Methods of treating solid tumors with activated FGFR3 gene alterations

Abstract

The present disclosure provides methods of treating cancers having activated FGFR3 gene alterations by administering a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I), as disclosed herein.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 373,933, filed on August 30, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to methods of treating cancer using FGFR3 inhibitors. Background Art

[0004] The fibroblast growth factor (FGF) family of receptor tyrosine kinases is composed of four highly conservative membrane-associated proteins (FGFR1, FGFR2, FGFR3 and FGFR4), and its function is to regulate cell growth, differentiation and homeostasis. The structure of FGFR comprises 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 a member of the FGF ligand family. 22 FGF family members have been identified; wherein, 18 are secretory and act as the ligand of FGFR. Most of these FGFs act locally in a paracrine manner to affect neighboring cells, and three kinds of FGF (FGF19, FGF21 and FGF23) circulate in the blood and act in an endocrine manner to regulate the FGFR in distant tissues. When activated, these receptors stimulate a variety of cell 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.

[0005] These 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, and include 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 receptors can be associated with genetic disorders (e.g., point mutations in FGFR3 can lead to achondroplasia, the most common form of dwarfism in humans).

[0006] In the FGFR receptor family, oncogenic changes can occur in the ligand binding and transmembrane domains as constitutive activators, or directly in the intracellular kinase domain. Similarly, in addition to mutations, tumorigenesis can occur in FGFR through gene rearrangement and gene amplification. Activating mutations, fusions, or amplifications trigger multiple intracellular pathways that are the same as other oncogenes, such as mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. See 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. Using next-generation sequencing (NGS), it has been shown that 7.1% of cancers have some form of FGFR alteration, of which gene amplification is the most common (66%), followed by activating mutations (26%). The most common cancers that exhibit 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.

[0007] Urothelial tumors are a major source of morbidity and mortality worldwide, with more than 420,000 new cases and more than 165,000 deaths each year. FGFR3 alterations are found in up to 80% of non-muscle-invasive bladder cancers and up to 15% to 20% of muscle-invasive tumors. The most common FGFR3 alteration is the mutation S249C found in the ligand-binding domain, followed by the mutation Y375C in the transmembrane domain; these 2 mutations account for approximately 80% of FGFR3 mutations in bladder cancer.

[0008] Currently approved and late-stage pan-FGFR inhibitors are susceptible to acquired resistance mutations at the gatekeeper position of the FGFR3 protein. These same pan-FGFR inhibitors are limited by significant toxicities associated with inhibition of off-target receptor tyrosine kinases, including other isoforms of the FGFR family. This off-target activity limits dosing and theoretically provides further opportunity for the development of acquired resistance due to frequent dose interruptions and dose reductions.

[0009] Therefore, there is a need for methods of treating cancers with activating FGFR3 genetic alterations using isoform-selective FGFR3 inhibitors.

[0010] The compound of formula (I) is a highly selective inhibitor of FGFR3, which is being developed for the treatment of FGFR3-driven cancers. The compound of formula (I) has the following structure:

[0011]

[0012] A description of the synthesis of compounds of formula (I) and their activity, as well as pharmaceutically acceptable salts of compounds of formula (I) and pharmaceutical compositions that may contain compounds of formula (I) (and / or their salts) can be found in WO2022 / 147246, which is incorporated herein by reference. Summary of the invention

[0013] The present disclosure satisfies the need for methods of treating cancer in patients with activating FGFR3 genetic alterations using isoform selective FGFR3 inhibitors, wherein the methods comprise administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer has an activating FGFR3 genetic alteration. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 A schematic diagram of the study design is shown.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

[0015] By reference to the following description, including the following definitions and examples, the present disclosure can be more fully understood. Some features of the disclosed method described herein in the context of the individual aspects may also be provided in combination in a single aspect. Alternatively, for the sake of brevity, the various features of the disclosed method described in the context of the individual aspects may also be provided individually or in any sub-combination.

[0016] With regard to the use of substantially any plural and / or singular terms herein, those skilled in the art may translate from the plural to the singular and / or from the singular to the plural, depending on the context and / or application. For the sake of clarity, various singular / plural arrangements may be expressly set forth herein. The indefinite article "a" or "an" does not exclude a plurality. The fact that specific 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.

[0017] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant stimulation to the organism to which it is applied and does not eliminate 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 the 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 the compound with an organic acid, such as an aliphatic or aromatic carboxylic acid or sulfonic acid, such as 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. Pharmaceutically acceptable salts can also be obtained by reacting the compound with a base to form salts such as ammonium salts, alkali metal salts (e.g., sodium salts or potassium salts), alkaline earth metal salts (e.g., calcium salts or magnesium salts), salts of organic bases (e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine) and salts with amino acids (e.g., arginine and lysine). Particularly preferred salts of compounds of formula (I) are described in WO2022 / 147246.

[0018] It should be understood that in any compound with one or more chiral centers described herein, if absolute stereochemistry is not explicitly indicated, each center can independently have R-configuration or S-configuration or a mixture thereof. Therefore, the compounds provided herein can be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure, diastereomerically enriched or stereoisomeric mixtures. In addition, it should be understood that in any compound with one or more double bonds that can be defined as E or Z as described herein, each double bond can independently be E or Z or a mixture thereof. It should be understood that in any compound with one or more chiral centers described herein, all possible diastereomers are also envisioned. It should be understood that in any compound described herein, all tautomers are envisioned. It should also be understood that in any compound described herein, all isotopes of the atoms contained are envisioned. 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 fluorine-18, fluorine-19, or one or more of other isotopes; any example of sulfur may include sulfur-32, sulfur-34, sulfur-35, sulfur-36, or one or more of other isotopes.

[0019] "Pharmaceutically acceptable excipient" refers to a non-toxic, biologically tolerable and otherwise biologically suitable substance (e.g., an inert substance) for administration to a subject, which is added to a pharmacological composition or otherwise used as a vehicle, carrier or diluent to facilitate administration of a compound of Formula (I) and is compatible therewith.

[0020] As used herein, "subject", "host", "patient", "participant" and "individual" are used interchangeably and should be given their ordinary meanings, and should also refer to organisms with FGFR proteins. This includes mammals, such as humans, non-human primates, ungulates, canines, felines, equines, mice, rats, etc. The term "mammal" includes humans and non-human mammals.

[0021] The terms "treatment", "treating", "treat", and the like shall be given their ordinary meanings and shall also include herein generally referring to obtaining a desired pharmacological and / or physiological effect. The effect may be preventive, in terms of completely or partially preventing a disease or a symptom thereof, and / or therapeutic, in terms of partially or completely stabilizing or curing a disease and / or side effects attributable to a disease. As used herein, "treatment" shall be given its ordinary meaning and shall also cover any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing a disease or symptom from occurring in a subject who may be susceptible to the disease or symptom but has not yet been diagnosed as having the disease or symptom; (b) inhibiting a disease symptom, such as arresting its development; and / or (c) alleviating a disease symptom, such as causing regression of the disease or symptom.

[0022] When used in the context of administering a therapeutic agent to a patient, the term "administering" refers to introducing the therapeutic agent into the patient's body. For example, the therapeutic agent can be introduced into the patient's body orally, nasally, subcutaneously, intravenously, intravesically, intramuscularly, transdermally, vaginally, rectally, or any combination thereof.

[0023] The terms "cancer", "neoplasm" and "tumor" are used interchangeably herein and should be given their ordinary meanings, and should also refer to cells that exhibit relatively autonomous growth, such that they exhibit an abnormal growth phenotype characterized by a significant loss of cell proliferation control. Generally, cells of interest for detection or treatment in the present application include precursors, precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells.

[0024] As used herein, "activating FGFR3 gene alteration" refers to a mutation or rearrangement of the FGFR3 gene relative to the wild-type FGFR3 gene, such that the FGFR3 gene with the activating FGFR3 gene alteration encodes a FGFR kinase having greater FGFR3 kinase activity than the FGFR kinase encoded by the wild-type FGFR3 gene.

[0025] In some aspects, the disclosure relates to methods of treating cancer in a patient, wherein the method comprises administering to the patient a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0026] In some aspects, the disclosure relates to a method of treating cancer in a patient, wherein the method comprises administering to the patient a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and wherein the cancer has an activating FGFR3 genetic alteration.

[0027] In some embodiments, the cancer is urothelial carcinoma, breast cancer, endometrial cancer, lung cancer, ovarian cancer, or bladder cancer.

[0028] In some embodiments, the cancer is urothelial carcinoma.

[0029] In other embodiments, the cancer is a urothelial tumor.

[0030] In other embodiments, the cancer is breast cancer.

[0031] In other embodiments, the cancer is endometrial cancer.

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

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

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

[0035] In some embodiments, the cancer is non-muscle invasive bladder cancer (NMIBC).

[0036] In other embodiments, the cancer is a locally advanced solid tumor.

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

[0038] In some aspects of the disclosed methods, the cancer has an activating FGFR3 genetic alteration.

[0039] In some embodiments, the activating FGFR3 gene change is a mutation. As used herein, the term "mutation" refers to a change in the FGFR3 gene that causes the encoded FGFR3 kinase to have an amino acid sequence different from that of the wild-type FGFR3 kinase. Methods for identifying FGFR3 mutations are known in the art.

[0040] In some embodiments, the mutation is any one or more of the following:

[0041] FGFR3 p.S84L;

[0042] FGFR3 p.G380R;

[0043] FGFR3 p.R621H;

[0044] FGFR3 p.R248C;

[0045] FGFR3 p.G380E;

[0046] FGFR3 p.K650E;

[0047] FGFR3 p.S249C;

[0048] FGFR3 p.A391V;

[0049] FGFR3 p.K650M;

[0050] FGFR3 p.P250R;

[0051] FGFR3 p.A391E;

[0052] FGFR3 p.K650T;

[0053] FGFR3 p.T264M;

[0054] FGFR3 p.M528I;

[0055] FGFR3 p.K650N;

[0056] FGFR3 p.G370C;

[0057] FGFR3 p.N540D;

[0058] FGFR3 p.R669Q;

[0059] FGFR3 p.S371C;

[0060] FGFR3 p.N540S;

[0061] FGFR3 p.G697C;

[0062] FGFR3 p.Y373C; or

[0063] FGFR3 p.N540K.

[0064] In other embodiments, the mutation is any one or more of the following:

[0065] FGFR3 p.V553M;

[0066] FGFR3 p.V555M; or

[0067] FGFR3 p.V555L.

[0068] In other embodiments, the activating FGFR3 gene alteration is a fusion gene mutation.As used herein, a "fusion" is a gene resulting from the joining of two previously independent genes.

[0069] In some embodiments, the fusion is a FGFR3 rearrangement with an intact FGFR3 kinase domain and:

[0070] breakpoints in intron 17 or exon 18 of FGFR3 and known partner genes (e.g., TACC3, BAIAP2L1);

[0071] A breakpoint in intron 17 or exon 18 of FGFR3 and an in-frame novel partner gene; or

[0072] Breakpoints in intron 17 or exon 18 of FGFR3 and intragenic region partner genes or out-of-frame partner genes.

[0073] In some aspects of the disclosed methods, a compound of formula (I) is administered to a patient.

[0074] In other aspects of the disclosed methods, a pharmaceutically acceptable salt of a compound of Formula (I) is administered to a patient.

[0075] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride, benzenesulfonate, maleate, toluenesulfonate, sulfate, 2-hydroxyethanesulfonate, ethanesulfonate (ethanesulfonate), methanesulfonate, dimethanesulfonate, R-camphorsulfonate, S-camphorsulfonate, or hydrobromide salt.

[0076] In some embodiments of the disclosed methods, an amount of 10 mg-120 mg / day of a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) (based on Formula (I)) is administered to the patient, for example, one of 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 an amount of 10 mg-200 mg / day of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) (based on formula (I)), 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, One of 100mg / days, 150mg / days, 160mg / days, 165mg / days, 170mg / days, 175mg / days, 180mg / days, 185mg / days, 190mg / days, 195mg / days or 200mg / days. When compound of formula (I) is used as a pharmaceutically acceptable salt, the amount of the salt used is based on compound of formula (I). That is, the amount of the salt used is the amount of the free alkali of formula (I) containing a specified amount.

[0077] In some embodiments of the disclosed methods, the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 10 mg / day.

[0078] In some embodiments of the disclosed methods, the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 20 mg / day.

[0079] In some embodiments of the disclosed methods, the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 40 mg / day.

[0080] In some embodiments of the disclosed methods, the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 60 mg / day.

[0081] In some embodiments of the disclosed methods, the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 75 mg / day.

[0082] In some embodiments of the disclosed methods, the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 80 mg / day.

[0083] In some embodiments of the disclosed methods, the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 90 mg / day.

[0084] In some embodiments of the disclosed methods, the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 120 mg / day.

[0085] In some embodiments of the methods of the present disclosure, the daily amount of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) (based on formula (I)) is administered as a single dose.

[0086] In some embodiments of the methods of the present disclosure, a daily amount 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, wherein each of the multiple doses contains a portion of the daily amount.

[0087] In some embodiments, the daily amount 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, wherein each of the two doses contains a portion of the daily amount.

[0088] In some embodiments, the daily amount 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, wherein each of the two doses contains half of the daily amount.

[0089] 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 by any suitable route of administration, such as oral, nasal, subcutaneous, intravenous, intravesical, intramuscular, transdermal, vaginal, rectal, or any combination thereof.

[0090] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt of the compound of Formula (I) is administered orally.

[0091] 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, solutions, etc. Pharmaceutical dosage forms are generally 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 includes one or more pharmaceutically acceptable excipients.

[0092] 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 a day. In some aspects, the administration is once a day.

[0093] 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 aspects, administration is at least once a day. In some aspects, administration is once a day.

[0094] In some aspects, the disclosed methods comprise administering a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) and an additional therapy.

[0095] In some embodiments, the additional therapy includes one or more of radiation therapy, chemotherapy, surgery (eg, at least partial resection of a tumor).

[0096] In some embodiments, the additional therapy is chemotherapy, ie, the administration of one or more additional therapeutic agents.

[0097] In some embodiments, the additional therapeutic agent is a checkpoint inhibitor.

[0098] In some embodiments, the checkpoint inhibitor is a PD-1 / PD-L1 inhibitor, such as one or more of pembrolizumab, nivolumab, avelumab, durvalumab, atezolizumab, cemiplimab, dostarlimab, JTX-4014, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012 (MGA012), AMP-224, or AMP-514 (MEDI0680).

[0099] In other embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor, such as one or more of ipilimumab, tremelimumab, or AGEN-1884.

[0100] In some embodiments, the additional therapeutic agent is an antibody-drug conjugate, such as enfortumab vendotin, sacituzumab govitecan, disitamab vedotin, or Vic-trastuzumab duocarmazine (SYD985).

[0101] In other embodiments, the additional therapeutic agent is cisplatin, carboplatin, gemcitabine, docetaxel, paclitaxel, vinflunine, methotrexate, vinblastine, mitomycin, valrubicin, or doxorubicin.

[0102] In some embodiments, the additional therapeutic agent is a MEK inhibitor, such as trametinib, cobimetinib, or binimetinib.

[0103] In some embodiments, the additional therapeutic agent is a PARP inhibitor, such as olaparib, veliparib, niraparib, rucaparib, or talazoparib.

[0104] In some embodiments, the additional therapeutic agent is a HER2 inhibitor, such as lapatinib, afatinib, AZD8931, AST-1306, AEE-788, canertinib (CI-1033), CP724, CP714, CUDC-101, TAK-285, AC-480 (BMS-599626), dacomitinib (PF299804PF299) (Dacomitinib), or pelitinib (EKB-569).

[0105] In some embodiments, the additional therapeutic agent is a SHP2 inhibitor, such as TNO-155 or RMC-4630.

[0106] In some embodiments, the additional therapeutic agent is an antibody.

[0107] In some embodiments, the antibody is a HER2 antibody, such as one or more of trastuzumab or pertuzumab.

[0108] In some embodiments, the antibody is a bispecific antibody, such as one or more of MM-111 or ertumaxomab.

[0109] In some embodiments, the additional therapy is a biological immunotherapy, such as intravesicular BCG (Bacillus Calmette-Guerin).

[0110] In embodiments of the disclosed methods comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt of a compound of Formula (I) and an additional therapy, the compound of Formula (I) (or its salt) is administered before, during, or after the administration or application of the additional therapy.

[0111] In embodiments of the disclosed methods where the additional therapy is chemotherapy, the chemotherapeutic agent can be administered by any suitable route of administration, e.g., orally, nasally, subcutaneously, intravenously, intravesically, intramuscularly, transdermally, vaginally, rectally, or any combination thereof.

[0112] In some embodiments, a compound of Formula (I) (or a salt thereof) is administered prior to the administration or application of an additional therapy.

[0113] In some embodiments, a compound of Formula (I) (or a salt thereof) is administered during the administration or application of an additional therapy.

[0114] In some embodiments, a compound of Formula (I) (or a salt thereof) is administered after the administration or application of an additional therapy.

[0115] In some aspects of the methods of the present disclosure, the cancer exhibits a complete response (CR) or 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 the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0116] In some embodiments, the cancer demonstrates 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 the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0117] 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 the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0118] The present disclosure also relates to the following aspects:

[0119] Aspect 1. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (I),

[0120]

[0121] or a pharmaceutically acceptable salt thereof.

[0122] Aspect 2. The method of Aspect 1, wherein the cancer has an activating FGFR3 gene alteration.

[0123] Aspect 3. The method of Aspect 1 or Aspect 2, wherein the cancer is urothelial carcinoma, breast cancer, endometrial cancer, lung cancer, ovarian cancer or bladder cancer.

[0124] Aspect 4. The method of Aspect 3, wherein the cancer is urothelial carcinoma.

[0125] Aspect 5. The method of Aspect 3, wherein the cancer is a urothelial tumor.

[0126] Aspect 6. The method of Aspect 3, wherein the cancer is breast cancer.

[0127] Aspect 7. The method of Aspect 3, wherein the cancer is endometrial cancer.

[0128] Aspect 8. The method of Aspect 3, wherein the cancer is lung cancer.

[0129] Aspect 9. The method of Aspect 3, wherein the cancer is ovarian cancer.

[0130] Aspect 10. The method of Aspect 3, wherein the cancer is bladder cancer.

[0131] Aspect 11. The method of any one of Aspects 1 to 10, wherein the cancer is a locally advanced solid tumor.

[0132] Aspect 12. The method of any one of Aspects 1 to 11, wherein the cancer is a metastatic solid tumor.

[0133] Aspect 13. The method of any one of Aspects 2 to 12, wherein the activating FGFR3 genetic alteration is a mutation.

[0134] Aspect 14. The method of aspect 13, wherein the mutation is or includes one or more of the following:

[0135] FGFR3 p.S84L;

[0136] FGFR3 p.G380R;

[0137] FGFR3 p.R621H;

[0138] FGFR3 p.R248C;

[0139] FGFR3 p.G380E;

[0140] FGFR3 p.K650E;

[0141] FGFR3 p.S249C;

[0142] FGFR3 p.A391V;

[0143] FGFR3 p.K650M;

[0144] FGFR3 p.P250R;

[0145] FGFR3 p.A391E;

[0146] FGFR3 p.K650T;

[0147] FGFR3 p.T264M;

[0148] FGFR3 p.M528I;

[0149] FGFR3 p.K650N;

[0150] FGFR3 p.G370C;

[0151] FGFR3 p.N540D;

[0152] FGFR3 p.R669Q;

[0153] FGFR3 p.S371C;

[0154] FGFR3 p.N540S;

[0155] FGFR3 p.G697C;

[0156] FGFR3 p.Y373C; or

[0157] FGFR3 p.N540K.

[0158] Aspect 15. The method of aspect 13, wherein the mutation is or includes one or more of the following:

[0159] FGFR3 p.V553M;

[0160] FGFR3 p.V555M; or

[0161] FGFR3 p.V555L.

[0162] Aspect 16. The method of any one of Aspects 2 to 12, wherein the activating FGFR3 gene alteration is a fusion.

[0163] Aspect 17. The method of aspect 16, wherein the fusion is a FGFR3 rearrangement having an intact FGFR3 kinase domain and:

[0164] Breakpoints in intron 17 or exon 18 of FGFR3 and known partner genes (e.g.

[0165] TACC3, BAIAP2L1);

[0166] A breakpoint in intron 17 or exon 18 of FGFR3 and an in-frame novel partner gene; or

[0167] Breakpoints in intron 17 or exon 18 of FGFR3 and intragenic region partner genes or out-of-frame partner genes.

[0168] Aspect 18. The method according to any one of the preceding aspects, wherein a compound of formula (I) is administered to the patient.

[0169] Aspect 19. The method according to any one of Aspects 1 to 17, wherein a pharmaceutically acceptable salt of a compound of formula (I) is administered to the patient.

[0170] Aspect 20. The method of Aspect 19, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a besylate salt.

[0171] Aspect 21. The method according to any one of the preceding aspects, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 10 mg to 120 mg / day.

[0172] Aspect 22. The method of Aspect 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 10 mg / day.

[0173] Aspect 23. The method of Aspect 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 20 mg / day.

[0174] Aspect 24. The method of Aspect 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 40 mg / day.

[0175] Aspect 25. The method of Aspect 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 60 mg / day.

[0176] Aspect 26. The method of Aspect 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 90 mg / day.

[0177] Aspect 27. The method of Aspect 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 120 mg / day.

[0178] 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.

[0179] Aspect 29. The method according to any one of the preceding aspects, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) is administered for at least 28 days.

[0180] 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.

[0181] Aspect 31. The method of any one of Aspects 1 to 30, wherein the cancer exhibits a complete response (CR) or 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 the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0182] 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 the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0183] Aspect 33. The method of Aspect 31 or Aspect 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 the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0184] The examples provided below further illustrate and exemplify the disclosed methods.It should be understood that the scope of the present invention is not limited in any way by the scope of the following examples.

[0185] Example

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192] Study title: Formula (I) in advanced urothelial tumors with activated FGFR3 gene changes

[0193] Multicenter, open-label, Phase 1 / 2 study in leukemia and other solid tumors Objectives: Primary Objectives:

[0194] ● Determine the optimal and maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of Formula (I) in participants with advanced solid tumors (Phase 1, A

[0195] and Part B)

[0196] ●Evaluate the preliminary antitumor activity of formula (I) at RP2D in participants in a selected expansion cohort whose tumors have activating fibroblast growth factor receptor (FGFR) 3 genetic alterations (Phase 2)

[0197] Secondary Objectives:

[0198] ● Characterize the safety and tolerability of Formula (I) in participants with advanced cancer (Phase 1, Parts A and B, and Phase 2)

[0199] ● Preliminary characterization of pharmacokinetic (PK) and pharmacodynamics in participants treated with Formula (I) (Phase 1, Parts A and B, and Phase 2)

[0200] Characterization of the objective response rate (ORR) in participants with activating FGFR3 genetic alterations (Phase 1, Part B)

[0201] ●Characterize duration of response (DOR; Phase 1, Part B, and Phase 2)

[0202] ● Characterize disease control rate (DCR) >12 weeks (Phase 1, Part B, and Phase 2)

[0203] ● Characterize time to response (TTR; Phase 1, Part B, and Phase 2)

[0204] ● Characterize progression-free survival (PFS) of participants treated with Formula (I) in specific tumor expansion cohorts (Cohorts 1 and 2 in Phase 2 only)

[0205] Exploratory objectives:

[0206] ● Identification of potential biomarkers of FGFR engagement / inhibition, toxicity, tumor response and resistance to Formula (I) in blood, urine and tissues

[0207] ●To evaluate the concordance between tissue and confirmatory clinical trial assay (CTA) results for the detection of FGFR3 genetic alterations in participants with locally advanced / metastatic urothelial tumors

[0208] ●Estimate overall survival (OS) for Phase 2 cohorts 1 and 2

[0209] Study Design:

[0210] This is a Phase 1 / 2, open-label, international, multicenter, dose-escalation / dose-expansion study of Formula (I) conducted in several parts.

[0211] Phase 1, Part A: Dose escalation

[0212] Participants with any advanced solid tumors and no approved standard therapy are eligible for enrollment, regardless of FGFR3 mutation status. The starting dose of Formula (I) in Part A is 10 mg daily (DL 1), and the dose escalation schedule is as follows:

[0213] DL1: 10 mg daily

[0214] DL2: 20 mg daily

[0215] DL3: 40 mg daily

[0216] DL4: 60 mg daily

[0217] DL5: 90 mg daily

[0218] DL6: 120 mg daily

[0219] The study used an i3+3 design with a target toxicity rate of 0.3 (0.25 to 0.35) at the MTD. Each DL was evaluated by a dose-limiting toxicity (DLT) assessment period (cycle 1 [28 days]) before enrollment in the next dose level (DL). Based on the number of participants and the number of DLTs observed, the decision was to escalate to a higher dose, or if at DL6, continue to enroll at the highest dose (E), maintain the same dose (S), decrement to the previous lower dose (D), or decrement to the previous lower dose and never repeat the current dose (DU).

[0220] DL1 and DL2 were conducted in an accelerated manner, with 1 participant monitored for toxicity during the DLT assessment period. Any grade ≥2 treatment-related adverse event (TRAE) constituted a DLT for DL1 and DL2. If no grade ≥2 TRAE occurred in DL1, the next participant was enrolled in DL2. Similarly, if no grade ≥2 TRAE occurred in DL2, the next cohort was dose-escalated (i.e., enrolled to DL3). If additional participants were enrolled in DL1 or DL2 due to this more stringent DLT definition, the study was converted to an i3+3 design, and all subsequent dose-escalation decisions used the same DLT definition as DL3 and above (i.e., grade ≥2 TRAE was no longer used as the definition of DLT).

[0221] DL3 and above will enroll at least 3 participants in each DL. These cohorts may enroll 1 to 3 additional participants at a time if required by the DLT rules. Dose escalation will continue to DL6 until the MTD is determined, or until approximately 30 participants have been enrolled in Part A.

[0222] Phase 1, Part B: Dose Expansion

[0223] When DL3 cleared dose escalation, dose expansion cohorts began to be enrolled in parallel to further explore pharmacodynamics and biomarkers in FGFR3 mutant cancers. Enrollment was limited to participants with advanced / metastatic solid tumors with FGFR3 activating genetic alterations for whom FGFR-directed therapy was appropriate. Participants in dose expansion underwent additional analyses of biomarker and pharmacodynamic endpoints, including but not limited to post-treatment and progression assessments of ctDNA, serial blood biomarker analysis, and skin biopsies for assessment of FGFR target inhibition.

[0224] Eligible FGFR3 gene mutations and fusions were defined as follows:

[0225] The table below lists eligible FGFR3 gene mutations.

[0226] Known and / or likely pathogenic activating fibroblast growth factor receptor 3 gene mutations

[0227]

[0228] Qualified fibroblast growth factor receptor 3 fusion

[0229] FGFR3 rearrangements with an intact FGFR3 kinase domain and:

[0230] Breakpoints in intron 17 or exon 18 of FGFR3 and known partner genes (eg, TACC3, BAIAP2L1);

[0231] Breakpoints in intron 17 or exon 18 of FGFR3 and novel in-frame partner genes;

[0232] ●Breakpoints in intron 17 or exon 18 of FGFR3 and intragenic region partner genes or out-of-frame partner genes.

[0233] Secondary Fibroblast Growth Factor Receptor 3 Mutations Resulting in Acquired Resistance to Current Generation Fibroblast Growth Factor Receptor Inhibitors:

[0234] FGFR3 p.V553M

[0235] FGFR3 p.V555M

[0236] FGFR3 p.V555L

[0237] Part B also uses an i3+3 design, but dose escalation is not applicable. Based on the probability of toxicity observed from participants in Parts A and B at this DL, the cohort can continue to expand. Since Part A is dose-escalated in parallel to DL4 to DL6, DLTs observed in Part B may lead to the need to pause or stop enrollment in Part A. Based on the number of participants and the number of DLTs observed, the decision is to continue Part B expansion (E), continue Part B expansion but suspend enrollment in Part A (S), or stop expansion to the DL and stop Part A (D or DU). If the probability of toxicity for the entire DL including Part A and Part B data is no higher than 0.35, cohort expansion will continue. If Part B leads to the suspension of enrollment in Part A, if dose expansion and continued monitoring in Part B reduce the toxicity rate to less than 0.25, enrollment in higher doses in Part A will be resumed.

[0238] When the MTD is established in Part A, up to 10 additional participants with locally advanced / metastatic FGFR3 mutation-positive urothelial tumors who have not received a prior FGFR inhibitor are enrolled at the MTD in Part B. This cohort evaluates the PK of the tablet formulation used in the Phase 2 portion of the study. The SRC reviews PK and AEs after 3 to 5 participants to ensure that there are no safety issues prior to completing enrollment in this expansion cohort.

[0239] Within-Participant Dose Escalation Decision-Making—Phase 1, Parts A and B

[0240] Intra-participant dose escalation was permitted for participants in these cohorts under the following circumstances:

[0241] • Higher doses were cleared in dose escalation (Part A) and were considered tolerated.

[0242] • Participants had no TRAEs > Grade 1 while taking Formula (I).

[0243] ●If any participant experienced grade ≥3 treatment-related toxicity at a given DL, within-participant dose escalation was not permitted at that DL.

[0244] ●The higher doses in the study may be safe and may be more effective in treating tumors in participants in the enrolling or completed cohorts than the current doses.

[0245] ●Participants have completed at least 2 cycles of study drug treatment and have at least 1 post-baseline tumor imaging assessment.

[0246] Participants with evidence of progressive disease (PD) (as defined by RECIST v1.1) continued to receive study drug if they would benefit from continued study drug. The following criteria must be met to ensure that participants are not exposed to unreasonable risk:

[0247] ●No symptoms or signs indicating clinically significant disease progression.

[0248] No decrease in ECOG PS or Karnofsky performance status (KPS).

[0249] ●No symptomatic rapid disease progression requiring urgent medical intervention (eg, symptomatic pleural effusion, spinal cord compression, etc).

[0250] At the time of radiographic progression, participants were re-informed and provided with details of all approved therapies and potential clinical benefits, and were informed that they might need to abandon the above therapies if they continued to receive Formula (I).

[0251] After exceeding DL3, dose increases were not to exceed 50% of the previous dose, and intermediate doses could be explored. The MTD was the highest DL at which no more than 35% of participants experienced an AE meeting DLT criteria. Participants could be replaced if they did not receive at least 75% of the planned doses for reasons other than TRAEs during the DLT assessment period, or if they discontinued the study for non-DLT reasons during the DLT assessment period.

[0252] Dose escalation decision-phase 1, parts A and B

[0253] Typically, dose escalation or expansion is performed according to i3+3.

[0254] If any participant / study stopping criteria are met within a dose cohort, further enrollment in that cohort will not proceed until all safety data for participants at that dose have been reviewed. If a decision is made not to initiate a new cohort before all planned prior cohorts are completed, this is not considered early termination of the study. After review of the safety data, one of the following recommendations is made:

[0255] ● Continue the study as planned (i.e., no major safety issues) or make appropriate study amendments to address emerging safety risks.

[0256] ●Continue the study but at a dose between the current dose and the next planned dose; or at a dose between the current dose and the previous lower dose.

[0257] ● Continue the study, but expand the current cohort or higher / lower dose cohorts with an appropriate number of participants to conduct a more detailed safety assessment.

[0258] ●Terminate the study.

[0259] Definition of dose-limiting toxicity

[0260] For an AE to qualify as a DLT, it 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 Cycle 1 of the DL and considered to be related to Formula (I). Common Terminology Criteria for Adverse Events (CTCAE) v5.0 was used to assess toxicity / AEs.

[0261] Hematologic dose-limiting toxicity

[0262] Absolute neutrophil count (ANC) <500 / mm 3 Lasts > 7 days

[0263] Febrile neutropenia (characterized by ANC <1000 / mm 3 and a single episode of temperature 38.3°C or temperature 38.0°C lasting for >1 hour); or grade 3 neutropenia lasting >7 days with or without medical intervention

[0264] Platelets <25,000 / mm 3

[0265] ●Grade 3 bleeding associated with grade 3 or higher thrombocytopenia

[0266] Non-hematologic dose-limiting toxicities

[0267] ● Non-hematologic grade 3 or 4 toxicities, including nausea and vomiting refractory to antiemetics. The following were not considered DLTs:

[0268] ○ Grade 3 nausea or vomiting lasting < 48 hours.

[0269] ○ Grade 3 fatigue for < 1 week.

[0270] ○3 lasting ≤ 72 hours, without clinical complications, spontaneously resolved or responsive to conventional medical intervention

[0271] Grade 1 or higher electrolyte abnormalities (excluding hyperphosphatemia).

[0272] ○ Grade 3 or higher amylase or lipase elevation not associated with symptoms or clinical manifestations of pancreatitis.

[0273] Grade 3 hyperphosphatemia (severe or medically significant but not immediately life-threatening; requiring hospitalization or prolongation of an existing hospitalization) will be considered a DLT regardless of whether it resolves with phosphate binders.

[0274] Hy's law:

[0275] ○ Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3× upper limit of normal (ULN) and

[0276] ○Total bilirubin >2×ULN and

[0277] ○Alkaline phosphatase <2×ULN and

[0278] ○ No other cause of liver damage.

[0279] Any AST or ALT elevation >8×ULN, regardless of duration, and AST or ALT assessment of 5 to 8×ULN for >2 weeks—regardless of the presence of liver metastases

[0280] ●Study drug administration was delayed for >14 days due to an AE.

[0281] ●Any death where it is unclear whether it was caused by the underlying disease or an external cause.

[0282] Other dose-limiting toxicities

[0283] If an unexpected drug-related toxicity is observed more frequently, that toxicity may be declared a DLT for the remainder of the study.

[0284] Any toxicity considered to be related to Formula (I) requires discontinuation of treatment for >7 days during the DLT assessment period. Such toxicity may be a Grade 1 or 2 toxicity that interferes with daily living activities (e.g., chronic fatigue or anorexia) and requires dose interruption / reduction to ensure participant compliance. Examples may include Grade 2 nail loss or Grade 3 paronychia that does not improve after 4 weeks of supportive treatment.

[0285] For certain toxicities, such as laboratory evaluations without clear clinical relevance (eg, elevated lipase without clinical signs of pancreatitis; or grade 2 hyperphosphatemia that does not recover to ≤ grade 1 within 7 days after treatment with phosphate binders and dietary modifications), determine whether the AE should be evaluated as a DLT requiring dose reduction.

[0286] A more stringent DLT definition was used for the first dosing cohorts (DL1 and DL2) than for DL3 and above: any grade ≥2 TRAE constituted a DLT for DL1 and DL2. If DL1 or DL2 was expanded due to this more stringent DLT definition, further dose escalation decisions were made using the same DLT definition as for DL3 and above (i.e., no longer using grade ≥2 TRAE as the definition of DLT).

[0287] Results from the dose escalation and dose expansion cohorts were analyzed for safety, as well as potential relationships between dose, PK, biomarkers for target engagement, and preliminary anti-tumor activity of Formula (I). An overall RP2D was selected using Phase 1 data.

[0288] Phase 2: Cohort Expansion

[0289] Once the MTD was determined and the RP2D was selected, participants were enrolled in Phase 2 expansion cohorts to further characterize preliminary efficacy, safety, and tolerability in the following cohorts:

[0290] 1. Patients with locally advanced / metastatic urothelial tumors who have been previously treated with FGFR inhibitors and have been confirmed to have FGFR3 resistance mutations to any FGFR inhibitor:

[0291] ○ Participants must have received previously approved therapies, including platinum-based chemotherapy, immune checkpoint inhibitors, and antibody-drug conjugates, unless the participant could not tolerate any of these approved drugs or the participant refused any / all of these therapies.

[0292] ○ Participants with urothelial tumors will be screened and evaluated for qualifying resistance mutations using a CTA that assesses somatic mutations in plasma ctDNA. Participants with qualifying genetic alterations based on a local test that is authorized / approved or validated under the Clinical Laboratory Improvement Amendments (CLIA) (or local equivalent) may be enrolled and must submit a specimen for central testing utilizing a CTA. These participants do not need to be confirmed prior to starting Formula (I).

[0293] ■ Participants who discontinued a prior FGFR inhibitor due to toxicity may be eligible if there is evidence of activating FGFR3 alterations and known FGFR3 acquired resistance mutations in the CTA or authorized / approved or CLIA (or local equivalent) validated local testing.

[0294] 2. Participants with locally advanced / metastatic urothelial tumors with activating FGFR3 genetic alterations who have not received previous FGFR inhibitors.

[0295] ○ Participants must have received previously approved therapies, including platinum-based chemotherapy, immune checkpoint inhibitors, and antibody-drug conjugates, unless the participant could not tolerate any of these approved drugs or the participant refused any / all of these therapies.

[0296] ○ Participants with urothelial tumors will be screened and evaluated for qualifying activating mutations and rearrangements using CTA. Participants with qualifying genetic alterations based on authorized / approved or CLIA (or local equivalent) validated local testing may be enrolled and must submit specimens for central testing utilizing CTA. These participants do not need to be confirmed prior to starting Formula (I).

[0297] 3. Participants with any locally advanced / metastatic solid tumors with activating FGFR3 genetic alterations and who have not received FGFR inhibitors previously.

[0298] ○ Participants must be receiving previously approved therapies unless the participant cannot tolerate approved medications or the participant refuses any / all of these therapies.

[0299] ○ Participants will be enrolled based on results from an FDA-authorized / approved companion diagnostic (CDx) or a CLIA (or local equivalent) validated local test performed in a certified laboratory. Blood specimens must be submitted to a central laboratory for analysis using a CTA. These participants do not need to be confirmed prior to starting Formula (I).

[0300] ○ Participants with disease progression on prior FGFR inhibitor therapy who have activating FGFR3 alterations and known FGFR3 acquired resistance mutations as determined by the CTA or authorized / approved or CLIA (or local equivalent) validated local test may be enrolled, with approval of the medical monitor.

[0301] For Phase 2, approximately 110 participants were enrolled in each of Cohorts 1 and 2. Simon's Phase 2 design was used for enrollment. In Phase 1, 39 participants were accrued, and if there were only 6 or fewer responses, enrollment in the cohort was stopped for futility. Otherwise, an additional 71 participants were accrued, bringing the total to 110 participants. Response was defined as CR or PR according to RECIST v1.1 at any time during treatment; for Cohort 1, clinical benefit (prolongation of SD during treatment for ≥6 months) was counted as response.

[0302] Cohort 3 was exploratory and enrolled approximately 40 participants in a single phase.

[0303] Study termination criteria

[0304] A study may be terminated at any time if the incidence and severity of AEs indicate that the risk-benefit ratio for participants is no longer justified for continued study. Examples include, but are not limited to, cases of severe hepatotoxicity without an underlying cause or unexplained participant death not due to disease progression or external causes.

[0305] Study duration

[0306] All enrolled participants received Formula (I) daily until disease progression, death, unacceptable toxicity, withdrawal of participant's informed consent for treatment, withdrawal from the study, or study termination, whichever occurred first.

[0307] Planned Sample Size and Treatment Groups: For Phase 1, the total number of participants enrolled depends on the number of escalation cohorts and the number of dose expansion cohorts evaluated. A maximum of 50 participants will be enrolled in Parts A and B combined (up to 30 participants in Part A and 20 participants in Part B).

[0310] For Phase 2, approximately 110 participants were enrolled in each of Cohorts 1 and 2. A Simon 2-phase design was used for enrollment. In Phase 1, 39 participants were cumulatively enrolled, and enrollment in the cohort was stopped for futility if there were only 6 or fewer responses. Otherwise, an additional 71 participants were cumulatively enrolled, bringing the total to 110 participants. If 23 or more responses were observed among the 110 participants, the null hypothesis was rejected. The design yielded a 5% one-sided type I error rate and 80% power when the true response rate was 25%. Responses were defined as complete responses (CR) or partial responses (PR) according to RECIST v1.1 at any time during treatment; for Cohort 1, clinical benefit (prolongation of stable disease [SD] during treatment for ≥6 months) was counted as a response. Cohort 3 was exploratory and enrolled approximately 40 participants in a single phase.

[0311] Target Population: Phase 1, Part A: Participants with any advanced solid tumor who have exhausted all standard treatment options.

[0312] Phase 1, Part B: Participants with locally advanced / metastatic solid tumors and FGFR3-activating genetic alterations who are candidates for FGFR3-targeted therapy. The MTD expansion will enroll up to 10 participants with locally advanced / metastatic urothelial tumors with FGFR3-activating genetic alterations who have not received prior FGFR inhibitors.

[0313] Phase 2, Cohort 1: Patients with locally advanced / metastatic urothelial tumors who have been previously treated with a FGFR inhibitor and have been identified to have FGFR3 resistance mutations

[0314] Phase 2, Cohort 2: Participants with locally advanced / metastatic urothelial tumors with confirmed activating FGFR3 genetic alterations who have not received prior FGFR inhibitor therapy.

[0315] Phase 2, Cohort 3: Participants with any locally advanced / metastatic solid tumor with confirmed activating FGFR3 genetic alterations who have not received prior FGFR inhibitor therapy.

[0316] Eligibility criteria: Inclusion criteria for Phase 1, Part A

[0317] 1. Male and female participants who are 18 years of age or older on the day of signing the Informed Consent Form (ICF).

[0318] 2. Life expectancy > 12 weeks.

[0319] 3. Able to understand and sign the ICF and comply with research procedures.

[0320] 4.ECOGPS≤1.

[0321] 5. Participants with any histologically confirmed advanced solid tumors who have exhausted standard treatment options.

[0322] 6. Ability to swallow capsules.

[0323] 7. The disease can be assessed by RECIST v1.1.

[0324] 8. Adequate organ and bone marrow function, as follows:

[0325] a. Absolute neutrophil count (ANC) ≥ 1500 / mm 3 .

[0326] b. Platelet count ≥ 75,000 / mm 3 .

[0327] c. International normalized ratio (INR) ≤ 1.5 × upper limit of normal (ULN).

[0328] i. Participants receiving anticoagulants (e.g., warfarin or heparin) will be allowed to participate provided there is no prior evidence of potential abnormalities in these parameters. Close monitoring will be performed with at least weekly assessments until INR is stable, based on pre-dose measurements as defined by local standards of care.

[0329] d. Total bilirubin ≤1.5×ULN. Documentation of Gilbert's syndrome is permitted if total bilirubin is mildly elevated (<6 mg / dL).

[0330] e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver cancer involvement).

[0331] f. Serum albumin>2g / dL.

[0332] g. Glomerular filtration rate (GFR) ≥ 60 mL / min / 1.73 m2 measured directly by 24-hour urine collection or calculated using the Cockroft-Gault formula 2 .

[0333] 9. Participants and their partners should adopt the contraceptive and reproductive restriction measures in the study as follows:

[0334] a. Female participants of no reproductive potential (i.e., surgically sterilized with hysterectomy and / or bilateral oophorectomy; or chemically sterilized; or amenorrhea for ≥12 months in the absence of chemotherapy, antiestrogens, or ovarian suppression) do not require pregnancy testing.

[0335] 10. Female participants of childbearing potential must have a negative pregnancy test within 7 days before starting Formula (I).

[0336] a. Female participants of childbearing potential and all male participants must agree to use highly effective contraceptive measures prior to study entry and within 120 days after the last dose of Formula (I).

[0337] 11. Have tested negative for coronavirus disease 2019 (COVID-19) by polymerase chain reaction (PCR)-based test within 48 hours or by rapid antigen test within 24 hours prior to starting Formula (I); and meet COVID-19 vaccination requirements according to local site regulations (if any). Participants who test positive for COVID-19 infection at screening and meet all other study eligibility criteria may be rescreened after test normalization and clinical recovery.

[0338] Inclusion criteria for Phase 1, Part B

[0339] 1. Male and female participants who are 18 years of age or older on the day they sign the ICF.

[0340] 2. Life expectancy > 12 weeks.

[0341] 3. Able to understand and sign the ICF and comply with research procedures.

[0342] 4.ECOGPS≤1.

[0343] 5. Participants with any histologically confirmed advanced solid tumors who have exhausted standard treatment options.

[0344] a. Tumors must have a qualifying FGFR3 gene mutation or fusion as diagnosed by any authorized / approved or CLIA (or local equivalent) local test performed at a certified laboratory facility.

[0345] b. Specimens must be submitted for analysis using CTA, but the results of CTA do not need to be obtained before starting formula (I).

[0346] c. Any number of prior therapies, including prior FGFR inhibitors, were allowed.

[0347] d. Up to 10 participants with metastatic urothelial tumors at the MTD who have a qualifying FGFR3 genetic alteration as determined by CTA or any authorized / approved or CLIA (or local equivalent) validated local test and have not received prior FGFR inhibitors.

[0348] 6. Ability to swallow capsules.

[0349] 7. At least 1 lesion measurable by RECIST v1.1.

[0350] 8. Adequate organ and bone marrow function, as follows:

[0351] a.ANC≥1500 / mm 3 .

[0352] b. Platelet count ≥ 75,000 / mm 3 .

[0353] c.INR ≤ 1.5 × ULN.

[0354] i. Participants receiving anticoagulants (e.g., warfarin or heparin) will be allowed to participate provided there is no prior evidence of potential abnormalities in these parameters. Close monitoring will be performed with at least weekly assessments until INR is stable, based on pre-dose measurements as defined by local standards of care.

[0355] d. Total bilirubin ≤1.5×ULN. Documentation of Gilbert's syndrome is permitted if total bilirubin is mildly elevated (<6 mg / dL).

[0356] e. ALT and AST ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver cancer involvement).

[0357] f. Serum albumin>2g / dL.

[0358] g. GFR ≥ 45 mL / min / 1.73 m2 measured directly by 24-hour urine collection or calculated using the Cockroft-Gault formula 2.

[0359] 9. Participants and their partners should adopt the contraceptive and reproductive restriction measures in the study as follows:

[0360] a. Female participants of no reproductive potential (i.e., surgically sterilized with hysterectomy and / or bilateral oophorectomy; or chemically sterilized; or amenorrhea for ≥12 months in the absence of chemotherapy, antiestrogens, or ovarian suppression) do not require pregnancy testing.

[0361] Female participants of childbearing potential must have a negative pregnancy test within 7 days prior to starting Formula (I).

[0362] c. Female participants of childbearing potential and all male participants must agree to use highly effective contraceptive measures prior to study entry and within 120 days after the last dose of Formula (I).

[0363] 10. Test negative for COVID-19 by PCR-based test within 48 hours or by rapid antigen test within 24 hours prior to starting Formula (I); and meet COVID-19 vaccination requirements according to local site regulations (if any). Participants who test positive for COVID-19 infection at screening and meet all other study eligibility criteria may be rescreened after test normalization and clinical recovery.

[0364] Inclusion criteria for phase 2

[0365] 1. Male and female participants who are 12 years of age or older on the day they sign the ICF.

[0366] 2. Life expectancy > 12 weeks.

[0367] 3. Able to understand and willing to sign the ICF. For participants under 18 years of age (or equivalent legal age), the parent / legal guardian is able to understand and sign the informed consent form and the child is able to understand and sign the consent statement.

[0368] 4. ECOGPS 0 to 2. KPS>70 for participants aged 12 to 17 years.

[0369] 5. Participants must have histologically confirmed locally advanced / metastatic tumors in one of the following categories:

[0370] a. Urothelial tumors with qualifying FGFR3 gene mutations or rearrangements that have progressed following prior FGFR inhibitor therapy and that present resistance mutations or other kinase domain mutations that may be responsive to Formula (I) as determined using a CTA or an FDA-authorized / approved CDx or CLIA (or local equivalent) validated local test performed in a certified laboratory.

[0371] b. Urothelial tumors with a qualifying FGFR3 genetic mutation or rearrangement as determined by central CTA or an FDA-authorized / approved CDx or CLIA (or local equivalent) validated local test performed in a certified laboratory and have not received prior FGFR inhibitors.

[0372] c. Any solid tumor with a qualifying FGFR3 gene mutation or rearrangement as determined by results of an authorized / approved or CLIA (or local equivalent) validated local test performed in a certified laboratory.

[0373] i. Subject to approval by the Medical Monitor, participants who have progressed after prior FGFR inhibitor therapy may be enrolled if they have documented FGFR3 resistance mutations or other kinase domain mutations and if it is determined based on preclinical studies that Formula (I) may be active against these mutations.

[0374] 6. Ability to swallow capsules.

[0375] 7. At least 1 lesion measurable by RECIST v1.1.

[0376] 8. Adequate organ and bone marrow function, as follows:

[0377] a.ANC≥1500 / mm 3 .

[0378] b. Platelet count ≥ 75,000 / mm 3 .

[0379] c.INR ≤ 1.5 × ULN.

[0380] i. Participants receiving anticoagulants (e.g., warfarin or heparin) will be allowed to participate provided there is no prior evidence of potential abnormalities in these parameters. Close monitoring will be performed with at least weekly assessments until INR is stable, based on pre-dose measurements as defined by local standards of care.

[0381] d. Total bilirubin ≤1.5×ULN. Documentation of Gilbert's syndrome is permitted if total bilirubin is mildly elevated (<6 mg / dL).

[0382] e. ALT and AST ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver cancer involvement).

[0383] f. Serum albumin>2g / dL.

[0384] g. GFR ≥ 45 mL / min / 1.73 m2 measured directly by 24-hour urine collection or calculated using the Cockroft-Gault formula 2 .

[0385] 9. Participants and their partners should adopt the contraceptive and reproductive restriction measures in the study as follows:

[0386] a. Female participants of no reproductive potential (i.e., surgically sterilized with hysterectomy and / or bilateral oophorectomy; or chemically sterilized; or amenorrhea for ≥12 months in the absence of chemotherapy, antiestrogens, or ovarian suppression) do not require pregnancy testing.

[0387] 10. Female participants of childbearing potential must have a negative pregnancy test within 7 days before starting Formula (I).

[0388] a. Female participants of childbearing potential and all male participants must agree to use highly effective contraceptive measures prior to study entry and within 120 days after the last dose of Formula (I).

[0389] 11. Test negative for COVID-19 by PCR-based test within 48 hours or by rapid antigen test within 24 hours prior to starting Formula (I); and meet COVID-19 vaccination requirements according to local site regulations (if any). Participants who test positive for COVID-19 infection at screening and meet all other study eligibility criteria may be rescreened after test normalization and clinical recovery.

[0390] Study Exclusion Criteria

[0391] 1. Participants received chemotherapy, targeted therapy, immunotherapy, or investigational therapy within 2 weeks or 5 half-lives before the first dose of study drug (for nitrosoureas and mitomycin, within 6 weeks).

[0392] 2. Participants have not recovered from reversible toxicity from previous anticancer therapy (except for toxicity that is not clinically significant, including but not limited to hair loss, skin discoloration, or grade 1 neuropathy).

[0393] 3. Underwent major surgery within 4 weeks before enrollment.

[0394] 4. Any reason that would seriously impair the participant's ability to comply with study procedures and increase the risk to the participant. Examples include poorly controlled diabetes (glycosylated hemoglobin [HbA1c]>8%) and ongoing active infection requiring intravenous (IV) antibiotics.

[0395] 5. Women who are pregnant, breastfeeding or planning to become pregnant within 120 days after the last dose of formula (I), and men who plan to have children when participating in this study or within 120 days after the last dose of formula (I).

[0396] 6. Impaired wound healing, defined as skin / decubitus ulcers, chronic leg ulcers, known gastric ulcers, or non-healing incisions.

[0397] 7. Serum phosphorus level > ULN during the screening period (within 14 days of treatment and before Day 1 of Cycle 1) and remains > ULN despite medical management with phosphate binders.

[0398] 8. Any ocular disease that may increase the risk of ocular toxicity, including:

[0399] a. History or current evidence of central serous retinopathy (CSR; including grade ≥2 CSR while previously receiving FGFR inhibitors) or retinal vascular occlusion (RVO).

[0400] b. Active wet age-related macular degeneration (AMD).

[0401] c. Diabetic retinopathy with macular edema.

[0402] d. Uncontrolled glaucoma (according to local standard of care).

[0403] 9. Previous or current uncontrolled cardiovascular disease, including:

[0404] a. Unstable angina, myocardial infarction, or known grade II to IV congestive heart failure within the past 12 months.

[0405] b. Cerebrovascular accident or transient ischemic attack in the past 3 months.

[0406] c. Pulmonary embolism within the past 2 months.

[0407] 10. Active, symptomatic or untreated brain metastases.

[0408] a. Prior brain metastases that were treated at least 3 weeks prior to signing the full study ICF or that were clinically and radiographically stable and not requiring chronic corticosteroid therapy for at least 1 month prior to Cycle 1 Day 1 were allowed.

[0409] 11. Gastrointestinal diseases that affect oral administration or absorption of formula (I).

[0410] 12. Known history of human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection.

[0411] a. Participants with a history of HIV, who are receiving antiviral treatment and have an undetectable viral load by PCR are allowed.

[0412] b. Participants with a history of hepatitis B virus infection and positive hepatitis B surface antibody or hepatitis B core antibody in PCR testing are allowed.

[0413] c. Participants with HCV infection who had previously received antiviral therapy and tested negative for HCV by PCR were permitted.

[0414] 13. History of a second primary malignancy within 3 years after signing the ICF (except for definitively treated early-stage cancers, such as resected skin cancer and / or completely resected prostate cancer).

[0415] 14. Known hypersensitivity to formula (I) or any excipients of the formulated product.

[0416] 15. Participants who are taking strong inhibitors and / or inducers of cytochrome P450 (CYP) 3A4 enzymes are prohibited. Strong inhibitors and inducers of CYP3A are prohibited from 2 weeks before study entry until 1 week after the last 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 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, St. John's wort.

[0417] a. A strong inhibitor is a drug that increases the AUC of a sensitive indicator substrate by ≥5 times.

[0418] b. A strong inducer is a drug that decreases the AUC of a sensitive index substrate by ≥80%.

[0419] Abbreviations: AUC = area under the concentration-time curve, CYP = cytochrome

[0420] P450. Source: U.S. Food and Drug Administration. Drug Development and Drug Interactions. Substrates, Inhibitors, and Inducers Table. U.S. Food and Drug Administration. Drug Development and Drug Interactions. Substrates, Inhibitors, and Inducers Table. March 10, 2020. www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers.

[0421] c. Participants who may be switched to a similar medication without CYP3A4 interactions will require a 2-week washout period prior to starting Formula (I).

[0422] Study drug: Capsules of formula (I) in the following specifications: 5 mg and 10 mg (based on free base). Capsules are packaged in high-density polyethylene bottles for research, each bottle containing 30 capsules. The capsules of formula (I) contain the study drug as an active ingredient (in free base form or in pharmaceutically acceptable salt form) and microcrystalline cellulose as an inactive ingredient.

[0423] Participants were instructed to take Formula (I) with food or within 30 to 60 minutes after food or a small meal at the same time each day.

[0424] Assessment timetable for Phase 1 Part A and Phase 1 Part B:

[0425]

[0426]

[0427]

[0428] 1 cycle = 4 weeks (28 days).

[0429] aUnplanned visits may be conducted at any time, with appropriate clinical assessments and laboratory measurements based on AEs or other findings. Data and results should be entered into the electronic case report form. PK blood samples should be collected at any unplanned visit due to an AE. The date and time of the last study drug administration, as well as the time of PK sampling (24-hour clock time), should be accurately recorded.

[0430] b Participants will be followed up for safety (by phone or video contact) 28 days (+7 days) after the last dose of study drug. Subsequent anticancer therapy will also be collected.

[0431] c Participants will be followed for survival every 3 months (±15 days) until the participant withdraws consent for further participation, is lost to follow-up, dies, or the study ends. Contact can be made by telephone, video, email, or registered mail. Subsequent anticancer therapy will also be collected.

[0432] d The following assessments and local laboratory samples required for C1D1 can be performed within the first 2 days of C1D1: review of concomitant medications; COVID-19 signs, symptoms, and recent exposures; physical examination, including weight; Amsler grid screening; laboratory evaluation (hematology, serum chemistry, and pregnancy test); and pharmacodynamic sampling (blood and urine).

[0433] e The assignment of reminder cards should be recorded in the source.

[0434] f COVID-19 signs, symptoms, and recent exposure will be assessed at each designated time point. A negative COVID-19 test result is required with a PCR-based test within 48 hours or a rapid antigen test within 24 hours prior to starting Formula (I) and thereafter as needed based on local guidance or practice.

[0435] g A complete physical examination was performed only at screening. A targeted physical examination was performed starting on C1D1; however, no physical examination was planned on C1D8. Vital signs included temperature, respiratory rate, sitting radial pulse rate, and sitting systolic and diastolic blood pressures.

[0436] h The ECG will be transmitted electronically from the site to a central provider designated by the sponsor for “collection and preservation.”

[0437] i12-lead ECG and PK blood sampling will be performed in triplicate on C1D1 (pre-dose, and 30 minutes and 1, 2, 4, 8, and 24 hours post-dose) and C1D15 (pre-dose, and 30 minutes and 1, 2, 4, 8, and 24 hours post-dose). When ECG measurements are planned at the time of PK blood sampling, the ECG measurements should be completed immediately prior to PK blood sampling.

[0438] j Evaluation includes noncontact intraocular pressure, slit-lamp, fundus examination, and optical coherence tomography. Changes in visual acuity during treatment should prompt referral for ophthalmologic examination.

[0439] k Ophthalmologic examinations will be performed at Screening, C3D1 (±7 days), on Day 1 of every 3 cycles thereafter (ie, C6D1, C9D1, C12D1, etc.; ±7 days), and as clinically indicated.

[0440] l An Amsler grid screening will be performed at all CxD1 visits (ie, C1D1, C2D1, C4D1, C5D1, C7D1, C8D1, etc.) where an ophthalmologic examination was not performed.

[0441] m Complete blood count with platelets, INR (screening INR only and monitoring anticoagulation as needed).

[0442] n If a screening laboratory evaluation is performed within 7 days of C1D1 and is found to be within normal local laboratory limits, these results may be used in lieu of the local laboratory evaluation planned for C1D1.

[0443] o Albumin, ALT, alkaline phosphatase, AST, bicarbonate, bilirubin (direct, indirect, and total), blood urea nitrogen / urea nitrogen, calcium, chloride, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, total protein, and sodium.

[0444] p According to local requirements, female participants of childbearing potential will undergo a urine pregnancy test at Screening and on Cycle Day 1. A positive urine pregnancy test result at Screening will be confirmed by a serum test.

[0445] q Hepatitis B virus and hepatitis C virus testing is required for screening.

[0446] rThe preferred tumor imaging assessment modality is CT with IV contrast; however, nonenhanced CT of the chest and MRI of the abdomen and pelvis are permitted if IV contrast is clinically contraindicated. The same imaging modality will be used for screening and post-baseline efficacy assessments.

[0447] s Baseline tumor assessments will be completed within 28 days prior to the first dose of study drug. CT of the chest, abdomen, pelvis, and any other locations where disease was present at baseline is recommended; additional tumor imaging assessments are mandatory if clinically indicated or if suspicious lesions are found in other areas. Baseline brain MRI is not required unless there is a history of brain metastases or neurologic symptoms suggestive of new brain metastases.

[0448] t Every 8 weeks (C3D1, C5D1, C7D1, C9D1, C11D1, and C13D1), the window was ±7 days.

[0449] u Once every 12 weeks, starting from C13D1 (C16D1, C19D1, etc.), with a window of ±7 days.

[0450] v If study drug is discontinued for reasons other than documented disease progression (e.g., toxicity), radiographic / imaging assessments should continue as planned until initiation of subsequent treatment or withdrawal from the study.

[0451] w WPK blood samples were collected on C1D1 (before and 30 minutes and 1, 2, 4, 8, and 24 hours after dosing), C1D15 (before and 30 minutes and 1, 2, 4, 8, and 24 hours after dosing), C2D1 (before dosing), C2D15 (before dosing), and C3D1 (before dosing). Formula (I) should be taken with food or within 30 to 60 minutes after food or a small meal (such as eggs, toast, yogurt, or a small sandwich), and the meal date and time should be recorded in the eCRF. For all PK samples, the actual study drug administration time and PK sampling time (24-hour clock time) should be accurately recorded.

[0452] x Blood and urine samples for circulating biomarkers were collected prior to dosing of C1D1, C1D15, and C2D1. Blood biomarkers include, but are not limited to, FGF23, parathyroid hormone, calcitriol, FGF19, and tumor-derived exosomes. In pediatric participants (12 to 21 years of age), CXM may also be assessed. Urine biomarkers include, but are not limited to, matrix metalloproteinase-1, matrix metalloproteinase-10, and FGF binding protein 1.

[0453] ySampling of ctDNA (blood and urine) is required only for participants with FGFR3 gene alterations in Phase 1 Part A and for all participants in Phase 1 Part B.

[0454] z Biomarker sampling will be performed using 2 mm skin punch biopsy / tape strips at Screening and C2D1. Optional at EOT and as needed to assess skin toxicity.

[0455] aa Archival tumor biopsy for participants with FGFR3 genetic alterations in Phase 1, Part A and for all participants in Phase 1, Part B. If available, an archival tumor biopsy specimen must be provided; however, if an archival specimen is not available, a new biopsy is not required.

[0456] Abbreviations: AE = adverse event, ALT = alanine aminotransferase, AST = aspartate aminotransferase, COVID-19 = coronavirus disease 2019, CT = computed tomography, ctDNA = circulating tumor DNA, CxDx = cycle x day x, CXM = serum type X collagen, ECG = electrocardiogram, eCRF = electronic case report form, ECOGPS = Eastern Cooperative Oncology Group performance status, EOT = end of treatment, FGF = fibroblast growth factor, FGFR = fibroblast growth factor receptor, INR = international normalized ratio, IRT = interactive reaction technique, IV = intravenous; MRI = magnetic resonance imaging, PCR = polymerase chain reaction, PK = pharmacokinetics.

[0457] Evaluation schedule for Phase 2:

[0458]

[0459]

[0460]

[0461] 1 cycle = 4 weeks (28 days).

[0462] a Unplanned visits may be conducted at any time, with appropriate clinical assessments and laboratory measurements based on AEs or other findings. Data and results should be entered into the electronic case report form. PK blood samples should be collected at any unplanned visit due to an AE. The date and time of the last study drug administration, as well as the time of PK sampling (24-hour clock time), should be accurately recorded.

[0463] b Participants will be followed up for safety (by phone or video contact) 28 days (+7 days) after the last dose of study drug. Subsequent anticancer therapy will also be collected.

[0464] c Participants will be followed for survival every 3 months (±15 days) until the participant withdraws consent for further participation, is lost to follow-up, dies, or the study ends. Contact can be made by telephone, video, email, or registered mail. Subsequent anticancer therapy will also be collected.

[0465] d The following assessments and local laboratory samples required for C1D1 can be performed within the first 2 days of C1D1: review of concomitant medications; COVID-19 signs, symptoms, and recent exposures; physical examination, including weight; Amsler grid screening; laboratory evaluation (hematology, serum chemistry, and pregnancy test); and pharmacodynamic sampling (blood and urine).

[0466] e The assignment of reminder cards should be recorded in the source.

[0467] f COVID-19 signs, symptoms, and recent exposure will be assessed at each designated time point. A negative COVID-19 test result is required with a PCR-based test within 48 hours or a rapid antigen test within 24 hours prior to starting Formula (I) and thereafter as needed based on local guidance or practice.

[0468] g Every 8 weeks, starting from C1D1 (C3D1, C5D1, C7D1, C9D1, etc.).

[0469] h Comprehensive physical examination only at screening. Focused physical examination from C1D1 onwards; however,

[0470] No physical examination was planned on C1D8. Vital signs included temperature, respiratory rate, sitting radial pulse rate, and sitting systolic and diastolic blood pressures.

[0471] i 12-lead ECGs were obtained in triplicate.

[0472] j Changes in vision during treatment should prompt referral for ophthalmologic examination.

[0473] k Ophthalmologic examinations will be performed at Screening, C3D1 (±7 days), on Day 1 of every 3 cycles thereafter (ie, C6D1, C9D1, C12D1, etc.; ±7 days), and as clinically indicated.

[0474] l An Amsler grid screening will be performed at all CxD1 visits (ie, C1D1, C2D1, C4D1, C5D1, C7D1, C8D1, etc.) where an ophthalmologic examination was not performed.

[0475] m Complete blood count with platelets, INR (screening INR only and monitoring anticoagulation as needed).

[0476] n If a screening laboratory evaluation is performed within 7 days of C1D1 and is found to be within normal local laboratory limits, these results may be used in lieu of the local laboratory evaluation planned for C1D1.

[0477] o Albumin, ALT, alkaline phosphatase, AST, bicarbonate, bilirubin (direct, indirect, and total), blood urea nitrogen / urea nitrogen, calcium, chloride, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, total protein, and sodium.

[0478] p According to local requirements, female participants of childbearing potential will undergo a urine pregnancy test at Screening and on Cycle Day 1. A positive urine pregnancy test result at Screening will be confirmed by a serum test.

[0479] q Hepatitis B virus and hepatitis C virus testing is required for screening.

[0480] r The preferred tumor imaging assessment modality is CT with IV contrast; however, nonenhanced CT of the chest and MRI of the abdomen and pelvis are permitted if IV contrast is clinically contraindicated. The same imaging modality will be used for screening and post-baseline efficacy assessments. For participants enrolled in Phase 2 (Cohorts 1 and 2 only), scanned digital images will be electronically transmitted from the site to a central radiology vendor designated by the sponsor for “collection and preservation.”

[0481] s Baseline tumor assessments will be completed within 28 days prior to the first dose of study drug. CT of the chest, abdomen, pelvis, and any other locations where disease was present at baseline is recommended; additional tumor imaging assessments are mandatory if clinically indicated or if suspicious lesions are found in other areas. Baseline brain MRI is not required unless there is a history of brain metastases or neurologic symptoms suggestive of new brain metastases.

[0482] t Every 8 weeks (C3D1, C5D1, C7D1, C9D1, C11D1, and C13D1), the window was ±7 days.

[0483] u Once every 12 weeks, starting from C13D1 (C16D1, C19D1, etc.), with a window of ±7 days.

[0484] v If study drug is discontinued for reasons other than documented disease progression (e.g., toxicity), radiographic / imaging assessments should continue as planned until initiation of subsequent treatment or withdrawal from the study.

[0485] w Collect PK blood samples on C1D1 (1, 2, and 4 hours post-dose), C2D1 (before and 1, 2, and 4 hours post-dose), C2D15 (before dose), and C3D1 (before dose). For all PK samples, the actual study drug administration time and PK sampling time (24-hour clock time) should be accurately recorded in the eCRF.

[0486] x Blood and urine samples were collected prior to dosing of C1D1, C1D15, and C2D1 for circulating biomarkers. Blood biomarkers included, but were not limited to, FGF23, parathyroid hormone, calcitriol, FGF19, and tumor-derived exosomes. In pediatric participants (12 to 21 years of age), CXM may also be assessed. Urine biomarkers included, but were not limited to, matrix metalloproteinase-1, matrix metalloproteinase-10, and FGF binding protein 1.

[0487] y Biomarker sampling was performed using 2-mm skin punch biopsy / tape strips at screening, EOT, and as needed to assess skin toxicity.

[0488] z If available, an archived tumor biopsy specimen must be provided; however, if an archived specimen is not available, a new biopsy is not required.

[0489] Abbreviations: AE = adverse event, ALT = alanine aminotransferase, AST = aspartate aminotransferase, CT = computed tomography, COVID19 = coronavirus disease 2019, ctDNA = circulating tumor DNA, CxDx = cycle x day x, ECG = electrocardiogram, ECOGPS = Eastern Cooperative Oncology Group performance status, EOT = end of treatment, FGF = fibroblast growth factor, INR = international normalized ratio, IRT = interactive reaction technique, IV = intravenous, MRI = magnetic resonance imaging, PCR = polymerase chain reaction, PK = pharmacokinetics.

[0490] Screening is the interval from signing of the ICF to the day the participant is enrolled in the study (Cycle 1, Day 1). The Screening visit should be conducted within 28 calendar days prior to the start of study drug administration.

[0491] For each participant, the treatment period continued in 4-week cycles (i.e., 28 days) until disease progression, unless the participant met 1 of the treatment discontinuation criteria.

[0492] The safety follow-up period is the interval between the EOT visit and the scheduled follow-up visit and should be conducted 28 to 35 days after the EOT visit (or after the last dose of study drug if no EOT visit was conducted).

[0493] Once participants completed safety follow-up visits and / or started new anticancer therapy, they entered the survival follow-up period and were contacted at least every 12 weeks by telephone, video, email, registered mail, or visit to assess their survival status until death, withdrawal of informed consent, or end of the study, whichever occurred first.

[0494] Primary endpoint: Period 1 (Parts A and B): Incidence of DLT events during the DLT assessment period (Cycle 1 [28 days]).

[0495] Phase 2: Investigator-assessed ORR, defined as CR or PR according to RECIST v1.1.

[0496] Secondary endpoints: Phase 1 (Parts A and B) and Phase 2:

[0497] ● AE incidence characterized by study phase, cohort, severity, relationship to study drug, timing, and severity

[0498] ●Changes in clinical laboratory parameters, vital signs, electrocardiogram (ECG) parameters, and physical examination status

[0499] Single-dose and steady-state PK parameters, including but not limited to cumulative ratio, C max 、T max , AUC 0-last , AUC Tau , AUC 0-∞ (only after the first dose), Vd / F, CL / F and t 1 / 2

[0500] ●Other secondary endpoints for phase 1, part B only:

[0501] ○ORR

[0502] Additional secondary endpoints in phase 1, part B, and phase 2:

[0503] ○DOR

[0504] ○DCR, defined as CR, PR, or SD lasting >12 weeks

[0505] ○TTR

[0506] ●Other secondary endpoints for phase 2 only:

[0507] ○ PFS in cohorts 1 and 2

[0508]

[0509] First-line tumor assessment. CT of the chest, abdomen, pelvis, and any other location where disease was present at baseline is recommended; additional tumor imaging assessment is mandatory if clinically indicated or if suspicious lesions are found in other areas. A baseline brain MRI is not required unless there is a history of prior brain metastases or neurologic symptoms suggestive of new brain metastases. The preferred tumor imaging assessment modality is CT with IV contrast; however, nonenhanced CT of the chest and MRI of the abdomen and pelvis are permitted if IV contrast is clinically contraindicated. Baseline and postbaseline efficacy assessments are performed using the same imaging modality and by the same investigator whenever possible (RECIST v1.1).

[0510] Tumor imaging assessments should be performed every 8 weeks (±7 days) until Day 1 of Cycle 13 and every 12 weeks (±7 days) thereafter, regardless of study treatment status, until disease progression, death, unacceptable toxicity, participant withdrawal of treatment consent, or study withdrawal, whichever occurs first. The timing of tumor imaging assessments is calculated based on the date of the first dose of study drug (i.e., Day 1 of Cycle 1). Participants who discontinue study drug for reasons other than disease progression or death should continue to have imaging assessments on a protocol-specified schedule until disease progression, death, participant withdrawal of treatment consent, or study withdrawal. If imaging results first show a CR or PR, repeat tumor imaging is required 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.

[0511] For participants enrolled in Phase 2 (Cohorts 1 and 2 only), scanned digital images were electronically transmitted from the site to a central radiology vendor designated by the sponsor for “collection and preservation.”

[0512] Efficacy evaluations included ORR, DCR, DOR, TTR, and PFS (RECIST v1.1).

[0513] Response Evaluation Criteria in Solid Tumor Guidelines:

[0514] The RECIST v1.1 guidelines are provided below. See 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.

[0515] definition:

[0516] At baseline, tumor lesions / nodes will be classified as measurable or non-measurable as follows:

[0517] Measurable

[0518] Tumor lesions: must be accurately measured in at least one dimension (record the longest diameter in the measurement plane), with a minimum size of:

[0519] ●When using CT scanning (CT scanning layer thickness is not more than 5mm), 10mm.

[0520] ● When measuring with calipers during clinical examination, 10 mm (lesions that cannot be accurately measured with calipers should be recorded as unmeasurable).

[0521] ●When using chest X-ray, 20mm.

[0522] Malignant lymph nodes: When evaluated by CT scan (CT scan slice thickness is recommended to be no greater than 5 mm), the short axis of the lymph node must be ≥15 mm to be considered pathologically enlarged and measurable. At baseline and follow-up, only the short axis is measured and followed up.

[0523] Unmeasurable

[0524] All other lesions, including small lesions (<10 mm in longest diameter, or pathological lymph nodes with a short axis ≥10 to <15 mm) and truly non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusions, inflammatory breast disease, lymphovascular infiltration of the skin or lungs, and abdominal masses / abdominal organomegaly identified by physical examination but not measurable by reproducible imaging techniques.

[0525] Special considerations regarding lesion measurability

[0526] Bone lesions:

[0527] Bone scans, positron emission tomography (PET), or plain radiographs are not considered appropriate imaging techniques for measuring bone lesions. However, these techniques can be used to confirm the presence or absence of bone lesions.

[0528] ●Osteolytic bone lesions or mixed osteolytic-osteoblastic lesions with an identifiable soft tissue component that can be assessed by cross-sectional imaging techniques (eg, CT or MRI) can be considered measurable lesions if the soft tissue component meets the definition of measurability above.

[0529] ●Osteogenic bone lesions are not measurable.

[0530] Cystic lesions:

[0531] ●Lesions that meet the criteria for a radiographically defined simple cyst should not be considered malignant lesions (whether measurable or nonmeasurable) because, by definition, they are simple cysts.

[0532] ● “Cystic lesions” thought to represent cystic metastases may be considered measurable lesions if they meet the definition of measurability above. However, if non-cystic lesions are present in the same participant, these lesions are preferred as target lesions.

[0533] Lesions previously treated with local therapy:

[0534] Tumor lesions located in previously irradiated areas or areas that have received other local treatments are generally considered non-measurable unless progression of the lesion has been demonstrated. The study protocol should specify the conditions under which such lesions are considered measurable.

[0535] Evaluation Methodology

[0536] Lesion measurement

[0537] If clinical assessments are performed, all measurements should be recorded in metric notation using calipers. All baseline assessments should be performed as close to the start of treatment as possible and no more than 4 weeks prior to the start of treatment.

[0538] The same assessment approach and the same techniques should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based assessment should always be performed rather than clinical examination, unless the lesion being followed cannot be imaged but can be assessed by clinical examination.

[0539] Clinical lesions: Clinical lesions are considered measurable (e.g., skin nodules) only if they are superficial and ≥10 mm in diameter when assessed with calipers. In the case of skin lesions, color photography with rulers is recommended to estimate the size of the lesion. As mentioned above, when lesions can be assessed by both clinical examination and imaging, imaging should be performed because it is more objective and can also be reviewed at the end of the study.

[0540] ●Chest X-ray: Chest CT is preferred over chest X-ray, especially when progression is an important endpoint, because CT is more sensitive than X-ray, especially in identifying new lesions. However, if a lesion on chest X-ray is well-defined and surrounded by aerated lung, it can be considered measurable.

[0541] CT, MRI: CT is the current best and most reproducible method for measuring lesions selected for response assessment. This guideline defines the measurability of lesions on CT scans based on the assumption that the CT slice thickness is 5 mm or less. When the slice thickness of a CT scan is 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).

[0542] Ultrasound: Ultrasound is not useful for assessing lesion size and should not be used as a measurement method. Ultrasound examinations cannot be exactly replicated for later independent review because they are operator dependent, so there is no guarantee that the same technique and measurements will be used from one evaluation to the next. If new lesions are identified by ultrasound during the study, confirmation by CT or MRI is recommended. MRI may be used instead of CT in selected circumstances if radiation exposure with CT is a concern.

[0543] ●Endoscopy, laparoscopy: These techniques are not recommended for objective tumor assessment. However, when biopsies are obtained, they can be used to confirm a complete pathological response or to identify recurrence in studies with CR or recurrence after surgical resection as the endpoint.

[0544] ●Tumor markers: Tumor markers cannot be used alone to assess objective tumor response. However, if markers are initially above the upper limit of normal, they must return to normal levels before the participant can be considered a CR. Because tumor markers are disease-specific, instructions for their measurement should be incorporated into the protocol on a disease-specific basis. Specific guidelines for CA-125 response (in recurrent ovarian cancer) and prostate-specific antigen response (in recurrent prostate cancer) have been published. In addition, the International Collaborative Group for Gynecologic Cancers has developed CA125 progression criteria, which will be used in conjunction with objective tumor assessments in first-line studies of ovarian cancer.

[0545] Cytology, histology: If required by the protocol, these techniques can be used to differentiate between PR and CR in rare circumstances (e.g., residual disease in tumor types such as germ cell tumors, where known residual benign tumor may remain). When effusions are known to be a potential adverse effect of treatment (e.g., use of certain taxane compounds or angiogenesis inhibitors), cytologic confirmation of the tumor origin of any effusion that develops or worsens during treatment may be considered to differentiate between response (or SD) and PD if the measurable tumor meets the criteria for response or SD.

[0546] Response Standard

[0547] Target lesion assessment

[0548] CR: All target lesions disappear. The short axis of any pathological lymph node (whether target or non-target) must shrink to <10 mm.

[0549] ●PR: The sum of target lesion diameters is reduced by at least 30% based on the baseline sum of diameters.

[0550] PD: At least a 20% increase in the sum of target lesion diameters, using the smallest sum on study as reference (including the baseline sum if that is the smallest sum on study). In addition to the 20% relative increase, the sum must also demonstrate an absolute increase of at least 5 mm (note: the appearance of 1 or more new lesions is also considered progression).

[0551] SD: Using the smallest sum of diameters during the study period as reference, there is neither enough shrinkage to meet the requirements of PR nor enough increase to meet the requirements of PD.

[0552] ●Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis measurement (measured in the same anatomical plane as the baseline examination) recorded, even if the node regresses to less than 10 mm during the study. This means that when lymph nodes are included as target lesions, the “sum” of lesions may not be zero even if CR criteria are met, as normal lymph nodes are defined as having a short axis of <10 mm. Therefore, case report forms or other data collection methods can be designed to record target lymph node lesions in a separate section, where each lymph node must achieve a short axis of <10 mm in order to qualify for CR. For PR, SD, and PD, the actual short axis measurement of the lymph node will be included in the sum of target lesions.

[0553] Target lesions that become “too small to measure”: All lesions (nodular and non-nodular) recorded at baseline should have their actual measurements recorded at each subsequent assessment during the study, even if very small (e.g., 2 mm). However, sometimes lesions or nodes recorded as target lesions at baseline become so faint on the CT scan that the radiologist may not be able to easily assign a precise measurement and may report them as “too small to measure.” When this occurs, it is important to record a value on the case report form. If the lesion may have disappeared, the measurement should be recorded as 0 mm. If the lesion is thought to be present and faintly visible but too small to measure, a default value of 5 mm should be assigned (note: this rule is unlikely to apply to lymph nodes because they are usually of 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 it is faintly visible but too small to measure, a default value of 5 mm should be assigned in this case as well). This default value is derived from the 5 mm CT slice thickness (but should not change with changes in CT slice thickness). Measurements of these lesions may not be reproducible, so providing this default value will prevent erroneous responses or progression based on measurement error. However, to reiterate, if the radiologist is able to provide the actual measurement, even if it is less than 5 mm, this should be recorded.

[0554] Lesions that have split or merged during treatment: When a non-nodular lesion "fragments", the longest diameters of the fragmented parts should be added to calculate the target lesion sum. Similarly, when lesions merge, the plane between them can be maintained, which will help obtain the maximum diameter measurement of each individual lesion. If the lesions have completely merged so that they are no longer separable, in this case, the vector of the longest diameter should be the largest longest diameter of the "merged lesion".

[0555] Evaluation of non-target lesions

[0556] Although some non-target lesions may in fact be measurable, they need not be measured but should only be assessed qualitatively at the time points specified in the protocol.

[0557] CR: All non-target lesions disappear and tumor marker levels normalize. The size of all lymph nodes must be non-pathological (short axis <10 mm).

[0558] ●Non-CR / non-PD: One or more non-target lesions persist and / or tumor marker levels remain above normal limits.

[0559] PD: Unequivocal progression of existing non-target lesions (see comments below) (note: the appearance of 1 or more new lesions is also considered progression).

[0560] ●When participants also have measurable disease: In this setting, to achieve "clear progression" based on non-target disease, there must be an overall level of significant worsening in non-target disease such that the overall tumor burden has increased enough to warrant discontinuation of treatment, even in the presence of SD or PR in target disease (see below for further details). A modest "increase" in the size of 1 or more non-target lesions is generally not sufficient to qualify as a clear progression status. Therefore, it is extremely rare to designate overall progression based solely on changes in non-target disease in the face of SD or PR in target disease.

[0561] ● When a participant has only non-measurable disease: This situation arises in some phase 3 studies when having measurable disease is not a criterion for study entry. As described above, the same general concepts apply here, however, in this case there is no measurable disease assessment to account for the increase in non-measurable disease burden. Since worsening of non-target disease is not easily quantifiable (by definition: if all lesions are truly non-measurable), a useful test that can be applied when assessing a participant for unequivocal progression is to consider whether the increase in overall disease burden based on the change in non-measurable disease is comparable in magnitude to the increase required to declare measurable disease PD: i.e., an increase in tumor burden representing an additional 73% increase in “volume” (equivalent to a 20% increase in the diameter of a measurable lesion). Examples include an increase in pleural effusion from “trace” to “massive”, an increase in lymphangitic disease from localized to extensive, or what may be described in the protocol as “sufficient to require a change in therapy”. If “unequivocal progression” is observed, the participant should be considered to have overall PD at that point. While it would be ideal to have objective criteria for non-measurable disease, the nature of this disease makes it impossible to do so, and therefore the increase must be substantial.

[0562] New lesions

[0563] The appearance of new malignant lesions indicates disease progression; therefore, some comments regarding the detection of new lesions are important. There are no specific criteria for the identification of new lesions on imaging; however, the finding of a new lesion should be unambiguous: that is, not attributable to differences in scanning technology, changes in imaging modalities, or findings that are thought to represent something other than a tumor (e.g., some “new” bone lesions may simply be healing or transient activity of preexisting lesions). This is particularly important when a participant’s baseline lesions show a partial response or CR. For example, necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, even though this is not the case.

[0564] Lesions identified in anatomic locations not scanned at baseline during the follow-up study were considered new lesions and would indicate disease progression. An example of this would be a participant with visceral disease at baseline and who had a CT or MRI brain scan during the study that showed metastases. A participant's brain metastases were considered evidence of PD even if he / she did not have brain imaging at baseline.

[0565] If the new lesion is ambiguous, for example because of its small size, continued treatment and follow-up assessment will clarify whether it represents true new disease. If a repeat scan confirms that there is definitely a new lesion, the date of the first scan should be used to declare progression.

[0566] Although additional studies are required for evaluation of fluorodeoxyglucose (FDG)-PET response, it is sometimes reasonable to supplement CT scanning with FDG-PET scanning when evaluating progression, particularly possible “new” disease. New lesions based on FDG-PET imaging can be identified according to the following algorithm:

[0567] a. Negative FDG-PET at baseline and positive FDG-PET at follow-up are signs of PD based on new lesions (a "positive" FDG-PET scan lesion is one that has FDG-avid uptake greater than twice that of surrounding tissue on attenuation-corrected images).

[0568] b. No FDG-PET at baseline, positive FDG-PET at follow-up:

[0569] i. If the positive FDG-PET on follow-up corresponds to a new site of disease confirmed on CT, this is PD. If the positive FDG-PET on follow-up is not confirmed as a new site of disease on CT, an additional follow-up CT scan is required to determine if progression has indeed occurred at that site (if so, the date of PD will be the date of the first abnormal FDG-PET scan).

[0570] ii. If the positivity on FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that has not progressed based on anatomical images, this is not PD.

[0571] Assessment of best overall response

[0572] The BOR is the best response documented from the start of study treatment to EOT, taking into account any confirmation requirements. Sometimes, a response may not be documented until after treatment has ended, so the protocol should make clear if post-treatment assessments are considered in determining the BOR. The protocol must specifically address how any new therapy introduced before progression will affect the best response designation. A participant's BOR designation depends on the findings of target and non-target disease, taking into account the appearance of new lesions. In addition, confirmatory measurements may also be required, depending on the nature of the study and protocol requirements. Specifically, in non-randomized studies with response as the primary endpoint, confirmation of a PR or CR is required for either to be considered a "BOR."

[0573] Once all the data of the participants are known, the BOR is determined. The best response is determined in studies that do not require confirmation of a complete response or PR: The best response in these studies is defined as the best response at all time points (e.g., SD at the first assessment, PR at the second assessment, and PD at the last assessment. The BOR of the participant is PR). When SD is considered the best response, it must also meet the shortest time from baseline specified in the protocol. If the shortest time is not met when SD is the best time point response, the participant's best response depends on subsequent assessments. For example, a participant who has SD at the first assessment, PD at the second assessment, and does not meet the shortest duration of SD will have the best response of PD. The same participant who is lost to follow-up after the first SD assessment will be considered unevaluable.

[0574] Time-point response: participants with target (± non-target) disease

[0575]

[0576] Abbreviations: CR = complete response, NE = not evaluable, PD = progressive disease, PR = partial response, SD = stable disease.

[0577] Time point response: participants with non-target disease only

[0578]

[0579] a For non-target disease, “non-CR / non-PD” is preferred over “stable disease” because SD is increasingly used as an endpoint for efficacy assessment in some studies, and thus it is not recommended to designate this category when lesions cannot be measured.

[0580] Abbreviations: CR = complete response, NE = not evaluable, PD = progressive disease.

[0581] Determination of best response in studies requiring confirmation of complete response or PR: A CR or PR may be claimed only if each criterion is met at a subsequent time point specified in the protocol (usually after 4 weeks). In this case, the BOR may be interpreted as shown in the table below.

[0582] Best overall response when confirmation of CR and PR is required

[0583]

[0584]

[0585] a If CR is indeed achieved at the first time point, any disease observed at subsequent time points, i.e.

[0586] For disease to meet the criteria for a PR relative to baseline, it also makes sense for the disease to be PD at that time point (because the disease must reappear after a CR). The best response will depend on whether the minimum duration of SD is met. However, sometimes a "CR" can be claimed when subsequent scans indicate that small lesions may still be present and the participant in fact had a PR rather than a CR at the first time point. In these cases, the original CR should be changed to a PR, with the best response being a PR.

[0587] Abbreviations: CR = complete response, NE = not evaluable, PD = progressive disease, PR = partial response, SD = stable disease.

[0588] When nodal disease is included in the sum of target lesions and nodes are reduced to a “normal” size (<10 mm), they may still have a measurement reported on the scan. This measurement should be recorded even if the nodes are normal so as not to exaggerate progression based on increased node size. As previously mentioned, this means that participants with a CR may not have a total of “zero” on the eCRF.

[0589] In studies where confirmation of response is required, repeated “NE” time point assessments may complicate the determination of best response. The analysis plan for the study must describe how missing data / assessments will be accounted for when defining 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 responder.

[0590] A participant's overall deterioration in health status that requires discontinuation of treatment, but without objective evidence of disease progression at that time, should be reported as "worsening." Every effort should be made to document objective progression, even after discontinuation of treatment. Worsening is not an assessment of objective response: it is reason to discontinue study drug. The objective response status of these participants will be determined by assessment of target disease and non-target disease, as shown in the tables herein.

[0591] The criteria defining “early progression, early death and not evaluable” are study-specific and should be clearly described in each protocol (depending on treatment duration, treatment cyclicity).

[0592] In some cases, it may be difficult to distinguish residual disease from normal tissue. When the assessment of CR depends on this determination, it is recommended to examine the residual disease (fine needle aspiration / biopsy) before assigning CR status. In cases where residual radiographic abnormalities are thought to represent fibrosis or scarring, FDG-PET can be used to upgrade the response to CR in a manner similar to biopsy. The use of FDG-PET in this setting should be clearly stated in advance in the protocol and supported by disease-specific medical literature supporting this indication. However, it must be acknowledged that both FDG-PET and biopsy methods may result in false-positive CRs due to limitations in resolution / sensitivity.

[0593] For suspicious findings of progression (e.g., very small and indeterminate new lesions; cystic changes or necrosis in existing lesions), treatment may be continued until the next scheduled assessment. If progression is confirmed at the next scheduled assessment, the date of progression should be the earlier date of suspected progression.

[0594] Confirmatory measurements and duration of response

[0595] confirm

[0596] In non-randomized studies with response as the primary endpoint, confirmation of PR and CR is required to ensure that the identified response is not the result of measurement error. This also allows for appropriate interpretation of the results in the context of historical data, where responses have traditionally required confirmation in such studies. However, in all other cases, i.e., in randomized studies (phase 2 or 3) or studies with SD or progression as the primary endpoint, confirmation of response is not required as it does not add value to the interpretation of the study results. However, removing the requirement for response confirmation may increase the importance of central review to prevent bias, especially in non-blinded studies.

[0597] In case of SD, the measurement results must meet the SD criteria at least once after study entry at the minimum interval specified in the study protocol (usually not less than 6 to 8 weeks).

[0598] Duration of overall response

[0599] Duration of overall response was measured from the time the CR / PR criteria were first met (whichever was first recorded) to the date of the first objectively documented relapse or progressive disease (with the lowest measurement recorded on the study as reference for PD).

[0600] The duration of overall CR was measured from the time the criteria for CR were first met to the date of the first objectively documented recurrent disease.

[0601] Duration of disease stability

[0602] SD was measured from the start of treatment (in randomized studies, from the date of randomization) until progression criteria were met, with the smallest sum in the study as reference (if the baseline sum was the smallest, this was the reference for calculating PD).

[0603] The clinical relevance of SD duration varies across studies and diseases. If the proportion of participants achieving SD in a minimum time period is an important endpoint in a particular study, the protocol should specify the minimum time interval required between 2 measurements to determine SD.

[0604] Note: DOR and SD, as well as PFS, are influenced by the frequency of follow-up after baseline assessment. The frequency should take into account many parameters, including disease type and stage, treatment periodicity, and standard practice. However, these limitations in the precision of measuring endpoints should be considered if comparisons between studies are to be made.

[0605] Pharmacokinetic evaluation

[0606] Collect plasma samples for measuring plasma concentrations of formula (I). If necessary, samples can be collected at other time points during the study. Samples collected for analyzing plasma concentrations of formula (I) can also be used to evaluate safety or efficacy related to problems that arise during or after the study. The actual date and time (24-hour clock time) of each sample is recorded. Testing of PK samples is performed by a designated bioanalytical contract research organization using a validated method.

[0607]

[0608]

[0609] Pharmacodynamic evaluation

[0610] Blood samples were collected for measurement of circulating biomarkers including, but not limited to, FGF23, parathyroid hormone, calcitriol, FGF19, and tumor-derived exosomes. In pediatric participants (12 to 21 years of age), serum type X collagen (CXM) was also assessed.

[0611] Urine samples were collected for evaluation of secreted biomarkers of FGFR3 inhibition. These markers include, but are not limited to, matrix metalloproteinase-1, matrix metalloproteinase-10, and fibroblast growth factor binding protein 1.

[0612] Excess biomarker or PK samples were used for further evaluation at the discretion of the sponsor. Analyses were performed by a central laboratory designated by the sponsor.

[0613]

[0614] Safety outcome indicators:

[0615] Safety was assessed through close monitoring and timely evaluation of AEs, laboratory parameters (hematology and clinical chemistry), vital signs (blood pressure and heart rate), participant's medical status (physical examination including weight), ophthalmologic examination, and overall health status and activities of daily living (ECOG PS).

Claims

1. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (I), or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the cancer has an activating FGFR3 genetic alteration.

3. The method of claim 2, wherein the cancer is urothelial carcinoma, breast cancer, endometrial cancer, lung cancer, ovarian cancer, or bladder cancer.

4. The method of claim 3, wherein the cancer is urothelial carcinoma.

5. The method of claim 3, wherein the cancer is a urothelial tumor. The method of claim 3 , wherein the cancer is breast cancer.

7. The method of claim 3, wherein the cancer is endometrial cancer.

8. The method of claim 3, wherein the cancer is lung cancer.

9. The method of claim 3, wherein the cancer is ovarian cancer.

10. The method of claim 3, wherein the cancer is bladder cancer.

11. The method of any one of claims 1 to 10, wherein the cancer is a locally advanced solid tumor.

12. The method of any one of claims 1 to 10, wherein the cancer is a metastatic solid tumor.

13. The method of any one of claims 2 to 10, wherein the activating FGFR3 genetic alteration is a mutation.

14. The method of claim 13, wherein the mutation is or includes one or more of the following: 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.

15. The method of claim 13, wherein the mutation is or includes one or more of the following: FGFR3 p.V553M; FGFR3 p.V555M; or FGFR3 p.V555L.

16. The method of any one of claims 2 to 10, wherein the activating FGFR3 genetic alteration is a fusion.

17. The method of claim 16, wherein the fusion is a FGFR3 rearrangement having an intact 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 region partner genes or out-of-frame partner genes.

18. The method according to any one of claims 1 to 10, wherein a compound of formula (I) is administered to the patient.

19. The method according to any one of claims 1 to 10, wherein a pharmaceutically acceptable salt of a compound of formula (I) is administered to the patient.

20. The method of claim 19, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a besylate salt.

21. The method according to any one of claims 1 to 10, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 10 mg to 120 mg / day.

22. The method according to claim 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 10 mg / day.

23. The method of claim 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 20 mg / day.

24. The method of claim 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 40 mg / day.

25. The method of claim 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 60 mg / day.

26. The method of claim 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 90 mg / day.

27. The method of claim 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered to the patient in an amount of 120 mg / day.

28. The method of claim 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) is administered orally.

29. The method of any one of claims 1 to 10, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) is administered for at least 28 days.

30. The method of claim 29, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) is administered for 28 days.

31. The method of any one of claims 1 to 10, wherein the cancer exhibits a complete response (CR) or 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 the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

32. The method of claim 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 the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

33. The method of claim 31, 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 the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

34. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating cancer in a patient in need thereof:

35. The compound for use according to claim 34, wherein the cancer has an activating FGFR3 gene alteration.

36. The compound for use according to claim 35, wherein the cancer is urothelial carcinoma, breast cancer, endometrial cancer, lung cancer, ovarian cancer or bladder cancer.

37. The compound for use according to claim 36, wherein the cancer is urothelial carcinoma.

38. The compound for use according to claim 36, wherein the cancer is a urothelial tumor.

39. The compound for use according to claim 36, wherein the cancer is breast cancer.

40. The compound for use according to claim 36, wherein the cancer is endometrial cancer.

41. The compound for use according to claim 36, wherein the cancer is lung cancer.

42. The compound for use according to claim 36, wherein the cancer is ovarian cancer.

43. The compound for use according to claim 36, wherein the cancer is bladder cancer.

44. The compound for use according to any one of claims 34 to 43, wherein the cancer is a locally advanced solid tumor.

45. The compound for use according to any one of claims 34 to 43, wherein the cancer is a metastatic solid tumor.

46. ​​The compound for use according to any one of claims 35 to 43, wherein the activating FGFR3 genetic alteration is a mutation.

47. The compound for use according to claim 46, wherein the mutation is or comprises one or more of the following: 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.

48. The compound for use according to claim 46, wherein the mutation is or comprises one or more of the following: FGFR3 p.V553M; FGFR3 p.V555M; or FGFR3 p.V555L.

49. The compound for use according to any one of claims 35 to 43, wherein the activating FGFR3 genetic alteration is a fusion.

50. The compound for use according to claim 49, wherein the fusion is a FGFR3 rearrangement having an intact 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 region partner genes or out-of-frame partner genes.

51. A compound for use according to any one of claims 34 to 43, wherein the compound is a compound of formula (I).

52. A compound for use according to any one of claims 34 to 43, wherein the compound is a pharmaceutically acceptable salt of a compound of formula (I).

53. The compound for use according to claim 52, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a besylate.

54. The compound for use according to any one of claims 34 to 43, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered in an amount of 10 mg-120 mg / day.

55. The compound for use according to claim 54, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered in an amount of 10 mg / day.

56. The compound for use according to claim 54, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered in an amount of 20 mg / day.

57. The compound for use according to claim 54, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered in an amount of 40 mg / day.

58. The compound for use according to claim 54, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered in an amount of 60 mg / day.

59. The compound for use according to claim 54, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered in an amount of 90 mg / day.

60. The compound for use according to claim 54, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (based on formula (I)) is administered in an amount of 120 mg / day.

61. The compound for use according to claim 54, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) is administered orally.

62. The compound for use according to any one of claims 34 to 43, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) is administered for at least 28 days.

63. The compound for use according to claim 62, wherein the compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) is administered for 28 days.

64. The compound for use according to any one of claims 34 to 43, wherein the cancer exhibits a complete response (CR) or 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 the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

65. The compound for use according to claim 64, 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 the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

66. The compound for use according to claim 64, 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 the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

Images