FGFR3 inhibitor dosing regimens for use in treating cancer

Abstract

Disclosed herein are dosing regimens for the administration of a compound of Formula (I) or Formula (II): or a combination thereof, or in combination with a second therapeutic agent, for use in treating cancer, preferably FGFR3-associated cancer, in a patient in need of such treatment.

Description

FGFR3 Inhibitor Dosing Regimens

[0001] This disclosure is directed to the field of cancer treatment. Background

[0002] Fibroblast growth factor (FGF) has been recognized as an important mediator of many physiological processes, such as morphogenesis during development, fibrosis, and angiogenesis. The fibroblast growth factor receptor (FGFR) family consists of five members four of which (FGFR 1-4) are glycoproteins composed of extracellular immunoglobulin (Ig)-like domains, a hydrophobic transmembrane region and a cytoplasmic part containing a tyrosine kinase domain. FGF binding leads to FGFR dimerization, followed by receptor autophosphorylation and activation of downstream signaling pathways. Receptor activation is sufficient for the recruitment and activation of specific downstream signaling partners that participate in the regulation of diverse processes such as cell growth, cell metabolism and cell survival. Thus, the FGF / FGFR signaling pathway has pleiotropic effects on many biological processes critical to tumor cell proliferation, migration, invasion, and angiogenesis.

[0003] Response rates and durations of response to erdafitinib and other pan-FGFR inhibitors are generally modest, due in part to clinical toxicity from off-target inhibition (i.e., inhibiting other non-altered FGFR isoforms) as well as acquired drug resistance mediated by the gatekeeper resistance mutations that sterically inhibit drug binding. In addition to off-target toxicity (i.e., inhibiting other nonaltered FGFR isoforms) observed with the pan-FGFR inhibitors, drug resistance through acquired gatekeeper resistance mutations (i.e., V555M and V565F) have been detected at time of disease progression in clinical trials. Innovative drugs, selective to the specific FGFR altered in a patient’s tumor while active against gatekeeper resistance mutations, are needed to avoid off-target side effects and acquired resistance observed with pan-FGFR inhibitors. Collectively, these data highlight the need for novel isoform-selective FGFR inhibitors that can address acquired resistance for the treatment of advanced solid tumors.

[0004] It would be useful to develop new treatment regimens and protocols that use the compound of Formula I or Formula II, either as a monotherapy, in combination with one or more other therapeutic agents, or as part of neoadjuvant, adjuvant, advanced, or metastatic therapy, to treat cancer. It would be useful to develop more tolerable treatment regimens and protocols than current treatment regimens or protocols. It wouldbe useful to develop less toxic treatment regimens and protocols than current treatment regimens or protocols. Summary

[0005] WO / 2022 / 187443 (International patent application number PCT / US2022 / 018644) and US2023 / 0095122 A1 (US patent application serial number 17 / 685,753) disclose compounds or salts thereof that can be used as FGFR3 inhibitors. One FGFR3 inhibitor disclosed therein is 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridyl)-2- hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1- carbonitrile, which has the following structure: .

[0006] This45 and 46, in each of WO / 2022 / 187443 (International patent application number PCT / US / 2022 / 018644) and US2023 / 0095122 A1 (US patent application serial number 17 / 685,753). As disclosed therein, this compound exists as enantiomers. Further as discussed in Examples 45 and 46 of these references, the isomers may be separated using prep-chiral-HPLC. Example 46 is the second isomer to elute off the HPLC column: ART Cellulose-SB, 2*25 cm, 5 µm, when eluting with 20% 5:1 Hex:DCM (0.5% 2M NH3in MeOH) in EtOH.

[0007] Example 45, 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile, Isomer 1, (hereinafter “Isomer 1”), corresponds to the R designation. Isomer 1 has the following structure: .

[0008] Example 46, 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile, Isomer 2, (hereinafter “Isomer 2”), corresponds to the S designation. Isomer 2 has the following structure: .

[0009] numberPCT / US2022 / 018644) 17 / 685,753) disclose how to make Examples 45 and 46.

[0010] Disclosed herein is a cocrystalline form comprising Isomer 2 and gallic acid coformer. In an embodiment, the cocrystalline form has a ratio of Isomer 2 to gallic acid about 2:1 (herein referred to as “Isomer 2 and Hemi-Gallate cocrystalline form”).

[0011] In an embodiment, the cocrystalline form has a solvent. In an embodiment, the solvent is a hydrate. In an embodiment, the cocrystalline form has a hemihydrate (herein referred to as “Isomer 2 and Hemi-Gallate cocrystalline form hemihydrate”). In one embodiment, the Isomer 2 and Hemi-Gallate cocrystalline form hemihydrate is .form hemihydrate has variable water content. In one embodiment, the Isomer 2 and Hemi- Gallate cocrystalline form hemihydrate has water content ranging from about 0% to about 3.2%.

[0013] In an embodiment, the Isomer 2 and Hemi-Gallate cocrystalline form is a dehydrated hydrate. In one embodiment, the Isomer 2 and Hemi-Gallate cocrystallineform hemihydrate is dehydrated (herein referred to as “Isomer 2 and Hemi-Gallate cocrystalline form dehydrated hydrate”). In one embodiment, the Isomer 2 and Hemi- Gallate cocrystalline form dehydrated hydrate is .2 and Hemi-Gallate cocrystalline form hemihydrate, Isomer 2 and Hemi-Gallate cocrystalline form dehydrated hydrate, or a combination thereof.

[0015] Disclosed herein are methods and uses of the compound of Formula I or Formula II, or pharmaceutically acceptable salts thereof, to treat cancers that are treatable by inhibiting FGFR3 or its ligands.

[0016] In an aspect, disclosed herein is a method of treating a cancer comprising administering to a patient in need of such treatment, a dose between about 160 mg and about 400 mg of a compound of Formula I or Formula II: I), II),or a

[0017] In another aspect, disclosed herein is a method of treating a cancer bearing an activating alteration in a fibroblast growth factor receptor-3 (FGFR3) gene or itsligands comprising administering to a patient in need of such treatment, a dose between about 160 mg and about 400 mg of a compound of Formula I or Formula II, or a combination thereof.

[0018] In still another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment, a dose between about 160 mg and about 400 mg of a compound of Formula I or Formula II, or a combination thereof, wherein the FGFR3-associated cancer is breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small-cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasive urothelial cancer, adjuvant muscle invasive urothelial cancer, muscle invasive bladder cancer, adjuvant muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, renal cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer. In one embodiment, the cancer is urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial bladder cancer, metastatic urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer, or solid tumor malignancy.

[0019] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 160 mg of the compound of Formula I or Formula II or a combination thereof.

[0020] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 160 mg of the compound of Formula I or Formula II or a combination thereof at least once a day.

[0021] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a doseof about 160 mg of the compound of Formula I or Formula II or a combination thereof at least twice a day.

[0022] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 160 mg of the compound of Formula I or Formula II or a combination thereof, wherein the FGFR3-associated cancer is advanced urothelial cancer.

[0023] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 160 mg of the compound of Formula I or Formula II or a combination thereof at least once a day, wherein the FGFR3-associated cancer is advanced urothelial bladder cancer.

[0024] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 160 mg of the compound of Formula I or Formula II or a combination thereof at least twice a day, wherein the FGFR3-associated cancer is muscle invasive urothelial cancer.

[0025] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 160 mg of the compound of Formula I or Formula II or a combination thereof, wherein the FGFR3-associated cancer is adjuvant muscle invasive urothelial cancer.

[0026] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 160 mg of the compound of Formula I or Formula II or a combination thereof at least once a day, wherein the FGFR3-associated cancer is muscle invasive bladder cancer.

[0027] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 160 mg of the compound of Formula I or Formula II or a combination thereof at least twice a day, wherein the FGFR3-associated cancer is adjuvant muscle invasive bladder cancer.

[0028] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 200 mg of the compound of Formula I or Formula II or a combination thereof.

[0029] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 200 mg of the compound of Formula I or Formula II or a combination thereof at least once a day.

[0030] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 200 mg of the compound of Formula I or Formula II or a combination thereof at least twice a day.

[0031] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 200 mg of the compound of Formula I or Formula II or a combination thereof, wherein the FGFR3-associated cancer is advanced urothelial cancer.

[0032] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 200 mg of the compound of Formula I or Formula II or a combination thereof at least once a day, wherein the FGFR3-associated cancer is advanced urothelial bladder cancer.

[0033] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 200 mg of the compound of Formula I or Formula II or a combination thereof at least twice a day, wherein the FGFR3-associated cancer is muscle invasive urothelial cancer.

[0034] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 200 mg of the compound of Formula I or Formula II or a combination thereof, wherein the FGFR3-associated cancer is adjuvant muscle invasive urothelial cancer.

[0035] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 200 mg of the compound of Formula I or Formula II or a combination thereof at least once a day, wherein the FGFR3-associated cancer is muscle invasive bladder cancer.

[0036] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a doseof about 200 mg of the compound of Formula I or Formula II or a combination thereof at least twice a day, wherein the FGFR3-associated cancer is adjuvant muscle invasive bladder cancer.

[0037] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 300 mg of the compound of Formula I or Formula II or a combination thereof.

[0038] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 300 mg of the compound of Formula I or Formula II or a combination thereof at least once a day.

[0039] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 300 mg of the compound of Formula I or Formula II or a combination thereof at least twice a day.

[0040] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 300 mg of the compound of Formula I or Formula II or a combination thereof, wherein the FGFR3-associated cancer is advanced urothelial cancer.

[0041] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 300 mg of the compound of Formula I or Formula II or a combination thereof at least once a day, wherein the FGFR3-associated cancer is advanced urothelial bladder cancer.

[0042] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 300 mg of the compound of Formula I or Formula II or a combination thereof at least twice a day, wherein the FGFR3-associated cancer is muscle invasive urothelial cancer.

[0043] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 300 mg of the compound of Formula I or Formula II or a combination thereof, wherein the FGFR3-associated cancer is adjuvant muscle invasive urothelial cancer.

[0044] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 300 mg of the compound of Formula I or Formula II or a combination thereof at least once a day, wherein the FGFR3-associated cancer is muscle invasive bladder cancer.

[0045] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 300 mg of the compound of Formula I or Formula II or a combination thereof at least twice a day, wherein the FGFR3-associated cancer is adjuvant muscle invasive bladder cancer.

[0046] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 400 mg of the compound of Formula I or Formula II or a combination thereof.

[0047] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 400 mg of the compound of Formula I or Formula II or a combination thereof at least once a day.

[0048] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 400 mg of the compound of Formula I or Formula II or a combination thereof at least twice a day.

[0049] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 400 mg of the compound of Formula I or Formula II or a combination thereof, wherein the FGFR3-associated cancer is advanced urothelial cancer.

[0050] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 400 mg of the compound of Formula I or Formula II or a combination thereof at least once a day, wherein the FGFR3-associated cancer is advanced urothelial bladder cancer.

[0051] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 400 mg of the compound of Formula I or Formula II or a combination thereof atleast twice a day, wherein the FGFR3-associated cancer is muscle invasive urothelial cancer.

[0052] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 400 mg of the compound of Formula I or Formula II or a combination thereof, wherein the FGFR3-associated cancer is adjuvant muscle invasive urothelial cancer.

[0053] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 400 mg of the compound of Formula I or Formula II or a combination thereof at least once a day, wherein the FGFR3-associated cancer is muscle invasive bladder cancer.

[0054] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need of such treatment a dose of about 400 mg of the compound of Formula I or Formula II or a combination thereof at least twice a day, wherein the FGFR3-associated cancer is adjuvant muscle invasive bladder cancer.

[0055] In yet another aspect, disclosed herein is a method of treating a FGFR3- associated cancer, comprising administering to a patient in need of such treatment, a first dose between about 160 mg and about 400 mg of a compound of Formula I or Formula II, or a combination thereof; monitoring the patient for a dose limiting toxicity; and administering a second dose of the compound of Formula I or Formula II or a combination thereof, if the patient exhibits the dose limiting toxicity, wherein the second dose is reduced as compared to the first dose.

[0056] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer comprising administering to a patient in need thereof, a dose between about 160 mg and about 400 mg of a compound of Formula I or Formula II, or a combination thereof, in simultaneous, separate, or sequential combination with a second therapeutic agent.

[0057] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer, comprising administering to a patient in need thereof, a dose between about 160 mg and about 400 mg of a compound of Formula I or Formula II, or a combination thereof, in simultaneous, separate, or sequential combination with pembrolizumab in the treatment of FGFR3-associated cancers.

[0058] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer, comprising administering to a patient in need thereof, a dose between about 160 mg and about 400 mg of a compound of Formula I or Formula II, or a combination thereof, in simultaneous, separate, or sequential combination with enfortumab vedotin in the treatment of FGFR3-associated cancers.

[0059] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer, comprising administering to a patient in need thereof, a dose between about 160 mg and about 400 mg of a compound of Formula I or Formula II, or a combination thereof, in simultaneous, separate, or sequential combination with pembrolizumab and enfortumab vedotin in the treatment of FGFR3-associated cancers.

[0060] In another aspect, disclosed herein is a method of treating a FGFR3- associated cancer, comprising administering to a patient in need thereof, a dose between about 160 mg and about 400 mg of a compound of Formula I or Formula II, or a combination thereof, in simultaneous, separate, or sequential combination with nivolumab in the treatment of FGFR3-associated cancers.

[0061] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg.

[0062] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least once a day.

[0063] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least twice a day.

[0064] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg, wherein the FGFR3-associated cancer is selected from the group consisting of urothelial cancer, bladder cancer, urothelial bladder cancer,advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non- muscle invasive bladder cancer, muscle invasive urothelial cancer, adjuvant muscle invasive urothelial cancer, muscle invasive bladder cancer, adjuvant muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, and solid tumor malignancy.

[0065] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least once a day, wherein the FGFR3- associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, or metastatic urothelial bladder cancer.

[0066] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least twice a day, wherein the FGFR3- associated cancer is advanced urothelial cancer or advanced urothelial bladder cancer.

[0067] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg, wherein the FGFR3-associated cancer is advanced urothelial cancer.

[0068] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least once a day, wherein the FGFR3- associated cancer is advanced urothelial bladder cancer.

[0069] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least twice a day, wherein the FGFR3- associated cancer is muscle invasive urothelial cancer or muscle invasive bladder cancer.

[0070] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg, wherein the FGFR3-associated cancer is muscle invasive urothelial cancer.

[0071] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least once a day, wherein the FGFR3- associated cancer is muscle invasive bladder cancer.

[0072] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg.

[0073] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg at least once a day.

[0074] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg at least twice a day.

[0075] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg, wherein the FGFR3-associated cancer is selected from the group consisting of urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non- muscle invasive bladder cancer, muscle invasive urothelial cancer, adjuvant muscle invasive urothelial cancer, muscle invasive bladder cancer, adjuvant muscle invasivebladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, and solid tumor malignancy.

[0076] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg at least once a day, wherein the FGFR3- associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, or metastatic urothelial bladder cancer.

[0077] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg at least twice a day, wherein the FGFR3- associated cancer is advanced urothelial cancer or advanced urothelial bladder cancer.

[0078] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg, wherein the FGFR3-associated cancer is advanced urothelial cancer.

[0079] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg at least once a day, wherein the FGFR3- associated cancer is advanced urothelial bladder cancer.

[0080] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg at least twice a day, wherein the FGFR3- associated cancer is muscle invasive urothelial cancer or muscle invasive bladder cancer.

[0081] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof isadministered at a dose of about 200 mg, wherein the FGFR3-associated cancer is muscle invasive urothelial cancer.

[0082] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg at least once a day, wherein the FGFR3- associated cancer is muscle invasive bladder cancer.

[0083] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg.

[0084] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg at least once a day.

[0085] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg at least twice a day.

[0086] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg, wherein the FGFR3-associated cancer is selected from the group consisting of urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non- muscle invasive bladder cancer, muscle invasive urothelial cancer, adjuvant muscle invasive urothelial cancer, muscle invasive bladder cancer, adjuvant muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, and solid tumor malignancy.

[0087] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer,wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg at least once a day, wherein the FGFR3- associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, or metastatic urothelial bladder cancer.

[0088] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg at least twice a day, wherein the FGFR3- associated cancer is advanced urothelial cancer or advanced urothelial bladder cancer.

[0089] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg, wherein the FGFR3-associated cancer is advanced urothelial cancer.

[0090] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg, wherein the FGFR3-associated cancer is advanced urothelial bladder cancer.

[0091] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg, wherein the FGFR3-associated cancer is muscle invasive urothelial cancer or muscle invasive bladder cancer.

[0092] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg, wherein the FGFR3-associated cancer is muscle invasive urothelial cancer.

[0093] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof isadministered at a dose of about 300 mg at least once a day, wherein the FGFR3- associated cancer is muscle invasive bladder cancer.

[0094] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg.

[0095] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg at least once a day.

[0096] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg at least twice a day.

[0097] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg, wherein the FGFR3-associated cancer is selected from the group consisting of urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non- muscle invasive bladder cancer, muscle invasive urothelial cancer, adjuvant muscle invasive urothelial cancer, muscle invasive bladder cancer, adjuvant muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, and solid tumor malignancy.

[0098] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg at least once a day, wherein the FGFR3- associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, or metastatic urothelial bladder cancer.

[0099] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg at least twice a day, wherein the FGFR3- associated cancer is advanced urothelial cancer or advanced urothelial bladder cancer.

[0100] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg, wherein the FGFR3-associated cancer is advanced urothelial cancer.

[0101] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg at least once a day, wherein the FGFR3- associated cancer is advanced urothelial bladder cancer.

[0102] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg at least twice a day, wherein the FGFR3- associated cancer is muscle invasive urothelial cancer or muscle invasive bladder cancer.

[0103] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg, wherein the FGFR3-associated cancer is muscle invasive urothelial cancer.

[0104] In another aspect, disclosed herein is the compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg at least once a day, wherein the FGFR3- associated cancer is muscle invasive bladder cancer.

[0105] In yet another aspect, disclosed herein is a compound of Formula I or Formula II, or a combination thereof, for use in treatment of a FGFR3-associated cancer,wherein the FGFR3-associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, muscle invasive urothelial cancer, or muscle invasive bladder cancer, wherein the compound of Formula I or Formula II or a combination thereof, is administered at a first dose between about 160 mg and about 400 mg; monitoring the patient for a dose limiting toxicity; and administering a second dose of the compound of Formula I or Formula II or a combination thereof, if the patient exhibits the dose limiting toxicity, wherein the second dose is reduced as compared to the first dose.

[0106] In another aspect, disclosed herein is a compound of Formula I or Formula II, or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the FGFR3-associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, muscle invasive urothelial cancer, or muscle invasive bladder cancer, administering to a patient in need thereof, a dose between about 160 mg and about 400 mg of the compound of Formula I or Formula II or a combination thereof, in simultaneous, separate or sequential combination with a second therapeutic agent.

[0107] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the FGFR3-associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, muscle invasive urothelial cancer, or muscle invasive bladder cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose between about 160 mg and about 400 mg.

[0108] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II:I), aassociated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg.

[0109] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least once a day.

[0110] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least twice a day.

[0111] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg, wherein the FGFR3- associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, muscle invasive urothelial cancer, or muscle invasive bladder cancer.

[0112] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment ofa FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least once a day, wherein the FGFR3-associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, muscle invasive urothelial cancer, or muscle invasive bladder cancer.

[0113] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least twice a day, wherein the FGFR3-associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, muscle invasive urothelial cancer, or muscle invasive bladder cancer.

[0114] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg, wherein the FGFR3- associated cancer is advanced urothelial cancer or metastatic urothelial cancer.

[0115] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least once a day, wherein the FGFR3-associated cancer is metastatic urothelial cancer.

[0116] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least twice a day, wherein the FGFR3-associated cancer is metastatic urothelial cancer.

[0117] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg, wherein the FGFR3- associated cancer is muscle invasive urothelial cancer, or muscle invasive bladder cancer.

[0118] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least once a day, wherein the muscle invasive bladder cancer.

[0119] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 160 mg at least twice a day, wherein the FGFR3-associated cancer is muscle invasive bladder cancer.

[0120] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg.

[0121] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg at least once a day.

[0122] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg at least twice a day.

[0123] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg, wherein the FGFR3- associated cancer is advanced urothelial cancer or metastatic urothelial cancer.

[0124] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg at least once a day, wherein the FGFR3-associated cancer is metastatic urothelial cancer.

[0125] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg at least twice a day, wherein the FGFR3-associated cancer is metastatic urothelial cancer.

[0126] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg, wherein the FGFR3- associated cancer is muscle invasive urothelial cancer, or muscle invasive bladder cancer.

[0127] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg at least once a day, wherein the FGFR3-associated cancer is muscle invasive bladder cancer.

[0128] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 200 mg at least twice a day, wherein the FGFR3-associated cancer is muscle invasive bladder cancer.

[0129] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg.

[0130] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg at least once a day.

[0131] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg at least twice a day.

[0132] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg, wherein the FGFR3- associated cancer is advanced urothelial cancer or metastatic urothelial cancer.

[0133] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg at least once a day, wherein the FGFR3-associated cancer is metastatic urothelial cancer.

[0134] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg at least twice a day, wherein the FGFR3-associated cancer is metastatic urothelial cancer.

[0135] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg, wherein the FGFR3- associated cancer is muscle invasive urothelial cancer, or muscle invasive bladder cancer.

[0136] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg at least once a day, wherein the FGFR3-associated cancer is muscle invasive bladder cancer.

[0137] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 300 mg at least twice a day, wherein the FGFR3-associated cancer is muscle invasive bladder cancer.

[0138] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment ofa FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg.

[0139] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg at least once a day.

[0140] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg at least twice a day.

[0141] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg, wherein the FGFR3- associated cancer is advanced urothelial cancer or metastatic urothelial cancer.

[0142] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg at least once a day, wherein the FGFR3-associated cancer is metastatic urothelial cancer.

[0143] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg at least twice a day, wherein the FGFR3-associated cancer is metastatic urothelial cancer.

[0144] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg, wherein the FGFR3- associated cancer is muscle invasive urothelial cancer, or muscle invasive bladder cancer.

[0145] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment ofa FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg at least once a day, wherein the FGFR3-associated cancer is muscle invasive bladder cancer.

[0146] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose of about 400 mg at least twice a day, wherein the FGFR3-associated cancer is muscle invasive bladder cancer.

[0147] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the FGFR3-associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, or metastatic urothelial bladder cancer, wherein the compound of Formula I or Formula II or a combination thereof, is administered at a first dose selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg; the patient is monitored for dose limiting toxicity; and if the patient exhibits dose limiting toxicity, a second dose of the compound of Formula I or Formula II or a combination thereof, is administered, wherein the second dose is reduced as compared to the first dose.

[0148] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the FGFR3-associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, or metastatic urothelial bladder cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose between about 160 mg and about 400 mg, in simultaneous, separate, or sequential combination with a second therapeutic agent.

[0149] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the FGFR3-associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, or metastatic urothelial bladder cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose between about 160 mg and about 400 mg, in simultaneous, separate, or sequential combination with pembrolizumab.

[0150] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the FGFR3-associated cancer is muscle invasive urothelial cancer, or muscle invasive bladder cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose between about 160 mg and about 400 mg, in simultaneous, separate, or sequential combination with nivolumab.

[0151] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the FGFR3-associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, or metastatic urothelial bladder cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose between about 160 mg and about 400 mg, in simultaneous, separate, or sequential combination with enfortumab vedotin.

[0152] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, or a combination thereof, in the manufacture of a medicament for treatment of a FGFR3-associated cancer, wherein the FGFR3-associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, or metastatic urothelial bladder cancer, wherein the compound of Formula I or Formula II or a combination thereof is administered at a dose between about 160 mg and about 400 mg, in simultaneous, separate, or sequential combination with pembrolizumab and enfortumab vedotin. BRIEF DESCRIPTION OF THE FIGURES

[0153] FIG 1 is serum phosphate levels in athymic mice. Detailed Description

[0154] Methods and uses that utilize the compound of Formula I or Formula II or a combination thereof are described below. Definitions TABLE 1: ABBREVIATIONS AND DEFINITIONS OF TERMS Abbreviation or Term DefinitionAbbreviation or Term Definition AST aspartate aminotransferase nAbbreviation or Term Definition IVDR In Vitro Diagnostic Regulation R m r

[0154] The term “dose” as used herein refers to the total amount of a compound of Formula I or Formula II, or a combination thereof, that is administered at one time. Said dose can be about 160 mg, about 200 mg, about 300 mg, and about 400 mg, all of which can be administered, for example, once a day, twice a day, three times a day, or four times a day. For example, the dose can be about 160 mg, about 200 mg, about 300 mg, about 320 mg, about 400 mg, about 480 mg, about 600 mg, about 640 mg, about 800 mg, about 900 mg, about 1200 mg, or about 1600 mg.

[0155] The term “dosage” refers to a dose administered at a specific frequency. The compound of Formula I or Formula II or a combination thereof may be administered as needed. Typically, the administration is once a day, twice a day, three times a day, or four times a day. In a preferred embodiment, the administration is administered QD, which is once a day, or BID, which is twice a day. Commonly, when administered twice a day, both doses are the same strength, e.g., both doses are 140 mg. But as described elsewhere herein, the doses may be different, for example if the patient exhibits a DLT. In such as case, the second dose would be reduced, relative to the first dose. A second dose is any dose administered after a first dose. A third dose is any dose administered after a second dose.

[0156] Alternatively, the first and second doses may be lower than the first and second doses that were administered on a previous day. For example, if about 140 mg was administered as the first and second doses on a day 15 of treatment, but the first and second doses on day 16 of treatment may be reduced relative to the doses on day 15; e.g., the first and second doses on day 16 could both be about 80 mg.

[0157] The term “total daily dose” as used herein refers to the total amount of a compound of Formula I or Formula II, or combination thereof that is taken within a 24 hour period. The total daily dose depends on the dose administered and the dosing frequency. For example, the total daily dose can be about 160 mg, about 200 mg, about 300 mg, about 320 mg, about 400 mg, about 480 mg, about 600 mg, about 640 mg, about 800 mg, about 900 mg, about 1200 mg or about 1600 mg. For example, if 160 mg was administered once a day, then the total daily dose for that day is 160 mg. If 160 mg was administered twice a day, then the total daily dose for that day is 320 mg. If 200 mg was administered three times a day, then the total daily dose for that day is 600 mg. If 200 mg was administered four times a day, then the total daily dose for that day is 800 mg.

[0158] A "DLT” is defined as any of the treatment-emergent adverse event (TEAEs), as defined by the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0), deemed clinically significant and occurring during the first 21 days of study drug per dose level per patient, unless the adverse event (AE) can be clearly related to the patient’s underlying disease, other medical condition, or concomitant medications including any AEs attributed by the Investigator to the combination agent alone. A TEAE is defined as an AE that starts or worsens on or after the date of the first dose of study drug (for example on Study Day 1) through 28 days (+14 days window) after the date of the last dose of study drug or the first date starting new anticancer therapy, whichever is earlier. A Serious TEAE is defined as an TEAE that is grade 3 or higher based on severity grade assignment as defined by the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0). A Fatal TEAE is defined as an TEAE that is grade 5 based on severity grade assignment as defined by the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0).

[0159] If the patient exhibits one or more symptoms, such as toxicity, a clinically significant adverse event, intolerability, and a drug-drug interaction, the dose of the drug may be reduced. The term “first dose” as used herein regarding DLT refers to a dose of the compound of Formula I or Formula II, or a combination thereof, that is administered prior to a second or subsequent dose. In an embodiment, it is not required that the first dose refer to only the first time a patient is administered a dose of the compound of Formula I or Formula II or a combination thereof,. For example, the first dose could refer to the third or fifth dose administered to a patient so long as the first dose precedes the patient experiencing a DLT. In an embodiment, the patient exhibits a clinically significant adverse event and the second and / or subsequent doses, are reduced, relative to the dose that was administered before the TEAE was identified.

[0160] The terms “NMIBC” or “non-muscle invasive bladder cancer” mean bladder cancer staged as T0, Ta, T1, or CIS according to the Tumor, Node, Metastasis Classification (TNM).

[0161] The terms “intermediate risk non-muscle invasive bladder cancer”, “intermediate risk NMIBC”, or “IR NMIBC” mean multiple or recurrent low-grade Ta tumors. The following factors to be considered are number of tumors such as greater thanone, size of tumors such as greater than 3 cm, timing such as recurrence within 1 year, frequency of recurrences such as greater than one recurrence per year, and previous treatment.

[0162] The terms “high risk non-muscle invasive bladder cancer", “high risk NMIBC”, or “HR NMIBC” mean recurrent, BCG unresponsive, high-grade, T1 or CIS tumors wherein recurrence can be after BCG therapy. The following factors to be considered are tumor grade, size of tumors such as greater than 3 cm, timing such as recurrence within 1 year, frequency of recurrences such as greater than one recurrence per year, and previous treatment.

[0163] The term “activating alteration” means a gene amplification, point mutation, fusion, or the like. Activating alterations in the FGFR3 gene or its ligands have been identified as oncogenic drivers stimulating cellular proliferation through constitutive ligand-independent signaling and have been observed in several solid tumor malignancies including high-grade and advanced urothelial, uterine carcinosarcoma, endometrial cancers, and less frequently in other solid tumor malignancies. The FGFR3 activating alteration status of one or more cancer cells can be determined by a number of assays known in the art. Typically, one or more biopsies containing one or more cancer cells are obtained, and subjected to sequencing and / or polymerase chain reaction (PCR). Circulating cell-free DNA can also be used, e.g. in advanced cancers. Non-limiting examples of sequencing and PCR techniques used to determine the activating alteration status (e.g. FGFR3 activating alteration status, in one or more cancer cells or in circulating cell-free DNA) include direct sequencing, next-generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), multiplex PCR, and pyrosequencing and multi-analyte profiling. Table 2 provides a list of FGFR3 and FGFR3 ligand alterations.

[0164] The term “QT prolongation” as used herein refers to a measure of delayed ventricular repolarization (i.e., lengthening of the time between the start of the Q wave and the end of the T wave in an electrocardiogram measurement).

[0165] The term “AST / ALT ratio” as used herein refers to the ratio between the concentrations of the enzymes aspartate transaminase (AST) and alanine transaminase, aka alanine aminotransferase (ALT) in the blood of a human or animal.

[0166] The term “pharmaceutically acceptable salt” as used herein refers to a salt of a compound considered to be acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and common methodology for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S.M. Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19, Gould, P.L., “Salt selection for basic drugs,” International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R.J., et al. “Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities,” Organic Process Research and Development, 4: 427-435 (2000).

[0167] As used herein, the term “effective amount” refers to an amount that is a dosage, which is effective in treating a disorder or disease, such as a cancerous lesion or progression of abnormal cell growth and / or cell division. Factors considered in the determination of an effective amount or dose of a compound include: whether the compound or its salt will be administered; the co-administration of other agents, if used; the species of patient to be treated; the patient’s size, age, and general health; the degree of involvement or stage and / or the severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of other concomitant medication.

[0168] Preferred pharmaceutical compositions are formulated for oral administration. Examples of preferred oral formulations include capsules and tablets. A capsule or a tablet can include a compound of Formula I or Formula II, in an amount effective for treating a patient in need of treatment for cancer.

[0169] As used herein, the terms “treating”, “to treat”, or “treatment”, includes slowing, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, which can include specifically slowing the growth of a cancerous lesion or progression of abnormal cell growth and / or cell division.

[0170] Preferably, the patient is a human that is in need of treatment for cancer, for example, FGFR3-associated cancers.Table 2: Qualifying FGFR3 / FGFR3 Ligand Alterations Exon1FGFR3 alterations 6 R248C, S249C 7,1 These alterations were defined in OncoKB as "oncogenic / likely oncogenic" or in the cBioportal for Cancer Genomics as “driver mutations”.

[0171] In one embodiment, the patient is a human that has not received prior pan- FGFR inhibitor therapy and is described herein as naïve to pan-FGFR inhibitor therapy. Patients may have received other therapies, including surgery, or one other prior therapy, or two other prior therapies, three other prior therapies or four or more other prior therapies, or other pharmaceuticals, but not prior pan-FGFR therapy.

[0172] In one preferred embodiment, the patient is a human that has received at least one treatment, including prior pan-FGFR inhibitor. The patients may have received an unlimited number of other therapies, including surgery or one other prior therapy, or two other prior therapies, three other prior therapies or four or more other prior therapies.

[0173] Prior pan-FGFR therapy requires the patient to have previously had prior treatment with a pan-FGFR inhibitor, such as Erdafitinib. Cancer

[0174] Cancers that may be treated using the methods and protocols described herein include those that are treatable by inhibiting FGFR3. In other embodiments, thecancer has one or more cancer cells that express an activating alteration in a FGFR3 gene or its ligands. In other embodiments, the cancer is urothelial carcinoma of the urinary tract including non-muscle invasive bladder cancer, muscle invasive bladder cancer, cancer of the ureters or renal pelvis or locally advanced or metastatic urothelial carcinoma or solid tumor malignancy.

[0175] Examples of these cancers that are treatable by inhibiting FGFR3 or cancers that have one or more cancer cells that express an activating alteration in a FGFR3 gene or its ligands include but are not limited to FGFR3-associated urothelial cancer, FGFR3-associated bladder cancer, FGFR3-associated urothelial bladder cancer, FGFR3-associated advanced urothelial cancer, FGFR3-associated advanced urothelial bladder cancer, FGFR3-associated metastatic urothelial cancer, FGFR3-associated metastatic urothelial bladder cancer, FGFR3-associated non-muscle invasive urothelial cancer, FGFR3-associated non-muscle invasive bladder cancer, FGFR3-associated muscle invasive urothelial cancer, FGFR3-associated adjuvant muscle invasive urothelial cancer, FGFR3-associated muscle invasive bladder cancer, FGFR3-associated adjuvant muscle invasive bladder cancer, FGFR3-associated upper tract cancer, FGFR3-associated urothelial upper tract cancer, FGFR3-associated urethral cancer, and FGFR3-associated solid tumor malignancy.

[0176] In preferred embodiments, the cancer is FGFR3-associated non-muscle invasive urothelial cancer, FGFR3-associated non-muscle invasive bladder cancer, FGFR3-associated urothelial bladder cancer, FGFR3-associated advanced urothelial bladder cancer, or FGFR3-associated metastatic urothelial bladder cancer. In still more preferred embodiments, the cancer is FGFR3-associated advanced urothelial bladder cancer or FGFR3-associated metastatic urothelial bladder cancer. In still more preferred embodiments, the cancer is FGFR3-associated advanced urothelial bladder cancer. In still more preferred embodiments, the cancer is FGFR3-associated metastatic urothelial bladder cancer.

[0177] In still more preferred embodiments, the cancer is FGFR3-associated non- muscle invasive urothelial cancer, or FGFR3-associated non-muscle invasive bladder cancer. In still more preferred embodiments, the cancer is FGFR3-associated non-muscle invasive urothelial cancer. In still more preferred embodiments, the cancer is FGFR3- associated non-muscle invasive bladder cancer.

[0178] In still more preferred embodiments, the cancer is FGFR3-associated solid tumor malignancy. Dose Amount

[0179] In some embodiments, the dose amount is between about 160 mg to about 400 mg, between about 160 mg to about 300 mg, about 160 mg, about 200 mg, about 300 mg, and about 400 mg. In some embodiments, the dose amount is 160 mg, 162 mg, 164 mg, 166 mg, 168 mg, 170 mg, 172 mg, 174 mg, 176 mg, 178 mg, 180 mg, 182 mg, 184 mg, 186 mg, 188 mg, 190 mg, 192 mg, 194 mg, 196 mg, 198 mg, 200 mg, 202 mg, 204 mg, 206 mg, 208 mg, 210 mg, 212 mg, 214 mg, 216 mg, 218 mg, 220 mg, 222 mg, 224 mg, 226 mg, 228 mg, 230 mg, 232 mg, 234 mg, 236 mg, 238 mg, 240 mg, 242 mg, 244 mg, 246 mg, 248 mg, 250 mg 252 mg, 254 mg, 256 mg, 258 mg, 260 mg, 262 mg, 264 mg, 266 mg, 268 mg, 270 mg, 272 mg, 274 mg, 276 mg, 278 mg, 280 mg, 282 mg, 284 mg, 286 mg, 288 mg, 290 mg, 292 mg, 294 mg, 296 mg, 298 mg, 300 mg, 302 mg, 304 mg, 306 mg, 308 mg, 310 mg, 312 mg, 314 mg, 316 mg, 318 mg, 320 mg, 322 mg, 324 mg, 326 mg, 328 mg, 330 mg, 332 mg, 334 mg, 336 mg, 338 mg, 340 mg, 342 mg, 344 mg, 346 mg, 348 mg, 350 mg, 352 mg, 354 mg, 356 mg, 358 mg, 360 mg, 362 mg, 364 mg, 366 mg, 368 mg, 370 mg, 372 mg, 374 mg, 376 mg, 378 mg, 380 mg, 382 mg, 384 mg, 386 mg, 388 mg, 390 mg, 392 mg, 394 mg, 396 mg, 398 mg, or 400 mg, of a compound of Formula I . In some embodiments, the dose amount is up to a 25% increase over the 400 mg dose level. In one preferred embodiment, the dose amount is about 160 mg, about 200 mg, about 300 mg, and about 400 mg. In an embodiment, the dose amount is about 160 mg. In an embodiment, the dose amount is about 200 mg. In an embodiment, the dose amount is about 300 mg. In an embodiment, the dose amount is about 400 mg.

[0180] For the avoidance of doubt, when a dose is described herein, the dose refers to the amount of the free base, for example, the non-salt version of the compound of Formula I or Formula II or a combination thereof that is administered. For example, an 200 mg dose would require more than 200 mg of a cocrystalline form including the compound of Formula I or Formula II or a combination thereof, because the weight of the coformer must be included. Similarly, an 200 mg dose would require more than 200 mg of a cocrystalline form including the compound of Formula I or Formula II or a combination thereof, because the weight of the solvate must be included.Dosing Frequency

[0181] The compound of Formula I or Formula II or a combination thereof may be administered. Typically, the administration is once a day, twice a day, three times a day, or four times a day. In an embodiment, once a day has a recommended interval of once every twenty-four hours. In an embodiment, twice a day has a recommended interval of once every twelve hours. In an embodiment, three times a day has a recommended interval of once every eight hours. In an embodiment, four times a day has a recommended interval of once every six hours. In a preferred embodiment, the administration is administered QD, which is once a day. Commonly, when administered once a day, dose remains at the same strength. In a preferred embodiment, the administration is administered BID, which is twice a day. In a preferred embodiment, the administration is administered TID, which is three times a day. In a preferred embodiment, the administration is administered QID, which is four times a day, or Q6H, which is once every six hours. Commonly, when administered twice a day, both doses are the same strength, e.g., both doses are 160 mg, both doses are 200 mg, both doses are 300 mg, or both doses are 400 mg. But as described elsewhere herein, the doses may be different, for example if the patient exhibits a dose limiting toxicity. In such as case, the second dose would be reduced, relative to the first dose. Alternatively, the first and second doses may be lower than the first and second doses that were administered on a previous day. For example, if about 300 mg was administered as the first and second doses on a day 15 of treatment, but the first and second doses on day 16 of treatment may be reduced relative to the doses on day 15; e.g., the first and second doses on day 16 could both be about 200 mg. Dosing Frequency: Pembrolizumab

[0182] Pembrolizumab is administered using IV infusion on Day 1 of each 21-day treatment cycle. Trial treatment of pembrolizumab may be administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. The compound of Formula I or Formula II or a combination thereof is administered ≥30 minutes before or after administration of pembrolizumab.

[0183] Pembrolizumab is administered as a dose of 200 mg using a 30-minute IV infusion. The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab infusion and administration of infusion solution.

[0184] In an embodiment, the step of administering pembrolizumab occurs up to 2 years, 35 cycles, or the end of the patient’s life. In an embodiment, the step of administering the dose occurs up to the end of the patient’s life. In an embodiment, the step of administering pembrolizumab occurs up to 2 years or 35 cycles. Dose Limiting Toxicity

[0185] A dose limiting toxicity (DLT) is defined as any of the treatment-emergent adverse event (TEAEs), as defined by the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0), occurring during the defined DLT period: the first 21 days of study drug per dose, unless the Safety Review Committee (SRC) determines that the adverse event (AE) can be clearly related to the patient’s underlying disease, other medical condition, or concomitant medications including any AEs attributed by the Investigator to the combination agent alone. A TEAE is defined as an AE that starts or worsens on or after the first dose of study drug.

[0186] In an embodiment, the treatment-emergent adverse event is any Grade 3 or greater nonhematologic toxicity, any Grade 3 or greater hematologic toxicity, any Grade 5 toxicity, or AE meeting definition criteria of Hy’s Law: 3-fold or greater elevations above the ULN of ALT or AST, Serum TBL to ≥ 2 × ULN, with normal alkaline phosphatase (alkaline phosphatase ≤ 2 × ULN), and no other reason can be found to explain the combination of increased ALT or AST and TBL, such as viral hepatitis A, B, or C, pre-existing or acute liver disease, or another drug capable of causing the observed injury.

[0187] In an embodiment, the treatment-emergent adverse event is any Grade 3 or greater nonhematologic toxicity except for: Grade 3 or greater electrolyte abnormalities resolving to Grade 2 or baseline if baseline is Grade 2 or greater within 72 hours with supportive treatment, unless the patient has clinical symptoms, in which case all Grade 3 or greater electrolyte abnormality regardless of duration is considered a TEAE, Grade 3 fatigue lasting less than 1 week, Grade 3 nausea, vomiting, diarrhea, or other manageable constitutional symptom that is responsive to supportive therapy and resolves within 72 hours,Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of care for the combination with pembrolizumab only, or AST or ALT less than eight times ULN for patients with hepatic metastases.

[0188] In an embodiment, the treatment-emergent adverse event is any Grade 3 or greater hematologic toxicity except for: Grade 3 neutropenia without fever and not requiring growth factor support for less than 7 days, Grade 3 thrombocytopenia without clinically significant bleeding or requiring platelet transfusion, or Grade 3 leukopenia / lymphopenia. All toxicities will be graded using NCI-CTCAE Version 5.0 based on the Investigator assessment.

[0189] In an embodiment including administration of a compound of Formula I and pembrolizumab, the occurrence of any of the following toxicities during Cycle 1 may be considered a DLT, if assessed by the Investigator to be possibly, probably, or definitely related to study treatment administration: 1. Grade 4 nonhematologic toxicity (not laboratory). 2. Grade 4 hematologic toxicity lasting greater than or equal to 7 days, except thrombocytopenia: ^ Grade 4 thrombocytopenia of any duration ^ Grade 3 thrombocytopenia associated with clinically significant bleeding. 3. Any nonhematologic AE greater than or equal to Grade 3 in severity should be considered a DLT, with the following exceptions: Grade 3 fatigue lasting less than or equal to 3 days; Grade 3 diarrhea, nausea, or vomiting without use of anti-emetics or anti- diarrheals per standard of care; Grade 3 rash without use of corticosteroids or anti- inflammatory agents per standard of care. 4. Any Grade 3 or Grade 4 non-hematologic laboratory value if: ^ Clinically significant medical intervention is required to treat the participant or ^ The abnormality leads to hospitalization, or ^ The abnormality persists for greater than 1 week.^ The abnormality results in a Drug-induced Liver Injury (DILI) ^ Exceptions: Clinically nonsignificant, treatable, or reversible laboratory abnormalities including liver function tests, uric acid, etc. 5. Febrile neutropenia Grade 3 or Grade 4: ^ Grade 3 is defined as ANC less than 1000 / mm3 with a single temperature of greater than 38.3 degrees C (101 degrees F) or a sustained temperature of greater than or equal to 38 degrees C (100.4 degrees F) for more than 1 hour. ^ Grade 4 is defined as ANC less than 1000 / mm3 with a single temperature of greater than 38.3 degrees C (101 degrees F) or a sustained temperature of greater than or equal to 38 degrees C (100.4 degrees F) for more than 1 hour, with life-threatening consequences and urgent intervention indicated. 6. Prolonged delay greater than 2 weeks in initiating Cycle 2 due to treatment-related toxicity. 7. Any treatment-related toxicity that causes the participant to discontinue treatment during Cycle 1. 8. Missing greater than 25% of compound of Formula I doses as a result of drug-related AE(s) during the first cycle. or 9. Grade 5 toxicity.

[0190] In an embodiment, the DLT window of observation may be during Cycle 1.

[0191] If the patient exhibits one or more TEAEs, such as toxicity, a clinically significant adverse event, intolerability, and a drug-drug interaction, the dose of the drug may be reduced. In an embodiment, the patient exhibits a clinically significant adverse event and the second and / or subsequent doses, are reduced, relative to the dose that was administered before the TEAE was identified.

[0192] Reducing the dose should help to alleviate one or more TEAEs, and preferably, help the patient stay on treatment. When one or more TEAEs is exhibited, each dose is typically reduced. In this embodiment, the second dose may be about 160 mg, about 180 mg, about 200 mg, about 206 mg, about 212 mg, about 220 mg, about 240 mg, about 200 mg, about 300 mg, about 306 mg, about 310 mg, about 312 mg, about 320 mg, about 340 mg, about 350 mg, about 300 mg, about 380 mg, about 386 mg, or about

[0193] If a patient is receiving a 400 mg dose BID, the most the dose could be reduced would be about 160 mg, about 200 mg, or about 300 mg. In some embodiments, the second dose is reduced, as compared to the first dose. In one embodiment, the second dose is reduced by 40 mg as compared to the first dose. In another embodiment, the first and second doses are reduced as compared to the first and second doses administered on a prior day.

[0194] In another embodiment, the second dose may be reduced by about 100 mg as compared to the first dose except for when the first dose is about 160 mg, or about 200 mg.

[0195] Alternatively, when one or more TEAEs is exhibited, each dose may be reduced by administering a dose once a day instead of twice a day.

[0196] If needed, the second dose can be reduced to a third dose. When one or more TEAEs are exhibited, the second dose may be reduced to a third dose. As before, the third dose cannot be reduced by an amount that is greater than the first dose or the second dose. In a preferred embodiment, the third dose is about 100 mg less than the second dose. To be clear, the third dose is not necessarily the third dose in a single day. Rather, it is the dose that is administered if the second dose causes a TEAE or otherwise needs to be decreased whether on the same day or on a subsequent day. For example, if a patient receives a first dose of 400 mg BID that results in dose limiting toxicity, a second dose of 300 mg BID may be administered. If a patient is receiving a second dose of 300 mg BID that results in dose limiting toxicity, a third dose of 200 mg BID may be administered. Dose Reduction

[0197] Also disclosed herein is a method of treating cancer, comprising administering to a patient in need of such treatment, a first dose between about 160 mg to about 400 mg of a compound of Formula I; monitoring the patient for a dose limiting toxicity; and administering a second dose of the compound of Formula I or Formula II or a combination thereof, if the patient exhibits the dose limiting toxicity, wherein the second dose is reduced as compared to the first dose. In an embodiment, the first dose is selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg. In an embodiment, the second dose is reduced by 100 mg as compared to the first dose.

[0198] In another aspect, disclosed herein is a method of treating a cancer comprising administering to a patient in need of such treatment a second dose selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg of a compound of Formula I; monitoring the patient for a dose limiting toxicity; and administering a third dose of a compound of Formula I or Formula II, if the patient exhibits a dose limiting toxicity, wherein the third dose is reduced as compared to the second dose. In an embodiment, the third dose is reduced by 100 mg as compared to the second dose.

[0199] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of the compound of Formula I or Formula II or a combination thereof, in simultaneous, separate, or sequential combination with a second therapeutic agent, wherein the dose of the compound of Formula I or Formula II or a combination thereof, is a reduced dose selected from the group consisting of about 160 mg, about 200 mg, and about 300 mg. Methods

[0200] The methods of treating the cancers described herein comprise administering the doses described herein with the dosing frequencies described herein. Specific examples of the methods are described below.

[0201] In another aspect, disclosed herein is a method of treating cancer, comprising administering to a patient in need thereof, a dose of about 160 mg of a compound of Formula I or Formula II, in which the cancer has one or more cells that express an activating alteration in a FGFR3 gene or its ligands. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered once a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered twice a day.

[0202] In another aspect, disclosed herein is a method of treating cancer, comprising administering to a patient in need thereof, a dose of about 200 mg of a compound of Formula I or Formula II, in which the cancer has one or more cells that express an activating alteration in a FGFR3 gene or its ligands. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered once a day. In an embodiment, the dose of the compound of Formula I orFormula II or a combination thereof, is administered twice a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered three times a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered four times a day.

[0203] In another aspect, disclosed herein is a method of treating cancer, comprising administering to a patient in need thereof, a dose of about 300 mg of a compound of Formula I or Formula II, in which the cancer has one or more cells that express an activating alteration in a FGFR3 gene or its ligands. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered once a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered twice a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered three times a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered four times a day.

[0204] In another aspect, disclosed herein is a method of treating cancer, comprising administering to a patient in need thereof, a dose of about 400 mg of a compound of Formula I or Formula II, in which the cancer has one or more cells that express an activating alteration in a FGFR3 gene or its ligands. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered once a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered twice a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered three times a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered four times a day.

[0205] In another aspect, disclosed herein is a method of treating cancer, comprising administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, wherein after the administration of a compound of Formula I or Formula II, the patient achieves a partial response (PR).

[0206] In another aspect, disclosed herein is a method of treating cancer, comprising administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, wherein after the administration of a compound of Formula I or Formula II, the patient achieves a complete response.

[0207] In another aspect, disclosed herein is a method of treating cancer, comprising administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, wherein after the administration of a compound of Formula I or Formula II, the patient achieves a stable disease (SD).

[0208] In another aspect, disclosed herein is use of a compound of Formula I or Formula II , in the manufacture of a medicament for treatment of cancer, wherein the compound of Formula I or Formula II or a combination thereof, is administered at a first dose selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg; the patient is monitored for dose limiting toxicity; and if the patient exhibits dose limiting toxicity, a second dose of the compound of Formula I or Formula II or a combination thereof, is administered, wherein the second dose is reduced as compared to the first dose. Combinations – Methods and Uses

[0209] In another aspect, disclosed herein is a method of treating a cancer comprising administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, in simultaneous, separate, or sequential combination with a second therapeutic agent. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg.

[0210] In an embodiment the second therapeutic agent is selected from the group consisting of: one or more of a PD-1 inhibitor, a PD-L1 inhibitor, and an antibody drug conjugate.

[0211] In another aspect, disclosed herein is a method of treating cancer comprising administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, in simultaneous, separate, or sequential combination with a PD-1 inhibitor, or a PD-L1 inhibitor, in the treatment of cancer. In another aspect, disclosed herein is a method of treating cancer, comprising administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, in simultaneous, separate, or sequential combination with pembrolizumab in the treatment of FGFR3-associated cancer. In another embodiment, the PD-1 inhibitor, is pembrolizumab, wherein pembrolizumab is dosed at 200 mg once every three weeks.

[0212] In another embodiment, the PD-1 inhibitor, or the PD-L1 inhibitor, is nivolumab. In another embodiment, the PD-1 inhibitor, or the PD-L1 inhibitor, is cemiplimab. In another embodiment, the PD-1 inhibitor, or the PD-L1 inhibitor, is sintilimab. In another embodiment, the PD-1 inhibitor, or the PD-L1 inhibitor, is atezolizumab. In another embodiment, the PD-1 inhibitor, or the PD-L1 inhibitor, is avelumab. In another embodiment, the PD-1 inhibitor, or the PD-L1 inhibitor, is durvalumab. In another embodiment, the PD-1 inhibitor, or the PD-L1 inhibitor, is lodapilimab.

[0213] In another aspect, disclosed herein is a method of treating cancer comprising administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, in simultaneous, separate, or sequential combination with an antibody drug conjugate in the treatment of cancer. In another aspect, disclosed herein is a method of treating cancer, comprising administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, in simultaneous, separate, or sequential combination with enfortumab vedotin in the treatment of FGFR3-associated cancer.

[0214] In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered once a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered twice a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg.

[0215] In another aspect, disclosed herein is a method of treating cancer, comprising administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, in simultaneous, separate, or sequential combination with pembrolizumab in the treatment of FGFR3-associated cancer, wherein pembrolizumab is dosed intravenously at 200 mg once every three weeks. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered once a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered twice a day. In an embodiment, the dose of the compound of Formula I or Formula II or acombination thereof, is selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg.

[0216] In another aspect, disclosed herein is a compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof, is administered at a dose between about 160 mg and about 400 mg.

[0217] In another aspect, disclosed herein is a compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the FGFR3-associated cancer is breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small-cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasive urothelial cancer, adjuvant muscle invasive urothelial cancer, muscle invasive bladder cancer, adjuvant muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, renal cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, or testicular cancer.

[0218] In another aspect, disclosed herein is a compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the compound of Formula I or Formula II or a combination thereof, is administered in simultaneous, separate or sequential combination with a second therapeutic agent.

[0219] In another aspect, disclosed herein is a compound of Formula I or Formula II or a combination thereof, for use in treatment of a FGFR3-associated cancer, wherein the second therapeutic agent is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and an antibody drug conjugate.

[0220] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, in the manufacture of a medicament for treating cancer, wherein the compound is administered at a dose between about 160 mg to about 400 mg, in simultaneous, separate, or sequential combination with a second therapeutic agent,wherein the second therapeutic agent is selected from the group consisting of: one or more of a PD-1 inhibitor, a PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, and an antibody drug conjugate.

[0221] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, in the manufacture of a medicament, administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, in simultaneous, separate, or sequential combination with a PD-1 inhibitor, a PD-L1 inhibitor, for treatment of cancer. In another embodiment, the PD-1 inhibitor, is pembrolizumab, wherein pembrolizumab is dosed at 200 mg once every three weeks. In another embodiment, the PD-1 inhibitor, is nivolumab. In another embodiment, the PD-1 inhibitor, is cemiplimab. In another embodiment, the PD-1 inhibitor, is sintilimab. In another embodiment, the PD-1 inhibitor is dostarlimab. In another embodiment, the PD-1 inhibitor is retifanlimab. In another embodiment, the PD-1 inhibitor is toripalimab. In another embodiment, the PD-L1 inhibitor, is atezolizumab. In another embodiment, the PD-L1 inhibitor, is avelumab. In another embodiment, the PD-L1 inhibitor, is durvalumab.

[0222] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, in the manufacture of a medicament, administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, in simultaneous, separate, or sequential combination with an antibody drug conjugate for treatment of cancer. In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, in the manufacture of a medicament, administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, in simultaneous, separate, or sequential combination with enfortumab vedotin for treatment of cancer. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered once a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered twice a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg.

[0223] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, in the manufacture of a medicament, administering to a patient in needthereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, in simultaneous, separate, or sequential combination with pembrolizumab in the treatment of FGFR3-associated cancer, wherein pembrolizumab is dosed intravenously at 200 mg once every three weeks. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered once a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is administered twice a day. In an embodiment, the dose of the compound of Formula I or Formula II or a combination thereof, is selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg.

[0224] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, in the manufacture of a medicament, administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, in simultaneous, separate, or sequential combination with enfortumab vedotin in the treatment of FGFR3-associated cancer.

[0225] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, in the manufacture of a medicament, administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, in simultaneous, separate, or sequential combination with pembrolizumab and enfortumab vedotin in the treatment of FGFR3-associated cancer.

[0226] In another aspect, disclosed herein is a use of a compound of Formula I or Formula II, in the manufacture of a medicament, administering to a patient in need thereof, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II, in simultaneous, separate, or sequential combination with nivolumab in the treatment of FGFR3-associated cancer. Examples Example 1 Biological Assay

[0227] FGFR3 and FGFR1 Enzyme Assay: FGFR3 protein was purchased from Reaction Biology (Cat. No.1068), and FGFR1 protein was purchased from ThermoFisher Scientific (Cat. No. PV4105). Enzyme activity was monitored using the KinEASETM-TK Assay Kit (CisBio, Cat. No.62TK0PEC) according to the manufacturer’s instructions. All assays were performed at the respective KmATP for each kinase in KinEASETMKinase Buffer. Reactions were performed in a white, small volume polystyrene 384 well plate (Greiner, Cat. No.784075-25).

[0228] An incubation was conducted with FGFR3 protein or FGFR1 protein, 125.0 nM TK-Biotin Substrate (CisBio), 7.81 nM Streptavidin-XL665 (CisBio), 0.25 x Anti-Phosphorylate TK-Biotin-Cryptate (CisBio). Final enzyme concentrations were 0.25 nM in 10 uL reactions. Titration of Isomers 1, 2, and A were performed in a half-log manner in 100% dimethyl sulfoxide (DMSO) starting at 1uM. Prior to the initiation of the reaction by adenosine triphosphate (ATP), FGFR1 protein and Isomers 1, 2, and A were pre-incubated for 15 minutes at room temperature, and FGFR3 protein and Isomers 1, 2, and A were pre-incubated on ice for 15 minutes. Reactions proceeded for 30 min at 30℃. Plates were quenched by the addition of the Anti-TK cryptate antibody / Streptavidin-XL665 mixture. After 1 hour. in the stopping solution, the plates were read on the Envision plate reader ((Perkin Elmer) (Ex. Filter.320 nm and Em1665 nm / Em2615 nm)).

[0229] Ratios were converted to a percent of control (POC) using a ratiometric emission factor. One hundred POC was determined using no test compound, and 0 POC was determined in the presence of 1uM of an appropriate control inhibitor. A 4-parameter logistic curve was fit to the POC values as a function of the concentration of Isomers 1, 2, and A, and the IC50value was the point where the best fit curve crossed 50 POC.

[0230] In the above assays Isomer 1, Isomer 2, and Isomer A each exhibited IC50 values of less than 350 nM for FGFR3. In the above assays Isomer 2 and Isomer A exhibited IC50 values of less than 100 nM for FGFR3 and were at least 3 fold more selective for FGFR3 than for FGFR1. In the above assays Isomer 2 and Isomer A exhibited IC50 values of less than 50 nM for FGFR3 and were at least 10 fold more selective for FGFR3 than for FGFR1. Example 2

[0231] Athymic nude mice (n=6, per group) were dosed orally, BID, for 3.5 days for a total of 7 doses, with one of a compound of Formula I or Erdafitinib. Serum phosphate levels were determined 8 hours post final dose as shown in Figure 1.

[0232] As shown in Figure 1, serum phosphate levels resulting in treatment with erdafitinib 30 mpk were statistically significant compared to vehicle control (p≤0.0001) using one way ANOVA Dunnett’s test comparison of means. As shown in Figure 1,serum phosphate levels resulting from treatments with Isomer 2 at 10 mpk, 30 mpk, or 90 mpk were not statistically significant compared to vehicle control using one way ANOVA Dunnett’s test comparison of means. Example 3

[0233] An Open-label, Multicenter Study of a Compound of Formula I in Advanced Solid Tumor Malignancies with FGFR3 Alterations Eligibility Criteria:

[0234] This study evaluates the pharmacokinetics (PK), safety, and preliminary efficacy of LOXO-435 in advanced solid tumors harboring alterations in FGFR3 or its ligands.

[0235] Tables 3 to 10 below provide total patient data including dose levels of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereof lower than 160 mg BID, 200 mg BID, 300 mg BID, and 400 mg BID. Tables 3 to 10 below separate out data of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereof for dose levels: 160 mg BID, 200 mg BID, 300 mg BID, and 400 mg BID. Table 3: Preliminary NCT05614739 data of Best Overall Response (BOR), Objective Response Rate, and Disease Control Rate by Starting Dose of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereofTotal 160 mg 200 mg 300 mg 400 mg (N=87) BID BID BID BID N 15 N 19 N 23 N 8, p starting dose level of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereof: 160 mg BID, 200 mg BID, 300 mg BID, and 400 mg BID.Table 4: Preliminary NCT05614739 data of Best Overall Response (BOR), Objective Response Rate, and Disease Control Rate by Starting Dose for Patients with Prior FGFR Inhibitor of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereof Total 160 mg 200 mg 300 mg 400 mg (N=21) BID BID BID BID

[0241] As can be seen in Table 4 above, responses have been observed at each starting dose level of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereof for patients with a prior FGFR inhibitor: 160 mg BID, 200 mg BID, 300 mg BID, and 400 mg BID. Table 5: Preliminary NCT05614739 data of Best Overall Response (BOR), Objective Response Rate, and Disease Control Rate by Starting Dose for Patients with No Prior FGFR Inhibitor of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereofTotal 160 mg 200 mg 300 mg 400 mg (N=66) BID BID BID BID N 13 N 15 N 17 N 7

[0242] As can be seen in Table 5 above, responses have been observed at each starting dose level of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereof for patients with no prior FGFR inhibitor: 160 mg BID, 200 mg BID, 300 mg BID, and 400 mg BID.Table 6: Preliminary NCT05614739 data of Best Overall Response (BOR), Objective Response Rate, and Disease Control Rate by Starting Dose for Patients with Measurable Disease and FGFR Mutations / Fusions of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereof Total 160 mg 200 mg 300 mg 400 mg (N=72) BID BID BID BID

[0243] As can be seen in Table 6 above, responses have been observed at each starting dose level of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereof for patients with measurable disease and FGFR mutations / fusions: 160 mg BID, 200 mg BID, 300 mg BID, and 400 mg BID. Table 7: Preliminary NCT05614739 data of Best Overall Response (BOR), Objective Response Rate, and Disease Control Rate by Starting Dose for Patients with Urothelial Carcinoma and Measurable Disease and FGFR Mutations / Fusions of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereofTotal 160 mg 200 mg 300 mg 400 mg (N=53) BID BID BID BID N 8 N 12 N 15 N 4starting dose level of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereof for patients with urothelial carcinoma and measurable disease and FGFR mutations / fusions: 160 mg BID, 200 mg BID, 300 mg BID, and 400 mg BID.Table 8: Preliminary NCT05614739 data of Treatment-Emergent Adverse Events (TEAE) by Starting Dose of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereof Total 160 mg 200 mg 300 mg 400 mg (N=101) BID BID BID BIDPts Discontinued Study Treatment due 1 0 1 0 0 t SAE (1.0) (0.0) (4.3) (0.0) (0.0) E,Table 9: Preliminary NCT05614739 data of Maximum Severity of Treatment- Emergent Adverse Events (TEAE) by Starting Dose of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereof Total 160 mg 200 mg 300 mg 400 mg (N=101) BID BID BID BIDEmergent Adverse Events (TEAE) Related to Study Treatment by Starting Dose of a compound of Formula I or Formula II, or a combination thereof, or pharmaceutically acceptable salt thereof Total 160 mg 200 mg 300 mg 400 mg BID BID BID BIDPts with Grade 3 Maximum Severity 8 1 2 3 1 % (7.9) (6.7) (8.7) (11.1) (7.1)

[0245] Each patient must meet all the following inclusion criteria to be eligible to participate in the study: Age 1. Must be ≥ 18 years of age, or age of majority if higher (>18 years of age) per local regulations, at the time of enrollment. Type of Patient and Disease Characteristics 2. Histologic diagnosis of locally advanced or metastatic solid tumor malignancy (except central nervous system [CNS] primary malignancy i.e., glioma), and where applicable, with an FGFR3 pathway alteration on molecular testing in tumor or blood sample that is deemed as actionable, as defined below per specific cohort. 3. NOTE: Testing must be performed in a Clinical Laboratory Improvement Amendments (CLIA), International Organization for Standardization (ISO) / International Electrotechnical Commission (IEC), College of American Pathologists (CAP), or other similarly certified laboratories as per local guidelines including but not limited to In Vitro Diagnostic Regulation (IVDR) compliance as applicable. An anonymized / redacted Molecular Pathology Report or other report(s) describing the FGFR3 or ligand alteration (and all other alterations) should be submitted to the Sponsor or designee during / prior to eligibility as permitted per local regulations. Sponsor should be contacted to discuss test results from laboratories where such certification is not clearly demonstrated to determine eligibility. a. Cohort A1 (Dose Escalation and Food Effect and Renal Insufficiency Substudies): Presence of an alteration in FGFR3 or its ligands deemed as a clinically or potentially clinically relevant alteration (any activating alteration, fusion, variant of uncertain significance, overexpression, or amplification) by treating investigator. b. Cohort A2 (Dose Optimization): Histological diagnosis of UC that is locally advanced or metastatic with a qualifying FGFR3 alteration. c. Cohorts B (mUC):a. Cohort B1 (Dose Expansion with prior pan-FGFR inhibitor): Histological diagnosis of urothelial cancer that is locally advanced or metastatic UC. Patients must have received prior pan-FGFR inhibitor. b. Cohort B2 (Dose Expansion pan-FGFR inhibitor naïve): Histological diagnosis of urothelial cancer that is locally advanced or metastatic UC with a qualifying FGFR3 alteration. c. Cohort B3 (Combination with pembrolizumab Dose Expansion pan-FGFR inhibitor naïve): Combination with pembrolizumab for progressed / intolerant to available therapies and pan-FGFR inhibitor naïve. Histological diagnosis of locally advanced or metastatic urothelial carcinoma (mUC) with a pre- specified activating FGFR3 alteration. Patients with mixed histology are eligible if a urothelial component is present. d. Cohort C1 (All other solid tumors Dose Expansion): Monotherapy for progressed / intolerant to available therapies and pan-FGFR inhibitor naïve. Histological diagnosis of a non-urothelial locally advanced or metastatic solid tumor with a pre-specified activating FGFR3 alteration. Measurability of disease: a Cohort A1: measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v 1.1 (RECIST v1.1) b Cohorts A2, B1, B2, B3, or C1: Measurable disease required as defined by RECIST v1.1 Life expectancy > 12 weeks. Have adequate archival tumor tissue sample available or undergo a screening biopsy. Archival Tissue: Preferably, if tissue was used to identify the FGFR3 alteration, a sample corresponding to the same collection should be provided if available. If tumor tissue from this specimen is not available or tumor tissue was not used for FGFR3 testing, the most recently obtained biopsy (non-bone sample) should be provided. Screening Biopsy: If sufficient quantity or quality of archival tissue cannot be provided, patients should undergo a new tumor biopsy, if medically feasible, prior to treatment initiation in accordance with the Schedule of Activities. Patients without an available tumor sample who cannot safely undergo a new tumor biopsy may be eligible after discussion with the Sponsor prior to enrollment. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 for Cohorts A1, A2, B2, and B3. a. Have an ECOG performance status of ≤ 2 for Cohorts B1 and C1. Patient has received all standard therapies for which the patient was deemed to be an appropriate candidate by the treating investigator; OR the patient is refusing the remaining most appropriate standard of care treatment; OR there is no standard therapy available for the disease. There is no restriction on number of prior therapies.0. Cohort specific requirements: a Cohort A1 and C1: The patient has received all standard therapies for which the patient was deemed to be an appropriate candidate, or the patient is refusing the remaining most appropriate standard of care treatment, or there is no standard therapy available for the disease. b Cohort A2, B2, or B3: Patients must have received at least one prior regimen in the advanced or metastatic setting. c Cohort B1: Patients must have progressed on or following discontinuation of at least 2 lines of prior therapy, including erdafitinib, in the metastatic or advanced setting. Neoadjuvant or adjuvant therapy that was completed less than or equal to 12 months prior tot the diagnosis of metastatic setting. d Cohort B1: Patients must have been previously treated with a pan-FGFR inhibitor such as erdafitinib. e Cohort B2: Patients must be pan-FGFR inhibitor naïve. f Cohort B3: Patients must be pan-FGFR inhibitor naïve. g Cohort C1: Patients must be pan-FGFR inhibitor naïve. 1. Must have adequate organ function, as defined in the following: System Laboratory Value edOther < 5.5 mg / dL (1.78 mmol / L) without requiring medical management ≤Chronic Kidney Disease Epidemiology Collaboration; CrCl = creatinine clearance; DL = dose level; G-CSF = granulocyte colony-stimulating factor; ULN = upper limit of normal. 2 Calculated using CKD-EPI 2021 (Miller et al.2022) 3 Upon completion of a sub-study in patients with moderate renal insufficiency (calculated CrCl ³ 30 to 49 mL / min), the Sponsor may allow enrollment of patients with moderate renal insufficiency in backfill slots after each DL is cleared. Contraception 12. Women of childbearing potential (WOCBP) (defined as not postmenopausal for at least 2 years or surgically sterile) and men with partners who are WOCBP must agree to use a highly effective method of birth control during the study treatment and for at least 6 months following the last dose of the study treatment. Sperm and egg donation are prohibited during the duration of participation in this protocol and for 6 months after the last dose of the study treatment. Highly effective methods of birth control are: a Total abstinence from intercourse; periodic abstinence is not acceptable. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. b Surgical sterilization as appropriate by vasectomy, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy c Intrauterine device d Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal): the specific contraceptive must have been used for at least 3 months prior to study treatment administration. Hormonal contraceptives must be associated with inhibition of ovulation and must be used with a barrier method of contraception. 13. WOCBP must have a negative serum pregnancy test documented within 14 days prior to initiation of treatment and a negative urine or serum pregnancy test obtained on Cycle 1 Day 1 (C1D1) if the serum pregnancy test was obtained more than 3 days prior to C1D1. Informed Consent14. The patient must be capable of demonstrating an understanding of the nature, significance, and implications of participation in the study and giving signed informed consent, which includes compliance with the requirements and restrictions listed in an informed consent form (ICF). Other Criteria 15. Must be able to swallow tablets and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation. Exclusion Criteria

[0246] Any patient who meets any of the following criteria will be excluded from study participation: Medical Conditions 16. There is no restriction on number of prior therapies; however, patients who have received the following therapies within the specified windows are excluded: Previous Treatment Cytotoxic therapies or targeted agents ≤ 14 days or ≤ 5 half-lives whichever is18. Known or suspected history of uncontrolled CNS involvement. Note: Patients with treated brain metastases are eligible for this study provided: ^ Completed prior CNS-directed therapy (including radiation and / or surgery) ≥ 28 days prior to the first dose of study treatment. ^ Are not receiving corticosteroids for at least 14 days prior to the first dose of study treatment. Prophylactic anticonvulsants are permitted, provided the patient is on a stable dose for at least 14 days prior to C1D1.^ Their disease is symptomatically and radiographically stable for at least 28 days prior to C1D1 by repeat imaging. Current evidence of corneal keratopathy or retinal disorder confirmed by ophthalmic examination at Screening. Patients with asymptomatic ophthalmic conditions assessed by the investigator to pose minimal risk for study participation may be enrolled in the study. Have a history and / or current evidence of extensive tissue calcification. Any unresolved toxicities from prior therapy greater than National Cancer Institute (NCI) Common Terminology Criteria in Adverse Events (CTCAE) (Version 5.0) Grade 1 at the time of starting study treatment except for alopecia and peripheral neuropathy. . Note: Patients who received prior immunotherapy and who developed endocrinopathies (i.e., diabetes, hypothyroidism, adrenal insufficiency) are eligible if on a stable treatment regimen as defined by principal investigator (PI). Significant cardiovascular disease, including any of the following: ^ Myocardial infarction or unstable angina within 6 months of C1D1 ^ History of myocardial infarction within 6 months prior to the planned start of study treatment ^ ≥ Grade 3 New York Heart Association functional classification system of heart failure, uncontrolled or symptomatic arrhythmias Prolongation of the QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥ 470 ms on triplicate electrocardiograms (ECGs) during Screening. QTcF is calculated using Fridericia’s Formula: QTcF = QT / (RR0.33). ^ Note: Correction of suspected drug-induced QTcF prolongation can be attempted at the Investigator’s discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation. ^ Correction for underlying bundle branch block (BBB) allowed. Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which, in the opinion of the Investigator and the Sponsor, makes it undesirable for the patient to participate in the study. Screening for chronic conditions is not required. Prophylactic antibiotic treatment is permitted. Active hepatitis B or C infection documented during Screening and defined as the following:a. Hepatitis B virus (HBV): positive hepatitis B surface antigen (HbsAg) or antihepatitis B core antibody (HBc). If anti-HBc positive with surface antigen negative, the patient will need to have a negative result for hepatitis B DNA before start of study therapy. Patients who are anti-HBc positive and hepatitis polymerase chain reaction (PCR) positive will be excluded. b. Note: For Cohort B3 only: a. Patients who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to C1D1. Note: Patients in Cohort B3 should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. c. Hepatitis C virus (HCV): positive hepatitis C antibody. If a positive hepatitis C antibody result, the patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before start of study therapy. Patients who are hepatitis C RNA positive will be excluded. Known human immunodeficiency virus (HIV) infection, regardless of CD4 count. Patients with unknown or negative status are eligible. Clinically significant active malabsorption syndrome or other conditions likely to affect gastrointestinal absorption of the oral administered study treatments. Have a second active primary malignancy or have been diagnosed and / or treated for an additional malignancy within 3 years prior to enrollment with the exception of curatively treated basal cell carcinoma of the skin, nonmetastatic prostate cancer treated with observation only, squamous cell carcinoma of the skin, and / or curatively resected in situ cervical and / or breast cancers. Incidentally, detected organ-confined prostate cancer at the time of radical cystectomy is allowed. Prior / Concomitant Therapy Vaccination with a live vaccine within 30 days prior to C1D1. 32. Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular country is allowed as long as they are messenger ribonucleic acid (mRNA) vaccines, adenoviral vaccines, or inactivated vaccines. Have initiated bisphosphonates or approved receptor activator of nuclear factor kappa-B ligand (RANK) ligand (RANK-L) targeted agents (e.g., denosumab) < 14 days prior to C1D1. The following patients will be excluded from Cohort B3:a Has an active autoimmune disease that has required systemic antiautoimmune treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. b Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. Patients who have had a transplant > 5 years ago are eligible as long as they have no symptoms of graft versus host disease. c Has had an allogeneic tissue / solid organ transplant. d Has severe hypersensitivity (≥Grade 3) to pembrolizumab and / or any of its excipients. e Has received radiation therapy to the lung that is >30Gy within 6 months of the first dose of trial treatment. Other Criteria 35. Patients who are pregnant, lactating, or plan to breastfeed during the study or within 6 months of the last dose of study treatment. 36. Patients with known hypersensitivity to any component or excipient of LOXO-435.

[0247] For Cohort B3 only, patients with a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease. Numbered Embodiments

[0248] Embodiment 1. A method of treating a cancer comprising: administering to a patient in need of such treatment, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II:I), ,

[0249] Embodiment 2. The method of embodiment 1, wherein the dose administered is between about 160 mg to about 400 mg of the compound of Formula I or Formula II or a combination thereof.

[0250] Embodiment 3. The method of embodiment 1, wherein the total daily dose is selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, about 320 mg, about 400 mg, about 480 mg, about 600 mg, about 640 mg, about 800 mg, about 900 mg, about 1200 mg, and about 1600 mg.

[0251] Embodiment 4. The method of embodiment 3, wherein the total daily dose is about 160 mg.

[0252] Embodiment 5. The method of embodiment 3, wherein the total daily dose is about 200 mg.

[0253] Embodiment 6. The method of embodiment 3, wherein the total daily dose is about 300 mg.

[0254] Embodiment 7. The method of embodiment 3, wherein the total daily dose is about 400 mg.

[0255] Embodiment 8. The method of embodiment 3, wherein the total daily dose is about 600 mg.

[0256] Embodiment 9. The method of embodiment 3, wherein the total daily dose is about 800 mg.

[0257] Embodiment 10. The method of any one of embodiments 1-7, wherein the cancer is selected from the group consisting of urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasive urothelial cancer, adjuvant muscle invasive urothelial cancer, muscle invasive bladder cancer, adjuvant muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, and solid tumor malignancy.

[0258] Embodiment 11. The method of any one of embodiments 1-9, wherein the cancer is selected from the group consisting of FGFR3-associated urothelial cancer, FGFR3-associated bladder cancer, FGFR3-associated urothelial bladder cancer, FGFR3- associated advanced urothelial cancer, FGFR3-associated advanced urothelial bladder cancer, FGFR3-associated metastatic urothelial cancer, FGFR3-associated metastatic urothelial bladder cancer, FGFR3-associated muscle invasive urothelial cancer, FGFR3- associated adjuvant muscle invasive urothelial cancer, FGFR3-associated muscle invasive bladder cancer, FGFR3-associated adjuvant muscle invasive bladder cancer, FGFR3- associated upper tract cancer, FGFR3-associated urothelial upper tract cancer, FGFR3- associated urethral cancer, or FGFR3-associated solid tumor malignancy.

[0259] Embodiment 12. The method of any one of embodiments 1-11, wherein the cancer is FGFR3-associated advanced urothelial cancer, FGFR3-associated advanced urothelial bladder cancer, FGFR3-associated metastatic urothelial cancer, or FGFR3- associated metastatic urothelial bladder cancer.

[0260] Embodiment 13. The method of any one of embodiments 1-11, wherein the cancer is FGFR3-associated advanced urothelial cancer or FGFR3-associated metastatic urothelial cancer.

[0261] Embodiment 14. The method of any one of embodiments 1-11, wherein the cancer is FGFR3-associated muscle invasive urothelial cancer, FGFR3-associated adjuvant muscle invasive urothelial cancer, FGFR3-associated muscle invasive bladder cancer, or FGFR3-associated adjuvant muscle invasive bladder cancer.

[0262] Embodiment 15. The method of any one of embodiments 1-11, wherein the cancer is FGFR3-associated muscle invasive bladder cancer.

[0263] Embodiment 16. The method of any one of embodiments 1-15, wherein the dose is in a capsule containing about 6 mg, about 100 mg, or about 20 mg of the compound of Formula I or Formula II or a combination thereof.

[0264] Embodiment 17. The method of any one of embodiments 1 to 3, or 10 to 16, wherein the dose is administered as a dose between about 160 mg to about 400 mg to the patient at least twice a day.

[0265] Embodiment 18. The method of any one of embodiments 1 to 3, 10 to 15, wherein the dose is administered as a dose of about 160 mg to the patient at least twice a day.

[0266] Embodiment 19. The method of any one of embodiments 1 to 3, 10 to 15, wherein the dose is administered as a dose of about 200 mg to the patient at least twice a day.

[0267] Embodiment 20. The method of any one of embodiments 1 to 3, 10 to 15, wherein the dose is administered as a dose of about 300 mg to the patient at least twice a day.

[0268] Embodiment 21. The method of any one of embodiments 1 to 3, 10 to 15, wherein the dose is administered as a dose of about 400 mg to the patient at least twice a day.

[0269] Embodiment 22. The method of any one of embodiments 1 to 21, comprising: monitoring the patient for a dose limiting toxicity; and administering a second dose of the compound of Formula I or Formula II or a combination thereof, if the patient exhibits the dose limiting toxicity, wherein the second dose is reduced as compared to a first dose.

[0270] Embodiment 23. A method of treating a cancer comprising: (a) administering to a patient in need of such treatment a first dose between about 200 mg to about 400 mg of a compound of Formula I or Formula II:I),(b) monitoring the patient for a dose limiting toxicity; and (c) administering a second dose of the compound of Formula I or Formula II or a combination thereof, if the patient exhibits the dose limiting toxicity, wherein the second dose is reduced as compared to the first dose.

[0271] Embodiment 24. The method of embodiments 23, wherein the first dose is selected from the group consisting of about 200 mg, about 300 mg, and about 400 mg.

[0272] Embodiment 25. The method of embodiments 23 or 24, wherein the second dose is selected from the group consisting of about 160 mg, about 200 mg, and about 300 mg.

[0273] Embodiment 26. The method of any one of embodiments 22 to 25, wherein the dose limiting toxicity occurs during the first 21 days after administering the first dose.

[0274] Embodiment 28. The method of embodiment 27, wherein a treatment- emergent adverse event is any Grade 5 toxicity, or an AE meeting definition criteria of Hy’s Law.

[0275] Embodiment 29. The method of embodiment 27, wherein a treatment- emergent adverse event is any Grade 3 or greater nonhematologic toxicity except for: Grade 3 or greater electrolyte abnormalities resolving to Grade 2 or baseline if baseline is Grade 2 or greater within 72 hours with supportive treatment, unless thepatient has clinical symptoms, in which case all Grade 3 or greater electrolyte abnormality regardless of duration is considered a TEAE, Grade 3 fatigue lasting less than 1 week, Grade 3 nausea, vomiting, diarrhea, or other manageable constitutional symptom that is responsive to supportive therapy and resolves within 72 hours, Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of care for the combination with pembrolizumab only, or AST or ALT less than eight times ULN or AST for patients with hepatic metastases.

[0276] Embodiment 30. The method of embodiment 27, wherein a treatment- emergent adverse event is any Grade 3 or greater hematologic toxicity except for: Grade 3 neutropenia without fever and not requiring growth factor support for less than 7 days, Grade 3 thrombocytopenia without clinically significant bleeding or requiring platelet transfusion, or Grade 3 leukopenia / lymphopenia.

[0277] Embodiment 31. The method of any one of embodiments 22 to 25, wherein a treatment-emergent adverse event is decrease in the number of red blood cells, reduced thyroid gland activity, feeling less hungry, headache, shortness of breath, cough, diarrhea, stomach pain, nausea, vomiting, constipation, itching, skin rash, pain in muscle or bones, joint pain, feeling tired, unusual tiredness or weakness, swelling, and fever.

[0278] Embodiment 32. The method of any one of embodiments 27 to 31, wherein a treatment-emergent adverse event is decrease in the number of red blood cells, reduced thyroid gland activity, feeling less hungry, headache, shortness of breath, cough, diarrhea, stomach pain, nausea, vomiting, constipation, itching, skin rash, pain in muscle or bones, joint pain, feeling tired, unusual tiredness or weakness, swelling, fever, lung infection, decrease in the number of platelets, decrease in the number of white blood cell, reactions related to the infusion of the medicine, overactive thyroid gland activity, hot flush or hot flash, decreased sodium, potassium, or calcium in the blood, trouble sleeping, dizziness, inflammation of the nerves causing numbness, weakness, tingling or burning pain of the arms and legs, lack of energy, change in sense of taste, dry eye, abnormal heart rhythm, high blood pressure, inflammation of the lungs, inflammation of the intestines, dry mouth, red raised rash optionally with blisters, patches of skin which havelost color, inflammation of the skin, hair loss, dry or itchy skin, acne-like skin problem, muscle pain, aches or tenderness, pain in arms or legs, joint pain with optional swelling, chills, flu-like illness, increased liver enzyme levels in the blood, increased calcium in the blood, abnormal kidney function test, a decreased number of white blood cells.

[0279] Embodiment 33. The method of embodiment 32, wherein the treatment- emergent adverse event is decrease in the number of red blood cells.

[0280] Embodiment 34. The method of embodiment 32, wherein the treatment- emergent adverse event is reduced thyroid gland activity.

[0281] Embodiment 35. The method of embodiment 32, wherein the treatment- emergent adverse event is feeling less hungry.

[0282] Embodiment 36. The method of embodiment 32, wherein the treatment- emergent adverse event is headache.

[0283] Embodiment 37. The method of embodiment 32, wherein the treatment- emergent adverse event is shortness of breath.

[0284] Embodiment 38. The method of embodiment 32, wherein the treatment- emergent adverse event is cough.

[0285] Embodiment 39. The method of embodiment 32, wherein the treatment- emergent adverse event is diarrhea.

[0286] Embodiment 40. The method of embodiment 32, wherein the treatment- emergent adverse event is stomach pain.

[0287] Embodiment 41. The method of embodiment 32, wherein the treatment- emergent adverse event is nausea.

[0288] Embodiment 42. The method of embodiment 32, wherein the treatment- emergent adverse event is vomiting.

[0289] Embodiment 43. The method of embodiment 32, wherein the treatment- emergent adverse event is constipation.

[0290] Embodiment 44. The method of embodiment 32, wherein the treatment- emergent adverse event is itching.

[0291] Embodiment 45. The method of embodiment 32, wherein the treatment- emergent adverse event is skin rash.

[0292] Embodiment 46. The method of embodiment 32, wherein the treatment- emergent adverse event is pain in muscle or bones.

[0293] Embodiment 47. The method of embodiment 32, wherein the treatment- emergent adverse event is joint pain.

[0294] Embodiment 48. The method of embodiment 32, wherein the treatment- emergent adverse event is feeling tired.

[0295] Embodiment 49. The method of embodiment 32, wherein the treatment- emergent adverse event is unusual tiredness or weakness.

[0296] Embodiment 50. The method of embodiment 32, wherein the treatment- emergent adverse event is swelling.

[0297] Embodiment 51. The method of embodiment 32, wherein the treatment- emergent adverse event is fever.

[0298] Embodiment 52. The method of embodiment 32, wherein the treatment- emergent adverse event is lung infection.

[0299] Embodiment 53. The method of embodiment 32, wherein the treatment- emergent adverse event is decrease in the number of platelets.

[0300] Embodiment 54. The method of embodiment 32, wherein the treatment- emergent adverse event is decrease in the number of white blood cell.

[0301] Embodiment 55. The method of embodiment 32, wherein the treatment- emergent adverse event is reactions related to the infusion of the medicine.

[0302] Embodiment 56. The method of embodiment 32, wherein the treatment- emergent adverse event is overactive thyroid gland activity.

[0303] Embodiment 57. The method of embodiment 32, wherein the treatment- emergent adverse event is hot flush or hot flash.

[0304] Embodiment 58. The method of embodiment 32, wherein the treatment- emergent adverse event is decreased sodium, potassium, or calcium in the blood.

[0305] Embodiment 59. The method of embodiment 32, wherein the treatment- emergent adverse event is trouble sleeping.

[0306] Embodiment 60. The method of embodiment 32, wherein the treatment- emergent adverse event is dizziness.

[0307] Embodiment 61. The method of embodiment 32, wherein the treatment- emergent adverse event is inflammation of the nerves causing numbness.

[0308] Embodiment 62. The method of embodiment 32, wherein the treatment- emergent adverse event is weakness.

[0309] Embodiment 63. The method of embodiment 32, wherein the treatment- emergent adverse event is tingling or burning pain of the arms and legs.

[0310] Embodiment 64. The method of embodiment 32, wherein the treatment- emergent adverse event is lack of energy.

[0311] Embodiment 65. The method of embodiment 32, wherein the treatment- emergent adverse event is change in sense of taste.

[0312] Embodiment 66. The method of embodiment 32, wherein the treatment- emergent adverse event is dry eye.

[0313] Embodiment 67. The method of embodiment 32, wherein the treatment- emergent adverse event is abnormal heart rhythm.

[0314] Embodiment 68. The method of embodiment 32, wherein the treatment- emergent adverse event is high blood pressure.

[0315] Embodiment 69. The method of embodiment 32, wherein the treatment- emergent adverse event is inflammation of the lungs.

[0316] Embodiment 70. The method of embodiment 32, wherein the treatment- emergent adverse event is inflammation of the intestines.

[0317] Embodiment 71. The method of embodiment 32, wherein the treatment- emergent adverse event is dry mouth.

[0318] Embodiment 72. The method of embodiment 32, wherein the treatment- emergent adverse event is red raised rash optionally with blisters.

[0319] Embodiment 73. The method of embodiment 32, wherein the treatment- emergent adverse event is patches of skin which have lost color.

[0320] Embodiment 74. The method of embodiment 32, wherein the treatment- emergent adverse event is inflammation of the skin.

[0321] Embodiment 75. The method of embodiment 32, wherein the treatment- emergent adverse event is hair loss.

[0322] Embodiment 76. The method of embodiment 32, wherein the treatment- emergent adverse event is dry or itchy skin.

[0323] Embodiment 77. The method of embodiment 32, wherein the treatment- emergent adverse event is acne-like skin problem.

[0324] Embodiment 78. The method of embodiment 32, wherein the treatment-emergent adverse event is muscle pain.

[0325] Embodiment 77. The method of embodiment 32, wherein the treatment-emergent adverse event is aches or tenderness.

[0326] Embodiment 80. The method of embodiment 32, wherein the treatment-emergent adverse event is pain in arms or legs.

[0327] Embodiment 81. The method of embodiment 32, wherein the treatment-emergent adverse event is joint pain with optional swelling.

[0328] Embodiment 82. The method of embodiment 32, wherein the treatment-emergent adverse event is chills.

[0329] Embodiment 83. The method of embodiment 32, wherein the treatment-emergent adverse event is flu-like illness.

[0330] Embodiment 84. The method of embodiment 32, wherein the treatment-emergent adverse event is increased liver enzyme levels in the blood.

[0331] Embodiment 85. The method of embodiment 32, wherein the treatment-emergent adverse event is increased calcium in the blood.

[0332] Embodiment 86. The method of embodiment 32, wherein the treatment-emergent adverse event is abnormal kidney function test.

[0333] Embodiment 87. The method of embodiment 32, wherein the treatment-emergent adverse event is a decreased number of white blood cells.

[0334] Embodiment 88. The method of any one of embodiments 22 to 87, wherein when the first dose is about 300 mg, or about 400 mg, the second dose is reduced by about 100 mg.

[0335] Embodiment 89. The method of embodiment 22, further comprising the steps of: (a) administering to a patient in need of such treatment the second dose selected from the group consisting of about 160 mg, about 200 mg, and about 300 mg of a compound of Formula I; (b) monitoring the patient for a dose limiting toxicity; and (c) administering a third dose of the compound of Formula I or Formula II or a combination thereof, if the patient exhibits a dose limiting toxicity, wherein the third dose is reduced as compared to the second dose.

[0336] Embodiment 90. The method of embodiment 89, wherein the dose limiting toxicity occurs during the first 21 days after administering the second dose.

[0337] Embodiment 91. The method of embodiments 89 or 90, wherein a treatment-emergent adverse event is grade 3 or higher.

[0338] Embodiment 92. The method of any one of embodiments 89 to 91, wherein a treatment-emergent adverse event is grade 4.

[0339] Embodiment 93. The method of any one of embodiments 89 to 92, wherein the third dose is reduced by about 100 mg as compared to the second dose when the second dose is about 300 mg.

[0340] Embodiment 94. The method of any one of embodiments 1 to 93, wherein after administration of the compound of Formula I or Formula II or a combination thereof, the patient achieves a partial response.

[0341] Embodiment 95. The method of any one of embodiments 1 to 93, wherein after administration of the compound of Formula I or Formula II or a combination thereof, the patient achieves a complete response.

[0342] Embodiment 96. The method of any one of embodiments 1 to 93, wherein after administration of the compound of Formula I or Formula II or a combination thereof, the patient achieves a stable disease.

[0343] Embodiment 97. A method of treating a cancer comprising administering to a patient in need thereof, a dose between about 160 mg and about 400 mg of a compound of Formula I or Formula II, or a combination thereof, in simultaneous, separate, or sequential combination with a second therapeutic agent.

[0344] Embodiment 98. The method of embodiment 97, wherein the second therapeutic agent is selected from one or more of the group consisting of: a PD-1 inhibitor, a PD-L1 inhibitor, and antibody drug conjugate.

[0345] Embodiment 99. The method of embodiment 98, wherein the PD-1 inhibitor is pembrolizumab.

[0346] Embodiment 100. The method of embodiment 98, wherein the PD-1 inhibitor is nivolumab.

[0347] Embodiment 101. The method of embodiment 98, wherein the PD-1 inhibitor is cemiplimab.

[0348] Embodiment 102. The method of embodiment 98, wherein the PD-1 inhibitor is sintilimab.

[0349] Embodiment 103. The method of embodiment 98, wherein the PD-L1 inhibitor is atezolizumab.

[0350] Embodiment 104. The method of embodiment 98, wherein the PD-L1 inhibitor, is avelumab.

[0351] Embodiment 105. The method of embodiment 98, wherein the PD-L1 inhibitor, is durvalumab.

[0352] Embodiment 106. The method of embodiment 98, wherein the PD-1 inhibitor is pembrolizumab or nivolumab.

[0353] Embodiment 107. The method of embodiment 98, wherein the antibody drug conjugate is enfortumab vedotin.

[0354] Embodiment 108. A method of treating cancer, comprising: administering to a patient in need thereof, a dose between about 160 mg and about 400 mg of a compound of Formula I or Formula II, or a combination thereof, in simultaneous, separate, or sequential combination with pembrolizumab and enfortumab vedotin in the treatment of FGFR3-associated cancer.

[0355] Embodiment 109. Use of a compound of Formula I or Formula II, or a combination thereof , in the manufacture of a medicament for treatment of cancer, wherein the compound of Formula I or Formula II, or a combination thereof , is administered at a dose between about 160 mg and about 400 mg.

[0356] Embodiment 110. The use of embodiment 109, wherein the dose is selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg.

[0357] Embodiment 111. The use of embodiment 109 or 110, wherein the cancer is selected from the group consisting of urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasive urothelial cancer, adjuvant muscle invasive urothelial cancer, muscle invasive bladder cancer, adjuvant muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, and solid tumor malignancy.

[0358] Embodiment 112. The use of any one of embodiments 109 to 111, wherein the dose is administered as a dose between about 160 mg to about 400 mg to the patient at least twice a day.

[0359] Embodiment 113. The use of any one of embodiments 109 to 112, wherein the dose is administered as a dose of about 200 mg to the patient at least twice a day.

[0360] Embodiment 114. The use of any one of embodiments 109 to 112, wherein the dose is administered as a dose of about 300 mg to the patient at least twice a day.

[0361] Embodiment 115. The use of any one of embodiments 109 to 112, wherein the dose is administered as a dose of about 400 mg to the patient at least twice a day.

[0362] Embodiment 116. Use of a compound of Formula I or Formula II , in the manufacture of a medicament for treatment of cancer, wherein the compound of Formula I or Formula II, or a combination thereof, (a) is administered at a first dose selected from the group consisting of about 200 mg, about 300 mg, and about 400 mg; (b) the patient is monitored for dose limiting toxicity; and (c) if the patient exhibits dose limiting toxicity, a second dose of the compound of Formula I or Formula II, is administered, wherein the second dose is reduced as compared to the first dose.

[0363] Embodiment 117. The use of embodiment 116, wherein the first dose is selected from the group consisting of about 200 mg, about 300 mg, and about 400 mg.

[0364] Embodiment 118. The use of embodiments 116 or 117, wherein the second dose is selected from the group consisting of about 160 mg, about 200 mg, and about 300 mg.

[0365] Embodiment 119. The use of any one of embodiments 116 to 118, wherein a treatment-emergent adverse event is any Grade 5 toxicity, or an AE meeting definition criteria of Hy’s Law.

[0366] Embodiment 120. The use of any one of embodiments 116 to 118, wherein a treatment-emergent adverse event is any Grade 3 or greater nonhematologic toxicity except for:Grade 3 or greater electrolyte abnormalities resolving to Grade 2 or baseline if baseline is Grade 2 or greater within 72 hours with supportive treatment, unless the patient has clinical symptoms, in which case all Grade 3 or greater electrolyte abnormality regardless of duration is considered a TEAE, Grade 3 fatigue lasting less than 1 week, Grade 3 nausea, vomiting, diarrhea, or other manageable constitutional symptom that is responsive to supportive therapy and resolves within 72 hours, Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of care for the combination with pembrolizumab only, or AST or ALT less than eight times ULN or AST for patients with hepatic metastases.

[0367] Embodiment 121. The use of any one of embodiments 116 to 118, wherein a treatment-emergent adverse event is any Grade 3 or greater hematologic toxicity except for: Grade 3 neutropenia without fever and not requiring growth factor support for less than 7 days, Grade 3 thrombocytopenia without clinically significant bleeding or requiring platelet transfusion, or Grade 3 leukopenia / lymphopenia.

[0368] Embodiment 122. The use of any one of embodiments 116 to 121, wherein a treatment-emergent adverse event is decrease in the number of red blood cells, reduced thyroid gland activity, feeling less hungry, headache, shortness of breath, cough, diarrhea, stomach pain, nausea, vomiting, constipation, itching, skin rash, pain in muscle or bones, joint pain, feeling tired, unusual tiredness or weakness, swelling, and fever.

[0369] Embodiment 123. The use of any one of embodiments 116 to 119, wherein a treatment-emergent adverse event is decrease in the number of red blood cells, reduced thyroid gland activity, feeling less hungry, headache, shortness of breath, cough, diarrhea, stomach pain, nausea, vomiting, constipation, itching, skin rash, pain in muscle or bones, joint pain, feeling tired, unusual tiredness or weakness, swelling, fever, lung infection, decrease in the number of platelets, decrease in the number of white blood cell, reactions related to the infusion of the medicine, overactive thyroid gland activity, hot flush or hot flash, decreased sodium, potassium, or calcium in the blood, trouble sleeping, dizziness, inflammation of the nerves causing numbness, weakness, tingling or burningpain of the arms and legs, lack of energy, change in sense of taste, dry eye, abnormal heart rhythm, high blood pressure, inflammation of the lungs, inflammation of the intestines, dry mouth, red raised rash optionally with blisters, patches of skin which have lost color, inflammation of the skin, hair loss, dry or itchy skin, acne-like skin problem, muscle pain, aches or tenderness, pain in arms or legs, joint pain with optional swelling, chills, flu-like illness, increased liver enzyme levels in the blood, increased calcium in the blood, abnormal kidney function test, a decreased number of white blood cells.

[0370] Embodiment 124. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is decrease in the number of red blood cells.

[0371] Embodiment 125. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is reduced thyroid gland activity.

[0372] Embodiment 126. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is feeling less hungry.

[0373] Embodiment 127. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is headache.

[0374] Embodiment 128. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is shortness of breath.

[0375] Embodiment 129. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is cough.

[0376] Embodiment 130. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is diarrhea.

[0377] Embodiment 131. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is stomach pain.

[0378] Embodiment 132. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is nausea.

[0379] Embodiment 133. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is vomiting.

[0380] Embodiment 134. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is constipation.

[0381] Embodiment 135. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is itching.

[0382] Embodiment 136. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is skin rash.

[0383] Embodiment 137. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is pain in muscle or bones.

[0384] Embodiment 138. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is joint pain.

[0385] Embodiment 139. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is feeling tired.

[0386] Embodiment 140. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is unusual tiredness or weakness.

[0387] Embodiment 141. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is swelling.

[0388] Embodiment 142. The use of embodiment 122 or 123, wherein the treatment-emergent adverse event is fever.

[0389] Embodiment 143. The use of embodiment 123, wherein the treatment- emergent adverse event is lung infection.

[0390] Embodiment 144. The use of embodiment 123, wherein the treatment- emergent adverse event is decrease in the number of platelets.

[0391] Embodiment 145. The use of embodiment 123, wherein the treatment- emergent adverse event is decrease in the number of white blood cell.

[0392] Embodiment 146. The use of embodiment 123, wherein the treatment- emergent adverse event is reactions related to the infusion of the medicine.

[0393] Embodiment 147. The use of embodiment 123, wherein the treatment- emergent adverse event is overactive thyroid gland activity.

[0394] Embodiment 148. The use of embodiment 123, wherein the treatment- emergent adverse event is hot flush or hot flash.

[0395] Embodiment 149. The use of embodiment 123, wherein the treatment- emergent adverse event is decreased sodium, potassium, or calcium in the blood.

[0396] Embodiment 150. The use of embodiment 123, wherein the treatment- emergent adverse event is trouble sleeping.

[0397] Embodiment 151. The use of embodiment 123, wherein the treatment- emergent adverse event is dizziness.

[0398] Embodiment 152. The use of embodiment 123, wherein the treatment- emergent adverse event is inflammation of the nerves causing numbness.

[0399] Embodiment 153. The use of embodiment 123, wherein the treatment- emergent adverse event is weakness.

[0400] Embodiment 154. The use of embodiment 123, wherein the treatment- emergent adverse event is tingling or burning pain of the arms and legs.

[0401] Embodiment 155. The use of embodiment 123, wherein the treatment- emergent adverse event is lack of energy.

[0402] Embodiment 156. The use of embodiment 123, wherein the treatment- emergent adverse event is change in sense of taste.

[0403] Embodiment 157. The use of embodiment 123, wherein the treatment- emergent adverse event is dry eye.

[0404] Embodiment 158. The use of embodiment 123, wherein the treatment- emergent adverse event is abnormal heart rhythm.

[0405] Embodiment 159. The use of embodiment 123, wherein the treatment- emergent adverse event is high blood pressure.

[0406] Embodiment 160. The use of embodiment 123, wherein the treatment- emergent adverse event is inflammation of the lungs.

[0407] Embodiment 161. The use of embodiment 123, wherein the treatment- emergent adverse event is inflammation of the intestines.

[0408] Embodiment 162. The use of embodiment 123, wherein the treatment- emergent adverse event is dry mouth.

[0409] Embodiment 163. The use of embodiment 123, wherein the treatment- emergent adverse event is red raised rash optionally with blisters.

[0410] Embodiment 164. The use of embodiment 123, wherein the treatment- emergent adverse event is patches of skin which have lost color.

[0411] Embodiment 165. The use of embodiment 123, wherein the treatment- emergent adverse event is inflammation of the skin.

[0412] Embodiment 166. The use of embodiment 123, wherein the treatment- emergent adverse event is hair loss.

[0413] Embodiment 167. The use of embodiment 123, wherein the treatment- emergent adverse event is dry or itchy skin.

[0414] Embodiment 168. The use of embodiment 123, wherein the treatment- emergent adverse event is acne-like skin problem.

[0415] Embodiment 169. The use of embodiment 123, wherein the treatment- emergent adverse event is muscle pain.

[0416] Embodiment 170. The use of embodiment 123, wherein the treatment- emergent adverse event is aches or tenderness.

[0417] Embodiment 171. The use of embodiment 123, wherein the treatment- emergent adverse event is pain in arms or legs.

[0418] Embodiment 172. The use of embodiment 123, wherein the treatment- emergent adverse event is joint pain with optional swelling.

[0419] Embodiment 173. The use of embodiment 123, wherein the treatment- emergent adverse event is chills.

[0420] Embodiment 174. The use of embodiment 123, wherein the treatment- emergent adverse event is flu-like illness.

[0421] Embodiment 175. The use of embodiment 123, wherein the treatment- emergent adverse event is increased liver enzyme levels in the blood.

[0422] Embodiment 176. The use of embodiment 123, wherein the treatment- emergent adverse event is increased calcium in the blood.

[0423] Embodiment 178. The use of embodiment 123, wherein the treatment- emergent adverse event is abnormal kidney function test.

[0424] Embodiment 179. The use of embodiment 123, wherein the treatment- emergent adverse event is a decreased number of white blood cells.

[0425] Embodiment 180. The use of any one of embodiments 109 to 179, wherein when the first dose is about 300 mg, or about 400 mg, the second dose is reduced by about 100 mg.

[0426] Embodiment 181. Use of a compound of Formula I or Formula II, or a combination thereof, administering to a patient in need thereof, a dose between about 160 mg and about 400 mg of the compound of Formula I or Formula II or a combination thereof, in simultaneous, separate, or sequential combination with a second therapeutic agent.

[0427] Embodiment 182. The use of embodiment 181, wherein the second therapeutic agent is selected from one or more of the group consisting of: a PD-1 inhibitor, a PD-L1 inhibitor, and an antibody drug conjugate.

[0428] Embodiment 183. The use of embodiment 182, wherein the PD-1 inhibitor, or the PD-L1 inhibitor, is pembrolizumab.

[0429] Embodiment 184. The use of embodiment 182, wherein the PD-1 inhibitor, or the PD-L1 inhibitor, is nivolumab.

[0430] Embodiment 185. The use of embodiment 182, wherein the PD-1 inhibitor, or the PD-L1 inhibitor, is cemiplimab.

[0431] Embodiment 186. The use of embodiment 182, wherein the PD-1 inhibitor, or the PD-L1 inhibitor, is sintilimab.

[0432] Embodiment 187. The use of embodiment 182, wherein the PD-1 inhibitor, or the PD-L1 inhibitor, is atezolizumab.

[0433] Embodiment 188. The use of embodiment 182, wherein the PD-1 inhibitor, or the PD-L1 inhibitor, is avelumab.

[0434] Embodiment 189. The use of embodiment 182, wherein the PD-1 inhibitor, or the PD-L1 inhibitor, is durvalumab.

[0435] Embodiment 190. The use of embodiment 182, wherein the PD-1 inhibitor, or the PD-L1 inhibitor, is lodapilimab.

[0436] Embodiment 191. The use of embodiment 182, wherein the antibody drug conjugate is enfortumab vedotin.

[0437] Embodiment 192. The use of embodiment 116, wherein the dose of the compound of Formula I or Formula II or a combination thereof, is a reduced dose.

[0438] Embodiment 193. The use of embodiment 192, wherein the dose is reduced about 100 mg when the first dose is about 300 mg or about 400 mg.

[0439] Embodiment 194. The compound of Formula I or Formula II, or a combination thereof, for use in the treatment of cancer wherein the dose of the compound administered is between about 160 mg and about 400 mg.

[0440] Embodiment 195. The compound of Formula I or Formula II, or a combination thereof, for use in the treatment of cancer in a patient wherein:(a) a first dose between about 160 mg and about 400 mg of the compound of Formula I is administered to the patient; (b) the patient is monitored for dose limiting toxicity; and (c) if the patient exhibits dose limiting toxicity, a second dose of the compound of Formula I is administered which is reduced as compared to the first dose.

[0441] Embodiment 196. The compound of Formula I or Formula II or a combination thereof, for use according to embodiment 195, wherein the first dose is selected from the group consisting of about 200 mg, about 300 mg, and about 400 mg.

[0442] Embodiment 197. The compound of Formula I or Formula II or a combination thereof, for use according to embodiment 196, wherein the second dose is selected from the group consisting of about 200 mg, and about 300 mg.

[0443] Embodiment 198. The compound of Formula I or Formula II or a combination thereof for use according to any one of embodiments 194 to 197, wherein the dose is administered to the patient at least once a day.

[0444] Embodiment 199. The compound of Formula I or Formula II or a combination thereof for use according to embodiments 194 to 198, wherein the dose is administered to the patient at least twice a day.

[0445] Embodiment 200. The compound of Formula I or Formula II or a combination thereof for use according to any one of embodiments 194 to 199, wherein the dose is administered to the patient twice a day.

[0446] Embodiment 201. The compound of Formula I or Formula II or a combination thereof for use according to any one of embodiments 194 to 200, in treatment of cancer, wherein the cancer is breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small-cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non- muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasive urothelial cancer, adjuvant muscle invasive urothelial cancer, muscle invasive bladder cancer, adjuvant muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neckcancer, oral cancer, thyroid cancer, renal cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, or testicular cancer.

[0447] Embodiment 202. The compound of Formula I or Formula II or a combination thereof for use according to any one of embodiments 194 to 201, in treatment of cancer, wherein the cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, or metastatic urothelial bladder cancer.

[0448] Embodiment 203. The compound of Formula I or Formula II or a combination thereof for use according to any one of embodiments 194 to 202, in treatment of cancer, wherein the cancer is advanced urothelial cancer or advanced urothelial bladder cancer.

[0449] Embodiment 204. The compound of Formula I or Formula II or a combination thereof for use according to any one of embodiments 194 to 201, in treatment of cancer, wherein the cancer is muscle invasive urothelial cancer or muscle invasive bladder cancer.

[0450] Embodiment 205. The compound of Formula I or Formula II or a combination thereof for use according to any one of embodiments 198 to 201, in treatment of cancer, wherein the dose is selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg.

[0451] Embodiment 206. The compound of Formula I or Formula II or a combination thereof for use according to any one of embodiments 194 to 205, further comprising: monitoring the patient for a dose limiting toxicity; and administering a second dose of the compound of Formula I or Formula II or a combination thereof, if the patient exhibits the dose limiting toxicity, wherein the second dose is reduced as compared to the first dose.

[0452] Embodiment 207. The compound of Formula I or Formula II or a combination thereof, for use according to any one of embodiments 194 to 206, wherein the compound of Formula I or Formula II or a combination thereof, is administered in simultaneous, separate or sequential combination with a second therapeutic agent.

[0453] Embodiment 208. The compound of Formula I or Formula II or a combination thereof, for use according to embodiment 207, wherein the second therapeutic agent is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and an antibody drug conjugate.

[0454] Embodiment 209. The compound of Formula I or Formula II or a combination thereof, for use according to embodiment 208, wherein the PD-1 inhibitor or the PD-L1 inhibitor is pembrolizumab, nivolumab, cemiplimab, sintilimab, dostarlimab, retifanlimab, toripalimab, atezolizumab, avelumab, or durvalumab.

[0455] Embodiment 210. The compound of Formula I or Formula II or a combination thereof, for use according to embodiment 209, wherein the PD-1 inhibitor is pembrolizumab.

[0456] Embodiment 211. The compound of Formula I or Formula II or a combination thereof, for use according to embodiment 209, wherein the PD-1 inhibitor is nivolumab.

[0457] Embodiment 212. The compound of Formula I or Formula II or a combination thereof, for use according to embodiment 208, wherein the antibody drug conjugate is enfortumab vedotin.

[0458] Embodiment 213. A method of treating cancer, comprising: administering to a patient in need thereof, a dose between about 160 mg and about 400 mg of a compound of Formula I or Formula II: I),in simultaneous, separate, or sequential combination with nivolumab in the treatment of FGFR3-associated cancer.

Claims

Claims 1. A method of treating a cancer comprising: administering to a patient in need of such treatment, a dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II: I), II), or a2. The method of claim 1, wherein the compound of Formula I is administered.

3. The method of claims 1 or 2, wherein the dose is selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, about 320 mg, about 400 mg, about 480 mg, about 600 mg, about 640 mg, about 800 mg, about 900 mg, about 1200 mg, and about 1600 mg.

4. The method of any one of claims 1 to 3, wherein the dose is selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg.

5. The method of any one of claims 1-4, wherein the cancer is a FGFR3- associated cancer selected from the group consisting of breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small-cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non-muscle invasive bladder cancer,muscle invasive urothelial cancer, adjuvant muscle invasive urothelial cancer, muscle invasive bladder cancer, adjuvant muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, renal cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, testicular cancer, and solid tumor malignancy.

6. The method of any one of claims 1-5, wherein the cancer is a FGFR3- associated cancer selected from the group consisting of urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasive urothelial cancer, adjuvant muscle invasive urothelial cancer, muscle invasive bladder cancer, adjuvant muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, and solid tumor malignancy.

7. The method of claim 6, wherein the FGFR3-associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, or metastatic urothelial bladder cancer.

8. The method of claim 7, wherein the FGFR3-associated cancer is advanced urothelial cancer or advanced urothelial bladder cancer.

9. The method of claim 8, wherein the FGFR3-associated cancer is advanced urothelial cancer.

10. The method of claim 8, wherein the FGFR3-associated cancer is advanced urothelial bladder cancer.

11. The method of claim 6, wherein the FGFR3-associated cancer is muscle invasive urothelial cancer or muscle invasive bladder cancer.

12. The method of claim 11, wherein the FGFR3-associated cancer is muscle invasive urothelial cancer.

13. The method of claim 11, wherein the FGFR3-associated cancer is muscle invasive bladder cancer.

14. The method of any one of claims 1 to 13, wherein the dose is administered to the patient at least once a day.

15. The method of claim 14, wherein the dose is administered to the patient at least twice a day.

16. The method of claim 14 or 15, wherein the dose is administered to the patient twice a day.

17. The method of any one of claims 1 to 16, wherein the dose is in a capsule.

18. The method of claim 17, wherein the capsule contains about 20 mg, or about 100 mg of the compound of Formula I or Formula II or a combination thereof.

19. The method of any one of claims 1 to 18, comprising: monitoring the patient for a dose limiting toxicity; and administering a second dose of the compound of Formula I or Formula II or a combination thereof, if the patient exhibits the dose limiting toxicity, wherein the second dose is reduced as compared to a first dose.

20. A method of treating a cancer comprising: (a) administering to a patient in need of such treatment a first dose between about 160 mg to about 400 mg of a compound of Formula I or Formula II: I),(b) monitoring the patient for a dose limiting toxicity; and (c) administering a second dose of the compound of Formula I or Formula II or a combination thereof, if the patient exhibits the dose limiting toxicity, wherein the second dose is reduced as compared to the first dose.

21. The method of claim 19 or 20, wherein the first dose is selected from the group consisting of about 200 mg, about 300 mg, and about 400 mg.

22. The method of any one of claims 19 to 21, wherein the second dose is selected from the group consisting of about 160 mg, about 200 mg, and about 300 mg.

23. The method of any one of claims 19 to 22, wherein monitoring occurs during the first 21 days after administering the first dose.

24. The method of any one of claims 19 to 23, wherein the dose limiting toxicity includes a treatment-emergent adverse event.

25. The method of claim 24, wherein the treatment-emergent adverse event is grade 3 or higher.

26. The method of claim 24 or 25, wherein the treatment-emergent adverse event is grade 4.

27. The method of claim 24, wherein the treatment-emergent adverse event is any Grade 5 toxicity; an AE meeting definition criteria of Hy’s Law; any Grade 3 or greater nonhematologic toxicity except for: Grade 3 or greater electrolyte abnormalities resolving to Grade 2 or baseline if baseline is Grade 2 or greater within 72 hours with supportive treatment, unless the patient has clinical symptoms, in which case all Grade 3 or greater electrolyte abnormality regardless of duration is considered a TEAE, Grade 3 fatigue lasting less than 1 week, Grade 3 nausea, vomiting, diarrhea, or other manageable constitutional symptom that is responsive to supportive therapy and resolves within 72 hours, Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of care for the combination with pembrolizumab only, or AST or ALT less than eight times ULN or AST for patients with hepatic metastases; or any Grade 3 or greater hematologic toxicity except for: Grade 3 neutropenia without fever and not requiring growth factor support for less than 7 days, Grade 3 thrombocytopenia without clinically significant bleeding or requiring platelet transfusion, or Grade 3 leukopenia / lymphopenia.

28. The method of any one of claims 19 to 27, further comprising the steps of: (a) monitoring the patient for a dose limiting toxicity after the second dose; and(b) administering a third dose of the compound of Formula I or Formula II or a combination thereof, if the patient exhibits a dose limiting toxicity, wherein the third dose is reduced as compared to the second dose.

29. The method of claim 28, wherein the third dose is reduced by about 100 mg as compared to the second dose when the second dose is about 300 mg.

30. A method of treating a FGFR3-associated cancer comprising: administering to a patient in need thereof, a dose between about 160 mg and about 400 mg of a compound of Formula I or Formula II: I), ,in simultaneous, separate, or sequential combination with a second therapeutic agent.

31. The method of claim 30, wherein the second therapeutic agent is selected from one or more of the group consisting of: a PD-1 inhibitor, a PD-L1 inhibitor, and an antibody drug conjugate.

32. The method of claim 31, wherein the PD-1 inhibitor or the PD-L1 inhibitor is pembrolizumab, nivolumab, cemiplimab, sintilimab, dostarlimab, retifanlimab, toripalimab, atezolizumab, avelumab, or durvalumab.

33. The method of claim 32, wherein the PD-1 inhibitor is pembrolizumab.

34. The method of claim 32, wherein the PD-1 inhibitor is nivolumab.

35. The method of claim 31, wherein the antibody drug conjugate is enfortumab vedotin.

36. A compound of Formula I or Formula II: I), II),wherein the compound of Formula I or Formula II or a combination thereof, is administered at a dose between about 160 mg and about 400 mg.

37. The compound of Formula I or Formula II or a combination thereof for use according to claim 36, wherein the dose is administered to the patient at least once a day.

38. The compound of Formula I or Formula II or a combination thereof for use according to claim 36 or 37, wherein the dose is administered to the patient at least twice a day.

39. The compound of Formula I or Formula II or a combination thereof for use according to any one of claims 36 to 38, wherein the dose is administered to the patient twice a day.

40. The compound of Formula I or Formula II or a combination thereof for use according to any one of claims 36 to 39, in treatment of a FGFR3-associated cancer, wherein the FGFR3-associated cancer is breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small-cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non- muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasiveurothelial cancer, adjuvant muscle invasive urothelial cancer, muscle invasive bladder cancer, adjuvant muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, renal cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, or testicular cancer.

41. The compound of Formula I or Formula II or a combination thereof for use according to any one of claims 36 to 40, in treatment of a FGFR3-associated cancer, wherein the FGFR3-associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, or metastatic urothelial bladder cancer.

42. The compound of Formula I or Formula II or a combination thereof for use according to any one of claims 36 to 41, in treatment of a FGFR3-associated cancer, wherein the FGFR3-associated cancer is advanced urothelial cancer or advanced urothelial bladder cancer.

43. The compound of Formula I or Formula II or a combination thereof for use according to any one of claims 36 to 40, in treatment of a FGFR3-associated cancer, wherein the FGFR3-associated cancer is muscle invasive urothelial cancer or muscle invasive bladder cancer.

44. The compound of Formula I or Formula II or a combination thereof for use according to any one of claims 36 to 43, in treatment of a FGFR3-associated cancer, wherein the dose is selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg.

45. The compound of Formula I or Formula II or a combination thereof for use according to claims 36 to 44, further comprising: monitoring the patient for a dose limiting toxicity; and administering a second dose of the compound of Formula I or Formula II or a combination thereof, if the patient exhibits the dose limiting toxicity, wherein the second dose is reduced as compared to the first dose.

46. The compound of Formula I or Formula II or a combination thereof, according to any one of claims 36 to 45, for use in simultaneous, separate or sequential combination with a second therapeutic agent in the treatment of a FGFR3-associated cancer.

47. The compound of Formula I or Formula II or a combination thereof, for use according to any one of claim 46, wherein the second therapeutic agent is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and an antibody drug conjugate.

48. Use of a compound of Formula I or Formula II: , II), orassociated cancer, wherein the compound of Formula I or Formula II or a combination thereof, is administered at a dose between about 160 mg and about 400 mg.

49. The use of claim 48, wherein the dose is selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg.

50. The use of claim 48 or 49, wherein the FGFR3-associated cancer is breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non- small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small-cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasive urothelial cancer, adjuvant muscle invasive urothelial cancer, muscle invasive bladder cancer, adjuvant muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, gastric cancer, pancreaticcancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, renal cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, or testicular cancer.

51. The use of any one of claims 48 to 50, wherein the FGFR3-associated cancer is advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, or metastatic urothelial bladder cancer.

52. The use of any one of claims 48 to 51, wherein the FGFR3-associated cancer is advanced urothelial cancer or advanced urothelial bladder cancer.

53. The use of any one of claims 48 to 51, wherein the FGFR3-associated cancer is muscle invasive urothelial cancer or muscle invasive bladder cancer.

54. Use of a compound of Formula I or Formula II: I), II), orassociated cancer, wherein the compound of Formula I or Formula II or a combination thereof, is administered at a first dose selected from the group consisting of about 160 mg, about 200 mg, about 300 mg, and about 400 mg; the patient is monitored for dose limiting toxicity; and if the patient exhibits dose limiting toxicity, a second dose of the compound of Formula I or Formula II or a combination thereof, is administered, wherein the second dose is reduced as compared to the first dose.

55. Use of a compound of Formula I or Formula II: I), II), orassociated cancer, wherein the compound of Formula I or Formula II or a combination thereof, is administered at a dose between about 160 mg and about 400 mg of the compound of Formula I or Formula II, in simultaneous, separate, or sequential combination with a second therapeutic agent.

56. The use of claim 55, wherein the second therapeutic agent is selected from the group consisting of: one or more of a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, a PD-L1 inhibitor, and an antibody drug conjugate.

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