence of central serous retinopathy (CSR; including grade ≥2 CSR while receiving a previous FGFR inhibitor) or retinal vascular occlusion (RVO). b. Active wet age-related macular degeneration (AMD). c. Diabetic retinopathy with macular edema. d. Uncontrolled glaucoma (based on local standard of care). 9. History of or current uncontrolled cardiovascular disease, including: a. Unstable angina, myocardial infarction, or known congestive heart failure class II-IV within the past 12 months. b. Cerebrovascular accident or transient ischemic attack within the past three months. c. Pulmonary embolism within the past 2 months. 10. Active, symptomatic, or untreated brain metastases. a. Previous brain metastases that have been treated at least 3 weeks prior to signing the ICF for the entire study or have been clinically and radiographically stable for at least 1 month prior to Cycle 1, Day 1 and are not requiring chronic corticosteroid treatment. 11. Gastrointestinal disorders that may affect the oral administration or absorption of formula (I). 12. Known history of human immunodeficiency virus (HIV) infection or active hepatitis B or C infection. a. Participants with a history of HIV who are on antiretroviral therapy and have an undetectable viral load by PCR will be accepted. b. Participants with a history of hepatitis B virus infection who are hepatitis B surface antibody positive or hepatitis B core antibody positive and PCR test negative are allowed. c. Participants whose hepatitis C infection has been previously treated with antiviral therapy and who test negative for hepatitis C virus by PCR are accepted. 13. History of a second primary malignancy within 3 years of signing the ICF (excluding definitively treated early stage cancers, e.g., excised skin cancer and / or completely excised prostate cancer). 14. Known allergy to any of the excipients of formula (I) or the combined formulation. 15. Participants taking strong inhibitors and / or inducers of the cytochrome P450 (CYP)3A4 enzyme are not permitted. Strong inhibitors and inducers of CYP3A are prohibited from 2 weeks before study entry until 1 week after administration of the final dose of Formula (I). Strong inhibitors of cytochrome P450 (CYP) 3A4: boceprevir, clarithromycin, cobicistat, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit juice, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir and / or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, telithromycin, troleandomycin, voriconazole. Strong inducers of cytochrome P450 (CYP) 3A4: apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, and St. John's wort. a. A strong inhibitor is a drug that increases the AUC of the index drug (sensitive substrate) by 5-fold or more. b. A strong inducer is a drug that reduces the AUC of the index drug (sensitive substrate) by 80% or more. Abbreviations: AUC = area under the concentration-time curve, CYP = cytochrome P450. Source: US Food and Drug Administration. Drug Development and Drug Interactions. Table of Substrates, Inhibitors and Inducers. US Food and Drug Administration. Drug Development and Drug Interactions. Table of Substrates, Inhibitors and Inducers. March 10, 2020. www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers c. Participants who can switch to a similar medication that does not have a CYP3A4 interaction will require a two-week washout period before starting Formula (I). Study Drugs: Capsules of Formula (I) in the following strengths: 5 mg and 10 mg (based on the free base). The capsules will be packaged in high-density polyethylene bottles for this study, each containing 30 capsules. The capsules of Formula (I) contain the study drug (as the free base or as a pharmaceutically acceptable salt) as the active ingredient and microcrystalline cellulose as an inactive ingredient. Participants will be instructed to take Formula (I) daily at the same time each day, with food or within 30-60 minutes after a meal or snack.

[0162] [Table 3A]

[0163] [Table 3B]

[0164] [Table 3C]

[0165] [Table 3D]

[0166] [Table 3E]

[0167] [Table 3F]

[0168] [Table 4A]

[0169] [Table 4B]

[0170] [Table 4C]

[0171] [Table 4D]

[0172] [Table 4E]

[0173] Screening is the period from signing the ICF to the day the participant is enrolled in the study (Cycle 1, Day 1). The screening visit occurs within 28 calendar days prior to the start of study medication administration. For each participant, the treatment period will continue in 4-week cycles (ie, 28 days) until disease progression, unless the participant meets one of the treatment discontinuation criteria. The safety follow-up period is the period from the EOT visit to the scheduled follow-up visit, which preferably occurs 28-35 days after the EOT visit (or the last dose of study drug if no EOT visit is performed). Once participants have completed safety follow-up visits and / or initiated new anti-cancer therapy, they will enter the survival follow-up period. Participants will be contacted at least every 12 weeks via telephone, video, email, certified mail, or in-person visits to assess survival status until death, withdrawal of consent, or end of study, whichever occurs first. Primary endpoint: Phase 1 (Parts A and B): Incidence of DLT events during the DLT evaluation period (1st cycle [28 days]). Phase 2: Investigator-assessed ORR, defined as either CR or PR by RECIST v1.1. Secondary endpoints: Phase 1 (Parts A and B) and Phase 2: Incidence of AEs characterized by study phase, cohort, severity, relationship to study drug, timing, and severity Changes in clinical laboratory parameters, vital signs, electrocardiogram (ECG) parameters, and physical examination status ·Accumulation ratio, C max , T max , AUC 0-last , AUC Tau , AUC 0-∞ (after the first dose only), Vd / F, CL / F, and t 1 / 2 Single dose and steady state PK parameters, including but not limited to Additional secondary endpoints for Phase 1, Part B only: ○ORR Additional secondary endpoints for Phase 1, Part B, and Phase 2: ○DOR DCR for more than 12 weeks, defined as CR, PR, or SD ○TTR Additional secondary endpoints for Phase 2 only: PFS in cohorts 1 and 2 Exploratory endpoints: Biomarkers of activity, safety, and efficacy of Formula (I). These biomarkers may include, but are not limited to, FGF23, parathyroid hormone, calcitriol, FGF19, and tumor-derived exosomes. Assessment of the concordance between tissue-based next-generation sequencing (NGS) results and CTA for the detection of FGFR3 genetic alterations in participants enrolled in Phase 2, Cohorts 1 and 2 Estimated OS in cohorts 1 and 2 of phase 2

[0174] Efficacy assessment: Baseline tumor assessments will be completed within 28 days prior to the first dose of study drug. CT scans of the chest, abdomen, pelvis, and any other areas with disease present at baseline are recommended, with additional tumor imaging assessments required if clinically indicated or if suspicious lesions are identified in other areas. Baseline brain MRI is not required unless there is a history of brain metastases or neurological symptoms suggestive of new brain metastases. The preferred tumor imaging modality is CT with IV contrast; however, if IV contrast is clinically contraindicated, non-contrast CT scans of the chest and MRI scans of the abdomen and pelvis are permitted. Baseline and post-baseline efficacy assessments will be performed by the same investigator, whenever possible, using the same imaging modality (RECIST v1.1).

[0175] Tumor imaging assessments are recommended to be performed every 8 weeks (± 7 days) until Cycle 13, Day 1, and then every 12 weeks (± 7 days) thereafter, regardless of study treatment status, until disease progression, death, unacceptable toxicity, participant withdrawal of consent for treatment, or withdrawal from the study, whichever occurs first. The timing of tumor imaging assessments is calculated based on the date of the first dose of study drug (i.e., Cycle 1, Day 1). Participants who discontinue study drug for reasons other than disease progression or death are recommended to continue imaging assessments according to the protocol-defined schedule until disease progression, death, participant withdrawal of consent for treatment, or withdrawal from the study. If imaging results initially indicate a CR or PR, tumor imaging should be repeated to confirm the response. Confirmatory tumor imaging must be performed at least 4 weeks after the previous imaging assessment. Further details are provided in the imaging manual.

[0176] For participants enrolled in Phase 2, Cohorts 1 and 2 only, digital images of the scans performed will be electronically transmitted from the site to a central radiology vendor designated by the sponsor for "collection and storage."

[0177] Efficacy assessments included ORR, DCR, DOR, TTR, and PFS (RECIST v1.1).

[0178] Response Evaluation Criteria Guidelines for Solid Tumors: The RECIST v1.1 guidelines are as follows: See Eisenhauser EA, Therasse P, Bogaerts J, et al., New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47.

[0179] Definition: At baseline, tumor lesions / lymph nodes will be classified as measurable or non-measurable as follows:

[0180] measurable Tumor lesions: must be accurately measured in at least one direction (the longest diameter in the plane of measurement should be recorded) and have the following minimum dimensions: · 10 mm by CT scan (CT scan slice thickness 5 mm or less). · 10mm by caliper measurement on clinical examination (lesions that cannot be accurately measured by caliper should be recorded as non-measurable). · Chest X-ray showed 20mm.

[0181] Malignant lymph nodes: To be considered pathologically enlarged and measurable, lymph nodes must measure 15 mm or greater in the short axis when assessed by CT scan (a CT scan slice thickness of 5 mm or less is recommended). At baseline and during follow-up, only the short axis will be measured and tracked.

[0182] unmeasurable All other lesions, including small lesions (lesions <10 mm in longest dimension or pathologic lymph nodes with a short axis ≥10 mm but <15 mm) and truly non-measurable lesions. Lesions considered truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphatic complications of the skin or lung, and intra-abdominal masses / organomegaly identified by physical examination that are not measurable by reproducible imaging techniques.

[0183] Special considerations regarding lesion measurability Bone lesions: Bone scans, positron emission tomography (PET) scans, or plain radiography are not considered adequate imaging techniques for measuring bone lesions. However, these techniques can be used to confirm the presence or absence of bone lesions. Osteolytic or mixed osteolytic-osteoblastic bone lesions with an identifiable soft tissue component that can be assessed by cross-sectional imaging techniques such as CT or MRI can be considered measurable lesions if the soft tissue component meets the definition of measurability described above. · Blastogenic bone lesions are not measurable.

[0184] Cystic lesions: Lesions that meet the criteria for a radiographically defined simple cyst should not be considered malignant because they are simple cysts by definition (neither measurable nor nonmeasurable). "Cystic lesions" thought to represent cystic metastases can be considered measurable lesions if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same participant, it is preferable to select the non-cystic lesions as target lesions.

[0185] Lesions with a history of local treatment: Tumor lesions located in previously irradiated areas or areas subjected to other locoregional therapies are not typically considered measurable unless progression of the lesion has been documented. Study protocols should detail the conditions under which such lesions are considered measurable.

[0186] Evaluation method Lesion measurement All measurements should be recorded in metric units, using calipers if clinically assessed. All baseline assessments should be performed as close to the start of treatment as possible, but always within 4 weeks before the start of treatment.

[0187] The same assessment methods and techniques should be used to characterize each identified and reported lesion at baseline and throughout the follow-up period. Assessment should always be based on imaging rather than clinical examination, except in cases where the lesion being followed is not amenable to imaging but is amenable to clinical evaluation. Clinical Lesions: Clinical lesions are considered measurable only if they are superficial and ≥10 mm in diameter when assessed using a caliper (e.g., skin nodules). In cases of skin lesions, color photographic documentation including a ruler to estimate the size of the lesion is suggested. As mentioned above, imaging assessment is more objective and can be reviewed at the end of the study, so imaging assessment should be performed if the lesion can be assessed by both clinical examination and imaging. Chest X-ray: Chest CT is preferred over chest X-ray because CT is more sensitive than X-ray, especially in identifying new lesions, especially when progression is the key endpoint. However, lesions on chest X-ray may be considered measurable if they are well defined and surrounded by aerated lung. CT, MRI: CT is currently the best available and reproducible method for measuring lesions selected for response assessment. This guideline defines lesion measurability on CT scans based on the assumption that the CT slice thickness is 5 mm or less. If the CT scan has a slice thickness greater than 5 mm, the minimum size of a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain circumstances (e.g., for body scans). Ultrasound: Ultrasound is not useful for assessing lesion size and should not be used as a measurement method. Ultrasound examinations cannot be fully reproduced at a later independent review and are operator-dependent, making it impossible to guarantee that the same technique and measurements are used with each evaluation. Even if new lesions are identified by ultrasound during the course of a study, confirmation by CT or MRI is recommended. MRI may be used instead of CT in selected cases if there are concerns about radiation exposure with CT. Endoscopy, laparoscopy: The use of these techniques for objective tumor assessment is not recommended. However, they may be useful to confirm pathologic complete response when biopsies are available, or to determine relapse in studies where CR or recurrence after surgical resection is the endpoint. Tumor markers: Tumor markers cannot be used alone to assess objective tumor response. However, if the marker was above the upper limit of normal at the initial time point, the marker must normalize for the participant to be considered in CR. Because tumor markers are disease-specific, instructions for their measurement should be incorporated into the protocol on a disease-specific basis. Specific guidelines have been published for both CA-125 response (recurrent ovarian cancer) and prostate-specific antigen response (recurrent prostate cancer). In addition, the Gynecologic Cancer Intergroup developed CA125 progression criteria that can be integrated with objective tumor assessment for use in primary treatment studies of ovarian cancer. Cytology, histology: These techniques, if required by protocol, can be used to distinguish between PR and CR in rare cases (e.g., residual disease in tumor types such as germ cell tumors where known residual benign tumor may remain). When effusion is known to be a potential adverse effect of treatment (e.g., with certain taxanes or angiogenesis inhibitors), and measurable tumor meets the criteria for response or SD, cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can be considered to distinguish between response (or SD) and PD.

[0188] Response criteria Target Lesion Evaluation CR: Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) must have shrunk to less than 10 mm in their short axis. PR: A reduction in the sum of target lesion diameters of at least 30% compared to baseline. PD: An increase in the sum of target lesion diameters of at least 20% relative to the smallest sum diameter during the study (this includes the baseline sum diameter if it is the smallest during the study). In addition to the 20% relative increase, the sum diameter must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progression). SD: Based on the smallest diameter during the study, there is neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD. Lymph nodes: For lymph nodes identified as target lesions, the actual short axis measurement should always be recorded (measured in the same anatomical plane as the baseline examination), even if they shrink to less than 10 mm during the study. This means that when lymph nodes are included as target lesions, the "sum diameter" of the lesion may not be zero, even if CR criteria are met because the short axis of a normal lymph node is defined as less than 10 mm. Therefore, case report forms or other data collection methods may be designed to record target lymph node lesions in a separate column, where each lymph node must achieve a short axis less than 10 mm to qualify for CR. For PR, SD, and PD, the actual short axis measurement of the lymph node should be included in the sum diameter of the target lesion. "Too Small to Measurable" Target Lesions: During the study, all lesions (nodal and non-nodal) recorded at baseline should have their actual measurements recorded at each subsequent assessment, even if they are very small (e.g., 2 mm). However, lesions or lymph nodes recorded as target lesions at baseline may become so obscured on the CT scan that radiologists may hesitate to assign an accurate measurement and report them as "too small to measurable." Even when this occurs, it is important to record the value in the case report form. If the lesion is likely to have disappeared, the measurement should be recorded as 0 mm. If a lesion is thought to be present and is faintly visible but is too small to measure, a default value of 5 mm should be assigned. (Note: This rule is unlikely to be used for lymph nodes, as they typically have a definable size when normal and are often surrounded by fat, such as in the retroperitoneum. However, if a lymph node is thought to be present and is faintly visible but is too small to measure, a default value of 5 mm should also be assigned in this situation.) This default value is derived from a CT slice thickness of 5 mm (but should not change with changes in CT slice thickness). Measurements of these lesions may be irreproducible, so this default value prevents false positives or negatives based on measurement error. However, again, if the radiologist is able to provide an actual measurement, it should be recorded, even if it is less than 5 mm. Lesions that split or coalesce during the procedure: If a non-lymph node lesion is "fragmented," the longest diameters of the fragments should be summed to calculate the sum of the target lesion diameters. Similarly, if lesions coalesce, a plane between them may be maintained, which can be useful in obtaining a measurement of the longest diameter of each individual lesion. If the lesions truly coalesce and are no longer separate lesions, the vector of the longest diameter in this case should be taken as the maximum longest diameter of the "fused lesion."

[0189] Evaluation of non-target lesions Some non-target lesions may in fact be measurable, but need not be measured and should instead be assessed only qualitatively at the time points specified in the protocol. CR: Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be of a non-pathological size (minor axis less than 10 mm). Non-CR / non-PD: persistence of one or more non-target lesions and / or maintenance of tumor marker levels above the upper limit of normal. PD: Overt progression of pre-existing non-target lesions (see comments below) (Note: the appearance of one or more new lesions is also considered progression). If the participant also has measurable disease: In this case, to achieve "overt progression" based on non-target disease, there must be a substantial worsening of the overall level of non-target disease, such that the overall tumor burden has increased sufficiently to merit discontinuation of therapy even in the presence of SD or PR in the target disease (see further details below). A modest "increase" in the size of one or more non-target lesions is typically not sufficient to constitute overt progression. Therefore, it is extremely rare to determine overall progression based solely on changes in non-target disease despite SD or PR in the target disease. Participants with only nonmeasurable disease: This situation arises in some Phase 3 studies where measurable disease is not a study entry criterion. The same general concepts as above apply here, but in this case, there is no assessment of measurable disease to allow for the interpretation of an increase in nonmeasurable disease burden. Because worsening nontarget disease cannot be easily quantified (by definition, i.e., if all lesions are truly nonmeasurable), a useful test that can be applied when evaluating participants for overt progression is whether the increase in overall disease burden based on changes in nonmeasurable disease is of the same magnitude as the increase that would be required to determine PD for measurable disease, i.e., an increase in tumor burden equivalent to an additional 73% increase in "volume" (which is equivalent to a 20% increase in the diameter of measurable lesions). Examples include an increase in pleural effusion from "trace" to "massive," an expansion of lymphatic disease from focal to widespread, or an example may be described in the protocol as "sufficient to require a change in therapy." If "overt progression" is observed, the participant should be considered to have PD overall at that point. Ideally, objective criteria would be applied to non-measurable disease, but because the nature of the disease makes this impossible, the increase must be substantial.

[0190] New lesions The appearance of new malignant lesions represents disease progression. Therefore, it is important to make some comments about the detection of new lesions. Although there are no specific criteria for identifying new lesions on radiographic examinations, the finding of new lesions should be obvious—that is, not attributable to differences in scanning technique, changes in imaging modality, or findings that may represent something other than tumor (e.g., some "new" bone lesions may simply be healing or recurrence of existing lesions). This is particularly important when a participant's baseline lesions indicate a partial response or CR. For example, necrosis of a liver lesion may be reported as a "new" cystic lesion on a CT scan report, when in fact this is not the case.

[0191] Lesions identified during follow-up studies in anatomical sites not scanned at baseline are considered new lesions and represent disease progression. An example of this is a participant with visceral disease at baseline who has a brain CT or MRI ordered during the study that reveals metastases. A participant's brain metastases are considered evidence of PD, even if brain imaging was not performed at baseline.

[0192] If the new lesion is not apparent, for example because of its small size, continued therapy and follow-up evaluation can clarify whether it is truly new disease. If a repeat scan confirms the presence of a new lesion, the date of the first scan should be used to determine progression.

[0193] Although fluorodeoxyglucose (FDG)-PET response assessment requires additional study, it may be justified to incorporate the use of FDG-PET scanning to complement CT scanning in the evaluation of progression, particularly for potential "new" disease. New lesions based on FDG-PET imaging can be identified according to the following algorithm: a. A negative baseline FDG-PET followed by a positive follow-up FDG-PET is an indication of PD based on a new lesion (an FDG-PET scan "positive" lesion means a single lesion that is FDG-accumulating and has uptake greater than twice that of the surrounding tissue on attenuation-corrected images). b. No FDG-PET at baseline and positive FDG-PET at follow-up: i. If a positive follow-up FDG-PET corresponds to a new site of disease confirmed by CT, this is PD. If a positive follow-up FDG-PET does not confirm a new site of disease on CT, an additional follow-up CT scan is required to determine whether progression has truly occurred at that site (if progression has truly occurred, the date of PD is the date of the first abnormal FDG-PET scan). ii. If a positive follow-up FDG-PET corresponds to an area of ​​pre-existing disease on CT that has not progressed based on anatomical imaging, this is not PD.

[0194] Best overall response assessment BOR is the best response recorded from the start of study treatment to the end of treatment, taking into account all requirements for confirmation. Because responses are sometimes not recorded until after the end of therapy, the protocol should clarify whether posttreatment assessments should be considered in determining BOR. The protocol must specify how any new therapy introduced before progression may affect the determination of best response. Assigning a participant's BOR depends on the findings of both target and non-target disease and also takes into account the appearance of new lesions. Furthermore, depending on the nature of the study and protocol requirements, a confirmation measure may be required. Specifically, in nonrandomized studies where response is the primary endpoint, a confirmed PR or CR should be considered the "BOR," either of which should be considered the "BOR."

[0195] BOR is determined when all data for a participant are known. Determining best response in studies that do not require confirmation of complete response or PR: Best response in these studies is defined as the best response across all time points (e.g., a participant with SD at the first assessment, PR at the second assessment, and PD at the final assessment has a BOR of PR). If SD is considered the best response, it must also meet the minimum time from baseline specified in the protocol. If the minimum time is not met but SD is otherwise the best time point effect, the participant's best response will depend on subsequent assessments. For example, a participant with SD at the first assessment and PD at the second assessment who does not meet the minimum duration of SD will have a best response of PD. The same participant who is lost to follow-up after the first SD assessment may be considered unevaluable.

[0196] [Table 5]

[0197] [Table 6]

[0198] Determination of best response in studies requiring confirmation of complete response or PR: CR or PR can only be claimed if the criteria for each are met at a later time point specified in the protocol (generally after 4 weeks). In this situation, the BOR can be interpreted as in the following table:

[0199] [Table 7]

[0200] If lymph node disease is included in the target lesion diameter sum and the lymph node shrinks to a "normal" size (less than 10 mm), the lymph node may still report a measurement on the scan. This measurement should be recorded even if the lymph node is normal, to avoid exaggerating progression when progression is based on an increase in lymph node size. As mentioned above, this means that participants with a CR may not have a sum of "0" in the eCRF.

[0201] In studies where confirmation of response is required, repeated "NE" time point assessments can complicate the determination of best response. The study's analysis plan must address how missing data / assessments will be handled in determining response and progression. For example, in most studies, it is reasonable to consider participants with a PR-NE-PR time point response as a confirmed response.

[0202] Participants whose overall worsening health status necessitates discontinuation of treatment without objective evidence of disease progression at that time should be reported as "symptom worsening." Every effort should be made to document objective progression, even after treatment has been discontinued. Symptom worsening is not a descriptor of objective response; it is a reason for discontinuation of study drug. The objective response status of such participants should be determined by assessment of target and non-target disease, as indicated in the tables herein.

[0203] The conditions that define "early progression, early death, and non-evaluable" are study-specific and should be clearly described in each protocol (depending on the duration of treatment, periodicity of treatment).

[0204] In some situations, it may be difficult to distinguish residual disease from normal tissue. When CR assessment relies on this determination, it is recommended that residual disease be examined (fine-needle aspiration / biopsy) before assigning CR status. If residual radiographic abnormalities are thought to represent fibrosis or scarring, FDG-PET, as well as biopsy, may be used to upgrade the response to CR. The use of FDG-PET in this setting should be prospectively documented in protocols and supported by disease-specific medical literature for the indication. However, it must be recognized that both techniques may result in false-positive CRs due to the resolution / sensitivity limitations of FDG-PET and biopsy.

[0205] In the event of non-evidence of progression (e.g., very small, equivocal new lesions; cystic changes or necrosis of existing lesions), treatment may continue until the next scheduled evaluation. If progression is confirmed at the next scheduled evaluation, the date of progression should be the date of the previous suspicion of progression.

[0206] Confirmatory measurements and duration of response Confirmed In nonrandomized studies where response is the primary endpoint, confirmation of PR and CR is required to ensure that the identified responses are not the result of measurement error. This also allows for the proper interpretation of results in the context of historical data, where confirmation of response has traditionally been required in such studies. However, in all other situations, i.e., randomized studies (phase 2 or 3) or studies where SD or progression is the primary endpoint, confirmation of response is not required because it does not add value to the interpretation of the study results. However, elimination of the requirement for confirmed response may increase the importance of central review to prevent bias, especially in unblinded studies.

[0207] For SD, measurements must have met the criteria for SD at least once within the shortest period defined in the study protocol after study entry (generally 6–8 weeks or more).

[0208] Total effect period Duration of overall response was the time from the first fulfillment of the CR / PR criteria (whichever was first recorded) to the first date of objectively documented disease recurrence or disease progression (PD was defined as the smallest measurement recorded during the study).

[0209] The overall duration of CR is the time from the first fulfillment of the metrics for CR to the first date of objectively documented disease recurrence.

[0210] Period of stable disease SD is the time from the start of treatment (the day of randomization in randomized studies) to the time when the criterion for progression is met, based on the smallest sum diameter during the study (if the baseline sum diameter is the smallest, this is the basis for calculating PD).

[0211] The clinical relevance of the duration of SD varies across studies and diseases. If the proportion of participants achieving SD over a minimum period is a key endpoint in a particular study, the protocol should specify the minimum interval between two measurements required for the determination of SD.

[0212] Note: DOR and SD, as well as PFS, are affected by the frequency of follow-up after baseline assessment. The frequency should take into account many parameters, including disease type and stage, periodicity of treatment, and standard of care. However, these limitations regarding the precision of the endpoints measured should be taken into account when making comparisons between studies.

[0213] Pharmacokinetic evaluation Plasma samples will be collected for measurement of Formula (I) plasma concentrations. Samples may be collected at additional time points during the study if justified. Samples collected for analysis of Formula (I) plasma concentrations may also be used to evaluate aspects of safety or efficacy related to concerns that arise during or after the study. The actual date and time (24-hour clock) of each sample will be recorded. Testing of PK samples will be performed by a designated bioanalytical contract research organization using validated methods.

[0214] [Table 8]

[0215] Pharmacodynamic evaluation Blood samples will be collected for measurement of circulating biomarkers, including but not limited to FGF23, parathyroid hormone, calcitriol, FGF19, and tumor-derived exosomes. In pediatric participants (12-21 years of age), serum type X collagen (CXM) may also be assessed.

[0216] Urine samples are collected to assess secreted biomarkers of FGFR3 inhibition, including but not limited to matrix metalloproteinase-1, matrix metalloproteinase-10, and fibroblast growth factor binding protein 1.

[0217] Further evaluation will be performed using excess biomarker or PK samples at the sponsor's discretion. Analysis will be performed by a central laboratory designated by the sponsor.

[0218] [Table 9]

[0219] Safety endpoints: Safety will be assessed by careful monitoring and timely evaluation of AEs, laboratory parameters (hematology and clinical chemistry), vital signs (blood pressure and heart rate), medical status of participants (physical examination including weight), ophthalmological examination, and general well-being and activities of daily living (ECOG PS).

Claims

1. A composition for use in treating cancer in patients requiring cancer treatment, Compound of formula (I): 【Chemistry 2】 or containing a pharmaceutically acceptable salt thereof, A composition comprising a compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)), administered in an amount of 10 mg to 120 mg per day.

2. The composition according to claim 1, wherein the cancer has an activated FGFR3 gene alteration.

3. The composition according to claim 2, wherein the cancer is urothelial carcinoma, breast cancer, endometrial cancer, lung cancer, ovarian cancer, or bladder cancer.

4. The composition according to claim 3, wherein the cancer is non-muscle-invasive bladder cancer.

5. The composition according to any one of claims 1 to 4, wherein the cancer is a locally advanced solid tumor or a metastatic solid tumor.

6. The composition according to any one of claims 2 to 4, wherein the activated FGFR3 gene alteration is a mutation.

7. The mutation is FGFR3 p.S84L, FGFR3 p.G380R, FGFR3 p.R621H, FGFR3 p.R248C, FGFR3 p.G380E, FGFR3 p.K650E, FGFR3 p.S249C, FGFR3 p.A391V, FGFR3 p.K650M, FGFR3 p.P250R, FGFR3 p.A391E, FGFR3 p.K650T, FGFR3 p.T264M, FGFR3 p.M528I, FGFR3 p.K650N, FGFR3 p.G370C, FGFR3 p.N540D, FGFR3 p.R669Q, FGFR3 p.S371C, FGFR3 p.N540S, FGFR3 p.G697C, FGFR3 p.Y373C, or FGFR3 p.N540K The composition according to claim 6, which is one or more of the above, or comprises one or more of the above.

8. The mutation is FGFR3 p.V553M, FGFR3 p.V555M, or FGFR3 p.V555L The composition according to claim 6, which is one or more of the above, or comprises one or more of the above.

9. The composition according to any one of claims 2 to 4, wherein the activated FGFR3 gene alteration is a fusion.

10. The fusion comprises a complete FGFR3 kinase domain, Breakpoints in intron 17 or exon 18 of FGFR3 and known partner genes (e.g., TACC3, BAIAP2L1), Breakpoints in intron 17 or exon 18 of FGFR3 and novel in-frame partner genes, or Breakpoints in intron 17 or exon 18 of FGFR3, and intragenetic regions or out-of-frame partner genes. The composition according to claim 9, wherein FGFR3 reconstruction is accompanied by the following.

11. The composition according to any one of claims 1 to 4, wherein the compound is a compound of formula (I).

12. The composition according to any one of claims 1 to 4, wherein the compound is a pharmaceutically acceptable salt of the compound of formula (I).

13. The composition according to claim 12, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a besylate.

14. The composition according to claim 1, wherein the composition is administered orally.

15. The composition according to any one of claims 1 to 4, wherein the composition is administered over a period of at least 28 days.

16. The composition according to claim 15, wherein the composition is administered over a period of 28 days.

17. The composition according to any one of claims 1 to 4, wherein the cancer exhibits a complete response (CR) or a partial response (PR) as evaluated by the Response Evaluation Criteria for Solid Tumors (RECIST) v1.1 criteria in response to administration of the composition.

Images