Method for treating cancer with oral dosage form of FGFR4 inhibitor

Abstract

To satisfy a need to devise a formulation and dosage regimen of H3B-6527.SOLUTION: The present invention relates to pharmaceutical compositions comprising an inhibitor of FGFR4, and methods of cancer therapy using the FGFR4 inhibitor. In particular, described herein are dosages of H3B-6527 with defined pharmacokinetic (PK) profiles that allow the inhibitor to be efficaciously and safely administered to a human subject in need thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to related applications Not applicable.

Background Art

[0002] Changes in fibroblast growth factor receptor (FGFR) signaling have been shown to correlate with the outcome of patients with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Cheng AL. Eur J Cancer. 2012;48(10):1452 - 1465; and Yoo C. Oncotarget. 2017;8(24):38592 - 38601. Fibroblast growth factor 19 (FGF19) is a protein hormone secreted from the intestine and functions to regulate bile acid synthesis in the liver through FGFR4. FGFR4 is the main receptor for FGF19 and is highly expressed in the liver. According to genomic studies in humans and functional studies in mice, FGF19 is considered to be related as an oncogene in HCC and ICC. Sawey ET. Cancer Cell. 2011;19(3):347 - 358; and Sia D. Gastroenterology. 2013;144(4):829 - 840. Genomic studies have shown that FGF19 is overexpressed in some HCC (about 30%), and it is hypothesized that this overexpression leads to enhanced tumor growth in HCC / ICC because it over - activates FGFR4 and its downstream signaling pathways. Targeting FGFR4 may provide a therapeutic benefit in HCC / ICC with changes in FGF19 signaling. Targeting FGFR4 may provide a therapeutic benefit in sarcomas, particularly rhabdomyosarcomas, with changes in FGF19 signaling.

[0003] Recently, compounds of formula I have been discovered and identified as potent and selective inhibitors of FGFR4:

Chemical formula

[0004] This compound is described in U.S. Patent No. 9,434,697. Various crystalline forms thereof are described in U.S. Patent Application Publication No. 2018 / 0093972. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0005] Formula I has been shown to be effective in in vitro and in vivo models, but the method by which Formula I should be administered to human cancer patients in need of treatment has not yet been determined. Therefore, in order to be able to determine the pharmacokinetic (hereinafter, PK) profile of Formula I, it is necessary to devise a formulation and dosing regimen of H3B-6527 that will enable the inhibitor to be administered effectively and safely to human subjects in need thereof. If the PK profile of Formula I can be estimated, the therapeutic dose or amount of Formula I can be determined and used in a cancer treatment method. When a PK profile that correlates with the efficacy and safety of HCC and sarcoma patients is identified, it will be generally available in human treatment methods for those cancers. MEANS FOR SOLVING THE PROBLEM

[0006] An embodiment is an oral dosage form comprising a compound given by Formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the compound of Formula I has the structure

Chemical formula

[0007] A further embodiment is an oral dosage form comprising a compound given by formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein said formula I is of the structure:

Chemical formula

[0008] A further embodiment is an oral dosage form for administration to a human subject comprising a compound provided by Formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the compound of Formula I has the structure:

Chemical formula

[0009] A further embodiment is an oral dosage form comprising a compound given by formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the compound of formula I has the structure:

Chemical formula

[0010] Another embodiment includes a dosage form as described herein having means for achieving the pharmacokinetic values described herein.

[0011] In some embodiments, the oral dosage form is a capsule comprising an inner phase containing formula I or a pharmaceutically acceptable salt, lactose monohydrate, calcium carbonate, copovidone, low-substituted hydroxypropyl cellulose, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the capsule further comprises an outer phase containing magnesium stearate. In some embodiments, the inner phase is contained in a hypromellose capsule. Some embodiments include the free base form of formula I.

[0012] A further embodiment relates to a method of treating cancer in a human subject comprising administering to the subject an oral dosage form comprising a therapeutically effective amount of a compound provided by formula I, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, wherein said formula I has the structure: [ka] wherein the therapeutically effective amount is a dose in the range of about 300 mg to about 2000 mg of formula I; and the oral dosage form has an average C of formula I of about 10 ng / mL to about 1000 ng / mL. max In some embodiments, the average C of formula I is max In some embodiments, the average C of formula I is about 100 ng / mL to about 400 ng / mL. max In some embodiments, the average C of formula I is about 100 ng / mL to about 300 ng / mL. max In some embodiments, the dosage form has a mean C of Formula I of about 0.5 hours to about 8 hours. max The average of t max In some embodiments, the dosage form has the mean C of about 2 hours to about 6 hours. max The average of t max In some embodiments, the dosage form has the mean C of about 2 hours to about 4 hours. max The average of t max In some embodiments, the dosage form has said average C max The average of t max In a further embodiment, the dosage form comprises from about 500 mg to about 1000 mg of total equivalents of formula I. In a further embodiment, the dosage form comprises from about 1000 to about 1400 mg of total equivalents of formula I.

[0013] A further embodiment is a method for treating cancer in a human subject, the method comprising administering to the subject, once daily, an oral dosage form comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein formula I is the structure:

Chemical formula

[0014] A further embodiment is a method for treating cancer in a human subject, the method comprising administering to the subject an oral dosage form comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein formula I is the structure:

Chemical formula

[0015] A further embodiment is a method of treating cancer in a human subject, comprising administering to said subject an oral dosage form containing a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient twice a day, wherein said Formula I has the structure:

Chemical formula

[0016] In a further embodiment of the methods reported herein, the oral dosage form is a capsule comprising an inner phase comprising Formula I or a pharmaceutically acceptable salt, lactose monohydrate, calcium carbonate, copovidone, low-substituted hydroxypropyl cellulose, colloidal silicon dioxide, and magnesium stearate. In a further embodiment, the capsule further comprises an outer phase comprising magnesium stearate. In a further embodiment, the inner phase is contained within a hypromellose capsule. In a further embodiment, the capsule comprises the free base form of Formula I. In a further embodiment, the cancer is hepatocellular carcinoma. In a further embodiment, the cancer is a sarcoma. In a further embodiment, the cancer is rhabdomyosarcoma. In a further embodiment, the cancer expresses, or overexpresses, FGFR4 or FGF19.

[0017] In some embodiments, the oral dosage form is administered to a human in a fasting state. In some embodiments, the oral dosage form is administered to a human in a fed state.

Brief Description of the Drawings

[0018]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0019] Definition The use of the articles "a", "an", and "the" in this specification shall be construed to include both the singular and the plural, unless specifically indicated otherwise in this specification or clearly inconsistent with the context. For example, the term "a disintegrant" refers to one or more disintegrants suitable for inclusion in or use in the formulations described herein. Similarly, the term "a therapeutically effective amount" refers to one or more therapeutically effective amounts suitable for inclusion in or use in a dosage form.

[0020] The terms "comprising", "having", "including", and "containing" shall be construed as open-ended terms (i.e., meaning "including but not limited to") unless otherwise noted. Additionally, when the term "comprising" or another open-ended term is used in an embodiment, it should always be understood that the scope of the claims for that embodiment can be narrowed using the intermediate term "consisting essentially of" or the closed-ended term "consisting of".

[0021] The expressions "biologically equivalent" or "biological equivalence" are terms of art and are intended to be defined in accordance with the 34th edition of "Approved Drug Products with Therapeutic Equivalence Evaluations", commonly known as the "Orange Book", issued by the U.S. Department of Health and Human Services. The biological equivalence of different formulations of the same active ingredient includes equivalence with respect to the rate and extent of drug absorption. The extent and rate of absorption of the test formulation are compared to the reference formulation to determine whether the two formulations are biologically equivalent. Standard bioequivalence tests are conducted in a crossover manner by a broad test that includes administering a single dose of the test drug and the reference drug to a number of volunteers, usually 12 to 24 normal healthy adults, and then measuring the blood or plasma levels of the drug over time. Detailed guidelines for establishing the biological equivalence of a formulation to its reference formulation have been issued by the Division of Bioequivalence, Office of Generic Drugs, FDA.

[0022] As used herein, the term "mean" refers to the geometric mean determined from a set of independent measurements. For example, the independent measurements may be collected from a statistically meaningful population. As a further example, when used to describe pharmacokinetic parameters (such as "mean C max ", "mean AUC 0-x ", "mean AUC 0-t」、 ", "mean AUC 0-inf ", "mean t max ", or "mean t 1 / 2 " (or "mean half-life")), "mean" refers to the geometric mean pharmacokinetic value derived from the original population from which the individual measurements were collected. Thus, as used herein, a dosage form may be administered to a human subject, where the dosage form has a mean pharmacokinetic value derived from a set of individually measured values.

[0023] The list of abbreviations and definitions of terms used in this application is as follows. AUC: area under the plasma concentration-time curve; AUC 0-x : area under the plasma concentration-time curve from time zero to x hours after administration (for example, x can refer to 12 or 24 hours); AUC 0-t : area under the plasma concentration-time curve from time zero to the last time point at which concentration can be quantified; AUC 0-inf : area under the plasma concentration-time curve from time zero to infinity; ANCOVA: analysis of covariance; CI: confidence interval; C max : maximum plasma concentration; C x : plasma concentration at x hours after administration; CV: coefficient of variation; LC-MS / MS: liquid chromatography-tandem mass spectrometry; MAD: multiple ascending dose; MTD: maximum tolerated dose; PD: pharmacodynamics; PK: pharmacokinetics; RT: reaction time; SAD: single ascending dose; SD: standard deviation; t 1 / 2 : terminal phase elimination half-life; t max : time to reach the highest (peak) concentration after drug administration. When used in this specification, t 1 / 2 includes the terminal phase elimination half-life of the drug concentration, which can be the terminal phase elimination half-life of C max When used in this specification, C max includes the maximum drug concentration of the substance when measured in human plasma.

[0024] Two dosage forms with differences in absorption rate and extent of -20% / +25% or less are generally considered to be "bioequivalent". Another approach for average bioequivalence involves the calculation of a 90% confidence interval for the ratio of the means (population geometric mean values) of the measurements of the test product and the reference product. To establish BE (bioequivalence), this calculated confidence interval must typically fall within the range of 80 to 125% of the ratio of the product means. In addition to this general approach, other approaches can be useful for establishing bioequivalence, including (1) logarithmic transformation of pharmacokinetic data, (2) methods for evaluating sequence effects, and (3) methods for evaluating outlier data. For example, in (1) above, the confidence interval must typically fall within the range of 80 to 125% for the difference in the mean values of the logarithmically transformed PK parameters.

[0025] As used herein, the terms "about", "approximately", or "approximate", when referring to measurable values such as amounts, durations of time, etc., are intended to encompass variations of ±20%, or 10%, more preferably 5%, even more preferably 1%, and still more preferably 0.1% from the specified value, as such variations are appropriate in the given context.

[0026] When the dosage amount or dosage range is referred to by mass or weight in the format of "compound of formula I", or "H3B-6527", or "free base of H3B-6527", one of ordinary skill in the art will understand that a larger mass of the salt will be required to provide the molar equivalent of the active compound as a pharmaceutically acceptable salt than would typically be required when administered as the compound alone (i.e., the amount of the free base and the amount of the salt have a 1:1 molar ratio). For example, the phrase "25 mg to 50 mg of the compound given by formula I or a pharmaceutically acceptable salt thereof" contemplates an amount of the free base of formula I from 25 mg to 50 mg, and also an amount of the monohydrochloride salt of the compound of formula I from 26 mg to 53 mg. This conversion may also be referred to, for example, as a "salt conversion factor", a "salt correction factor", or a "potency adjustment factor".

[0027] Potency adjustment factor conversion is also applicable to hydrates, solvates, or crystalline forms of Formula I that exist as hydrates, solvates, or crystalline forms of Formula I having both i) a hydrate or solvate and ii) a salt counterion. Further, such potency adjustment factor conversion is applicable whether the stoichiometric ratio when the cocrystallized solvent molecules and / or salt counterions are present in crystalline form would be an integer or a non-integer. Accordingly, one of ordinary skill in the art will understand that different potency adjustments can be made for the monohydrochloride of H3B-6527, the hemihydrochloride of H3B-6527, or other ratios such as 1:1.3, 1:1.25, etc.

[0028] Consistent with the foregoing preceding paragraph, as used herein, the “equivalent” amount (e.g., mass, weight, dosage, etc.) of Formula I (or H3B-6527, the free base of H3B-6527 or any other of its synonyms as used herein) refers to the amount of any salt and / or hydrate according to its potency adjustment factor.

[0029] “H3B-6527 drug substance” refers to the free base of H3B-6527 as reported in U.S. Patent No. 10,562,888, which is incorporated herein by reference.

[0030] As used herein, “human subject” is synonymous with “human subject in need of treatment” or “human subject requiring the same,” all of which refer to a human subject having hepatocellular carcinoma or sarcoma, or a human subject having a higher risk of developing hepatocellular carcinoma or sarcoma compared to the entire population. A human subject in need of the same may be one who has been diagnosed or identified as having had hepatocellular carcinoma or sarcoma or a pre-cancerous condition in the past. Alternatively, a human subject in need of the same may be one who has a higher risk of developing such a disorder compared to the entire population (i.e., a subject having a predisposition to developing such a disorder more easily compared to the entire population). A human subject in need of the same may have a pre-cancerous condition.

[0031] The human subject in need thereof can have refractory or resistant cancer (i.e., cancer that does not respond to treatment or has not yet responded to treatment). The subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof has a cancer recurrence after remission with a recent therapy. In some embodiments, the subject in need thereof has failed all known effective therapies for cancer treatment. In some embodiments, the subject in need thereof has received at least one prior therapy. In a preferred embodiment, the subject has cancer or a cancerous condition.

[0032] As used herein, "fasting condition" refers to a human subject in need thereof who has undergone an overnight fast of at least 10 hours prior to administration. No food shall be permitted for at least 4 hours after administration. Water may be permitted as needed, except for 1 hour before and after drug administration.

[0033] As used herein, "fed state" refers to a human subject who has fasted for 2 hours prior to pharmacokinetic evaluation and has eaten a meal before or in conjunction with the administration of the test drug.

[0034] As used herein, "treating" or "treatment" refers to the management and care of a human subject for the purpose of combating a disease, condition, or disorder, and includes reducing the symptoms or complications of a disease, condition, or disorder, or eliminating the disease, condition, or disorder, by administration of a dosage form of H3B-6527, or a pharmaceutically acceptable salt, polymorph, hydrate, or solvate thereof.

[0035] H3B-6527, or a pharmaceutically acceptable salt and / or solvate thereof, can also be used, or may be used, for the prevention of a related disease, condition, or disorder, or for the identification of suitable candidates for such purposes. As used herein, "preventing", "prevention", or "preventing... from" refers to reducing or eliminating the occurrence of symptoms or complications of such a disease, condition, or disorder.

[0036] As used herein, "sample" means any biological sample derived from a human subject, including but not limited to cells, tissue samples, body fluids (including but not limited to mucus, blood, plasma, serum, urine, saliva, and semen), tumor cells, and tumor tissue. Preferably, the sample is selected from bone marrow, peripheral blood cells, blood, plasma, and serum. The sample can be provided by a subject under treatment or examination. Alternatively, the sample may be obtained by a physician in the ordinary course of business in the art.

[0037] As used herein, the term "dosage form" refers to a physically discrete unit suitable as a unit dosage for a human subject to be treated; each unit contains a predetermined amount of an active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Dosage forms are classified in terms of the route of administration and site of application, including, for example, oral, topical, rectal, vaginal, intravenous, subcutaneous, intramuscular, ophthalmic, nasal, otic, and inhalation administration. Alternatively, dosage forms are classified in terms of physical form, such as solid, semi-solid, or liquid. Dosage forms can be in any of a variety of forms, including, for example, an IV bag, tablets, an aerosol inhaler with a single pump or vial attached. "Oral dosage form" refers to a dosage form that is easy to administer orally to a human subject. Non-limiting examples of oral dosage forms include capsules and tablets. The amount of the active ingredient (e.g., a formulation of the disclosed compound or a salt, hydrate, or solvate thereof) in a unit dose is an effective amount, which will vary depending on the particulars of the treatment involved.

[0038] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, carriers, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, or other problems or complications within the scope of sound medical judgment and commensurate with a reasonable risk / benefit ratio.

[0039] As used herein, the phrase "pharmaceutically acceptable excipient" generally means an excipient useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients acceptable for use in animals and for use as human pharmaceuticals. "Pharmaceutically acceptable excipient" includes one and both one or more such excipients when used herein and in the claims. For example, pharmaceutically acceptable excipients used in the formulations of the present invention can be diluents or inert carriers, lubricants, binders, or combinations thereof. Pharmaceutically acceptable excipients used in the formulations of the present invention further include fillers, antibacterial agents, antioxidants, anti-caking agents, coating agents, or mixtures thereof.

[0040] As used herein, the term "composition" includes a product containing specific ingredients in specific amounts and any product directly or indirectly resulting from a combination of specific amounts of specific ingredients. Such term includes, when it relates to a pharmaceutical composition, a product containing an active ingredient (herein, any of Formula I or a pharmaceutically acceptable salt, hydrate and / or solvate thereof) and an inert ingredient constituting a carrier, and is intended to include any product directly or indirectly resulting from a combination, complexation or aggregation of any two or more ingredients, or dissociation of one or more ingredients, or other types of reaction or interaction. Accordingly, pharmaceutical compositions of the present invention include any composition prepared by mixing a compound provided by Formula I (or a pharmaceutically acceptable salt, hydrate and / or solvate) with a pharmaceutically acceptable excipient.

[0041] As used herein, the term "therapeutically effective amount" refers to the amount of H3B-6527 that can produce a therapeutic effect in a human subject. A therapeutically effective amount is an amount that can treat, ameliorate, or prevent an identified disease or condition, or an amount that exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective amount for a particular subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0042] In a preferred embodiment, the disease or condition to be treated is cancer. In another embodiment, the disease or condition to be treated is a cell proliferative disorder. The therapeutically effective amount of H3B-6527 may be administered in a dosage form. The therapeutically effective amount of H3B-6527 may be in the form of the free base, a pharmaceutically acceptable salt, a solvate, and / or a hydrate.

[0043] As used herein, "therapeutic effect" is the outcome of any kind of medical treatment, the result of which is judged to be desirable and beneficial. This applies whether the result is the expected outcome of the treatment, an unexpected outcome, or even an unintended outcome. Desirable or beneficial results may include inhibition of an altered cell signaling pathway, inhibition of cell growth, preferably cancer cell growth, promotion of cell death, preferably cancer cell death, or reduction of a tumor, all of which are observed without severe adverse effects. Slowing the growth of a tumor, preferably shrinking it, and more preferably causing complete regression of cancer are also examples of therapeutic effects. A therapeutic effect can also be an objectively identifiable improvement as recognized by a clinician or other qualified observer. For example, regression of a patient's tumor may be measured based on the diameter of the tumor. A decrease in the diameter of the tumor indicates regression. Regression is also indicated by the non-recurrence of the tumor after discontinuation of treatment.

[0044] Serious adverse effects may include those that threaten life (such as liver failure, abnormal heart rhythm, and certain types of allergic reactions), those that cause persistent or significant physical impairment or hospitalization, or those that cause congenital abnormalities.

[0045] As used herein, "pharmaceutically acceptable salt" refers to derivatives of H3B-6527 in which the parent compound is modified by making its acidic or basic salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed with, for example, non-toxic inorganic or organic acids.

[0046] As used herein, "quantifiable" means capable of being measured, calculated, or expressed as a quantity or numerical value. A quantifiable plasma concentration is the concentration of H3B-6527 that can be detected and measured in the plasma of a human subject after administration. A quantifiable AUC bioavailability is the proportion of H3B-6527 that reaches the systemic circulation of a human subject that can be calculated from the analysis of the plasma concentration of H3B-6527 in plasma samples taken from the human subject over a set period of time. A quantifiable half-life is the detectable or calculated time at which the plasma concentration of H3B-6527 decreases by 50% along the concentration-time curve of H3B-6527. Methods and materials necessary for quantifying the aforementioned PK parameters are generally known to those of ordinary skill in the art. Specific quantification methods are presented in this application.

[0047] As used herein, the term "solvate" means a solvate form containing a solvent in either a stoichiometric or non-stoichiometric amount.

[0048] Unless specifically stated or otherwise apparent from the context, as used herein, the term "or" is understood to be inclusive.

[0049] Aspects of the invention provide a dosage form comprising a therapeutically effective amount of H3B-6527, or a pharmaceutically acceptable salt thereof, which can be administered to a human subject in need thereof, and at least one pharmaceutically acceptable carrier or excipient, wherein the therapeutically effective amount achieves a quantifiable plasma concentration after administration.

[0050] In certain embodiments of the invention, the dosage form is an oral dosage form. In another embodiment of the invention, the dosage form is a solid dosage form. In another embodiment of the invention, the dosage form is a solid oral dosage form. In yet another embodiment, the solid oral dosage form may be an immediate release oral solid dosage form. The oral solid dosage form may be in the form of a tablet or a capsule. These forms may have multiple phases, for example, including an inner phase and an outer phase.

[0051] In one embodiment, the dosage form is substantially free of water. In this context, "substantially" free of water means that the water content of the formulation at the time of packaging is less than 7%, less than 5%, less than 1%, or less than 0.5% of the total weight of the formulation. In one embodiment, the amount of water is from 0.1% to 5% (e.g., 0.1% to 1% or 0.1% to 0.5%) of the total weight of the formulation. In one embodiment, the amount of water in a formulation of the invention produced via a spray coating process is less than 0.5%.

[0052] The at least one pharmaceutically acceptable excipient may be a diluent or inert carrier, a disintegrant, a lubricant, a binder, or a combination thereof. Pharmaceutically acceptable excipients may also include fillers, antibacterial agents, antioxidants, anti-caking agents, coating agents, or mixtures thereof.

[0053] Exemplary binders include, but are not limited to, corn starch, potato starch, other starches, gelatin, natural and synthetic rubbers such as acacia, xanthan, sodium alginate, alginic acid, other alginates, tragacanth powder, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone (e.g., povidone, crospovidone, copovidone, etc.), methyl cellulose, methocel, pregelatinized starch (e.g., STARCH 1500 (registered trademark) and STARCH 1500 LM (registered trademark), sold by Colorcon, Ltd.), hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose (FMC Corporation, Marcus Hook, PA, USA), Emdex, Plasdone, or mixtures thereof; fillers such as talc, calcium carbonate (e.g., granules or powder), calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silica, sorbitol, starch, pregelatinized starch, dextrose, fructose, honey, lactose anhydrous, lactose monohydrate, lactose and aspartame, lactose and cellulose, lactose and microcrystalline cellulose, maltodextrin, maltose, mannitol, microcrystalline cellulose & guar gum, molasses, sucrose, or mixtures thereof.

[0054] Exemplary disintegrants include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polyacrilin potassium, sodium starch glycolate (such as Explotab), potato or tapioca starch, other starches, pregelatinized starch, clay, other algins, other celluloses, gums (such as gellan), low-substituted hydroxypropyl cellulose, polyplasdone, or mixtures thereof.

[0055] Exemplary lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, Compritol, stearic acid, sodium lauryl sulfate, sodium stearyl fumarate (such as Pruv), plant-derived fatty acid lubricants, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, Syloid silica gel (AEROSIL 200, W.R. Grace Co., Baltimore, MD, USA), coagulated aerosol of synthetic silica (Deaussa Co., Piano, TX, USA), pyrogenic silicon dioxide (CAB-O-SIL, Cabot Co., Boston, MA, USA), or mixtures thereof.

[0056] Exemplary coating agents include, but are not limited to, sodium carboxymethyl cellulose, cellulose acetate phthalate, ethyl cellulose, gelatin, pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose), hydroxypropyl methyl cellulose phthalate, methyl cellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, gellan gum, maltodextrin, methacrylates, microcrystalline cellulose, and carrageenan, or mixtures thereof.

[0057] In one embodiment, the dosage form may optionally be treated with a coating system (e.g., Opadry® fx film coating system), for example, a solid oral dosage form that will be coated with Opadry® Blue (OY-LS-20921), Opadry® White (YS-2-7063), Opadry® White (YS-1-7040), and black ink (S-1-8106).

[0058] In one embodiment, the oral dosage form is configured to be a capsule having an inner phase comprising a therapeutically effective amount of H3B-6527 or a pharmaceutically acceptable salt thereof, lactose monohydrate, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose, and colloidal anhydrous silica. The capsule also comprises an outer phase comprising magnesium stearate.

[0059] In one embodiment, the capsule is hypromellose.

[0060] In another embodiment, the capsule is hypromellose and further comprises red iron oxide and titanium dioxide.

[0061] Pharmaceutically acceptable salts can include, for example, conventional non-toxic salts of the parent compound or quaternary ammonium salts formed with non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicyclic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and those derived from common amino acids such as glycine, alanine, phenylalanine, arginine, etc., selected from inorganic and organic acids.

[0062] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, and the like. The present invention also includes salts formed when the acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when it coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, or the like. In salt form, the ratio of the compound to the cation or anion of the salt may be 1:1 or any ratio other than 1:1, for example, 3:1, 2:1, 1:2, or 1:3.

[0063] In another embodiment, the dosage form may also include one or more active compounds (e.g., H3B-6527 or a salt thereof) in combination with at least one pharmaceutically acceptable excipient or carrier.

[0064] Examples of solvates can be given. When the solvent is water, the solvate formed is a hydrate; and when the solvent is an alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more molecules of water with one molecule of the substance, where water retains its molecular state as H 2 O. A hemihydrate is formed by the combination of one molecule of water with two or more molecules of the substance, where water retains its molecular state as H 2 O.

[0065] An oral dosage form comprising a therapeutically effective amount of H3B-6527, or a pharmaceutically acceptable salt thereof, which can be administered to a human subject in need thereof, and at least one pharmaceutically acceptable carrier or excipient, can achieve a quantifiable plasma concentration at about 2 hours to about 6 hours, about 3 hours to about 5 hours, about 3 hours to about 4 hours, or about 4 hours after administration.

[0066] The therapeutically effective amount of H3B-6527, or a pharmaceutically acceptable salt thereof, that may be present in the oral dosage form ranges from about 300 mg to about 2000 mg, about 500 mg to about 1400 mg, about 600 mg to about 1000 mg, or about 600 mg to about 700 mg.

[0067] An oral dosage form comprising a therapeutically effective amount of H3B-6527, or a pharmaceutically acceptable salt thereof, which can be administered to a human subject in need thereof, and at least one pharmaceutically acceptable carrier or excipient, can achieve a quantifiable maximum plasma concentration of about 10 ng / mL to about 900 ng / mL, about 20 ng / mL to about 800 ng / mL, about 100 ng / mL to about 400 ng / mL, or about 150 ng / mL to about 250 ng / mL after administration.

[0068] An oral dosage form comprising a therapeutically effective amount of H3B-6527, or a pharmaceutically acceptable salt thereof, which can be administered to a human subject in need thereof, and at least one pharmaceutically acceptable carrier or excipient, can achieve a half-life at about 2 hours to about 7 hours, about 2 hours to about 5 hours, about 3 hours to about 4 hours, or about 4 hours after administration.

[0069] An oral dosage form comprising a therapeutically effective amount of H3B-6527, or a pharmaceutically acceptable salt thereof, which can be administered to a human subject in need thereof, and at least one pharmaceutically acceptable carrier or excipient, can achieve a quantifiable AUC bioavailability of about 50 ng·hr / mL to about 7,000 ng·hr / mL, about 150 ng·hr / mL to about 5,700 ng·hr / mL, about 400 ng·hr / mL to about 700 ng·hr / mL, or about 500 ng·hr / mL to about 650 ng·hr / mL after administration.

[0070] An oral dosage form comprising a therapeutically effective amount of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient, which can be administered to a human subject in need thereof, may be orally administered once daily as a single dose during an 8-day cycle, a 15-day cycle, a 20-day cycle, a 21-day cycle, a 22-day cycle, a 23-day cycle, a 24-day cycle, a 25-day cycle, a 26-day cycle, a 27-day cycle, a 28-day cycle, or until a therapeutic effect occurs in the body of the subject in need thereof. The dosage form may also be administered in a cycle of less than 20 days.

[0071] A. An oral dosage form comprising from about 300 mg to about 2000 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0072] In some embodiments, the oral dosage form comprises from about 300 mg to about 2,000 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, this dosing achieves a quantifiable maximum plasma concentration, Cmax (in ng / mL units), of about 100 ng / mL to about 970 ng / mL after administration to a subject in need of treatment at fed state. In other embodiments, this dosing achieves a quantifiable maximum plasma concentration of about 150 ng / mL to about 850 ng / mL after administration to a subject in need of treatment at fed state. In other embodiments, this dosing achieves a quantifiable maximum plasma concentration of about 250 ng / mL to about 650 ng / mL after administration to a subject in need of treatment at fed state. In other embodiments, this dosing achieves a quantifiable maximum plasma concentration of about 350 ng / mL to about 550 ng / mL after administration to a subject in need of treatment at fed state. In these embodiments, the presented Cmax may be achieved at a time of about 2 hours to about 6 hours; about 2 hours to about 4 hours; about 4 hours to about 6 hours; or about 5 hours.

[0073] In some embodiments, the oral dosage form comprises from about 300 mg to about 2,000 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some of those embodiments, this dosage form achieves a half-life of from about 2.0 hours to about 7.0 hours; a half-life of from about 3.0 hours to about 6.0 hours; or a half-life of from about 4.0 hours to about 5.0 hours after administration to a human subject in need thereof with food.

[0074] In one embodiment, the oral dosage form comprises from about 300 mg to about 2,000 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In such embodiments, this dosage may achieve a quantifiable AUC bioavailability (0 - 12 or 0 - 24) of from about 500 ng·hr / mL to about 7,000 ng·hr / mL; from about 1,000 ng·hr / mL to about 5,070 ng·hr / mL; from about 3,000 ng·hr / mL to about 5,070 ng·hr / mL; or from about 1,000 ng·hr / mL to about 3,100 ng·hr / mL after administration to a human subject in need thereof with food.

[0075] In some embodiments, the oral dosage form comprises from about 300 mg to about 2,000 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, this dosage achieves a quantifiable maximum plasma concentration, Cmax (in ng / mL units), of from about 10 ng / mL to about 370 ng / mL after administration to a subject in need of treatment in the fasting state. In other embodiments, this dosage achieves a quantifiable maximum plasma concentration of from about 20 ng / mL to about 146 ng / mL after administration to a subject in need of treatment in the fasting state. In other embodiments, this dosage achieves a quantifiable maximum plasma concentration of from about 100 ng / mL to about 260 ng / mL after administration to a subject in need of treatment in the fasting state. In these embodiments, the presented Cmax may be achieved at a time of from about 0.5 hours to about 4 hours; from about 0.5 hours to about 2 hours; from about 1 hour to about 3 hours; or about 2 hours.

[0076] In some embodiments, an oral dosage form comprises from about 300 mg to about 2,000 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some of those embodiments, this dosage form achieves a half-life of from about 1.0 hour to about 6.0 hours; a half-life of from about 2.0 hours to about 5.0 hours; or a half-life of from about 3.0 hours to about 4.0 hours after administration to a human subject in need thereof in a fasting state.

[0077] In one embodiment, an oral dosage form comprises from about 300 mg to about 2,000 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In such embodiments, this dosage achieves a quantifiable AUC bioavailability (0 - 12 or 0 - 24) of from about 50 ng·hr / mL to about 1,500 ng·hr / mL; from about 400 ng·hr / mL to about 1,500 ng·hr / mL; from about 400 ng·hr / mL to about 1,000 ng·hr / mL; or from about 400 ng·hr / mL to about 650 ng·hr / mL after administration to a human subject in need thereof in a fasting state.

[0078] B. An oral dosage form comprising from about 300 mg to about 700 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0079] In some embodiments, the oral dosage form comprises from about 300 mg to about 700 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, this dosage achieves a quantifiable maximum plasma concentration, Cmax (in ng / mL), of from about 100 ng / mL to about 270 ng / mL after administration to a subject in need of treatment at the time of a meal. In other embodiments, this dosage achieves a quantifiable maximum plasma concentration of from about 163 ng / mL to about 255 ng / mL after administration to a subject in need of treatment at the time of a meal. In other embodiments, this dosage achieves a quantifiable maximum plasma concentration of from about 150 ng / mL to about 241 ng / mL after administration to a subject in need of treatment at the time of a meal. In these embodiments, the presented Cmax can be achieved in a time of from about 2 hours to about 4 hours.

[0080] In some embodiments, the oral dosage form comprises from about 300 mg to about 700 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some of those embodiments, this dosage form achieves a half-life of from about 2.0 hours to about 4.0 hours; or from about 2.0 hours to about 3.0 hours after administration to a human subject in need thereof at the time of a meal.

[0081] In one embodiment, the oral dosage form comprises from about 300 mg to about 700 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In such embodiments, this dosage can achieve a quantifiable AUC bioavailability (0 - 12 or 0 - 24) of from about 500 ng·hr / mL to about 1,300 ng·hr / mL; from about 500 ng·hr / mL to about 1,000 ng·hr / mL; from about 500 ng·hr / mL to about 800 ng·hr / mL; or from about 500 ng·hr / mL to about 650 ng·hr / mL after administration to a human subject in need thereof at the time of a meal.

[0082] In some embodiments, the oral dosage form comprises from about 300 mg to about 700 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, this dosage achieves a quantifiable maximum plasma concentration, Cmax (in ng / mL), of from about 11 ng / mL to about 255 ng / mL after administration to a subject in need of treatment in the fasting state. In other embodiments, this dosage achieves a quantifiable maximum plasma concentration of from about 20 ng / mL to about 125 ng / mL after administration to a subject in need of treatment in the fasting state. In other embodiments, this dosage achieves a quantifiable maximum plasma concentration of from about 11 ng / mL to about 200 ng / mL after administration to a subject in need of treatment in the fasting state. In these embodiments, the Cmax presented can be achieved at a time of from about 0.5 hours to about 4 hours; from about 0.5 hours to about 2 hours; from about 1 hour to about 3 hours; or about 2 hours.

[0083] In some embodiments, the oral dosage form comprises from about 300 mg to about 700 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some of those embodiments, this dosage form achieves a half-life of from about 1.0 hour to about 5.0 hours; from about 2.0 hours to about 4.0 hours; or from about 3.0 hours to about 4.0 hours after administration to a human subject in need of it in the fasting state.

[0084] In one embodiment, the oral dosage form comprises from about 300 mg to about 700 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In such embodiments, this dosage can achieve a quantifiable AUC bioavailability (0 - 12 or 0 - 24) of from about 50 ng·hr / mL to about 1,200 ng·hr / mL; from about 50 ng·hr / mL to about 650 ng·hr / mL; from about 50 ng·hr / mL to about 200 ng·hr / mL; or from about 400 ng·hr / mL to about 650 ng·hr / mL after administration to a human subject in need of it in the fasting state.

[0085] An oral dosage form comprising from about 1000 mg to about 2000 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0086] In some embodiments, the oral dosage form comprises from about 1,000 mg to about 2,000 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, this dosage achieves a quantifiable maximum plasma concentration, Cmax (in ng / mL), of from about 182 ng / mL to about 965 ng / mL after administration to a subject in need of treatment at fed state. In other embodiments, this dosage achieves a quantifiable maximum plasma concentration of from about 182 ng / mL to about 904 ng / mL after administration to a subject in need of treatment at fed state. In other embodiments, this dosage achieves a quantifiable maximum plasma concentration of from about 650 ng / mL to about 965 ng / mL after administration to a subject in need of treatment at fed state. In these embodiments, the presented Cmax can be achieved at a time of from about 2 hours to about 6 hours; from about 3 hours to about 5 hours; from about 2 hours to about 4 hours; or about 4 hours.

[0087] In some embodiments, the oral dosage form comprises from about 1,000 mg to about 2,000 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some of those embodiments, this dosage form achieves a half-life of from about 3.0 hours to about 7.0 hours; a half-life of from about 4.0 hours to 6.0 hours; or a half-life of from about 4.0 hours to about 5.0 hours after administration to a human subject in need thereof at fed state.

[0088] In one embodiment, the oral dosage form comprises about 1,000 mg to about 2,000 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In such an embodiment, this dosage, after administration to a human subject in need thereof with a meal, can achieve a quantifiable AUC bioavailability (0 - 12 or 0 - 24) of about 800 ng·hr / mL to about 7,000 ng·hr / mL; about 1,000 ng·hr / mL to about 6,000 ng·hr / mL; about 3,000 ng·hr / mL to about 6,000 ng·hr / mL; or about 5,000 ng·hr / mL to about 7,000 ng·hr / mL.

[0089] In some embodiments, the oral dosage form comprises about 1,000 mg to about 2,000 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, this dosage, after administration to a subject in need of treatment in the fasting state, achieves a quantifiable maximum plasma concentration, Cmax (in ng / mL units), of about 135 ng / mL to about 365 ng / mL. In other embodiments, this dosage, after administration to a subject in need of treatment in the fasting state, achieves a quantifiable maximum plasma concentration of about 130 ng / mL to about 150 ng / mL. In other embodiments, this dosage, after administration to a subject in need of treatment in the fasting state, achieves a quantifiable maximum plasma concentration of about 195 ng / mL to about 365 ng / mL. In these embodiments, the presented Cmax can be achieved in a time of about 1 hour to about 2 hours.

[0090] In some embodiments, the oral dosage form comprises about 1,000 mg to about 2,000 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some of those embodiments, the dosage form achieves a half-life of about 4.0 hours to about 5.0 hours after administration to a human subject in need thereof in the fasting state.

[0091] In one embodiment, the oral dosage form comprises about 1,000 mg to about 2,000 mg of H3B-6527, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In such an embodiment, dosing can achieve a quantifiable AUC bioavailability (0 - 12 or 0 - 24) of about 400 ng·hr / mL to about 1,500 ng·hr / mL; about 400 ng·hr / mL to about 1,000 ng·hr / mL; about 400 ng·hr / mL to about 650 ng·hr / mL; or about 600 ng·hr / mL to about 1,500 ng·hr / mL after administration to a human subject in need thereof in the fasting state.

Example

[0092] Example Example 1: Capsule formulation Capsules of 50 mg, 100 mg and 200 mg strengths were formulated as shown in the following table:

[0093]

Table 1

[0094]

Table 2

[0095]

Table 3

[0096] The capsules are formed as follows: The H3B-6527 active pharmaceutical ingredient, lactose monohydrate, calcium carbonate, copovidone, low-substituted hydroxypropyl cellulose and colloidal silicon dioxide are placed in a high-shear mixer and mixed to form a first mixture. Next, the first mixture and magnesium stearate are mixed using a high-shear mixer to form a final mixture. This final mixture is granulated by its compression into a ribbon using a roller compactor and then classification by passing the resulting ribbon through a sieve. The classified granules are filled into HPMC capsules using an encapsulator. Capsules with overweight and underweight are removed using a weight inspection machine.

[0097] Example 2: Pharmacokinetic (PK) measurements of the capsules in patients For a description of the first-in-human clinical trial of H3B-6527, reference can be made by searching at ClinicalTrials.gov with the trial identifier NCT02834780. Briefly, this trial incorporated a study population with the following characteristics: adult patients aged 18 years or older with advanced HCC or ICC; progression after at least one previous treatment; ECOG score 0 or 1; sufficient compensated liver function; FGF19 positive (only in the dose escalation phase); patients were excluded if they had serious active infections (excluding hepatitis B virus (HBV) and hepatitis C virus (HCV)), gastric or esophageal varices, or a history of FGF19-FGFR4 targeted therapy.

[0098] Blood samples are collected from each patient at the planned time points and centrifuged. Next, the plasma fraction of each sample is transferred to a K2EDTA tube and then shipped to a bioanalytical laboratory for concentration measurement using LC-MS / MS. Next, the concentration data are analyzed using Phoenix (registered trademark) WinNonlin software to obtain PK parameters. The obtained PK parameters are further summarized using analytical software.

[0099] Drug Administration and Dosage for Dose Escalation: H3B-6527 was orally administered QD or BID in 21-day cycles. Dose escalation followed the standard 3+3 cohort design with dose cohorts of 300, 600, 1000, and 1400 mg QD fasting or 500 and 700 mg BID fed. Patients in the dose escalation phase were treated regardless of FGF19 status. Efficacy was determined by RECIST 1.1 / Modified RECIST every 6 weeks.

[0100] Pharmacokinetic (PK) Results: · H3B-6527 was rapidly absorbed, with a plasma t max median of approximately 1 - 3 hours (fasting). · H3B-6527 plasma levels increased with dose up to 1000 mg QD and reached a plateau (fasting) (Figure 1). · H3B-6527 showed an average terminal-phase half-life of approximately 4 - 5 hours after a 1000 mg dose (fasting). · Figure 1. Mean plasma-concentration time profile of H3B-6527 (Cycle 1, Day 8). Preliminary PK analysis showed that H3B-6527 plasma exposure increased with dose up to 1000 mg QD in the fasting state. With the BID schedule, higher minimum plasma concentrations were maintained.

[0101] For the once-daily fasting schedule: · Two (7.4%) HCC patients achieved partial response. · Twenty (74.1%) had disease stabilization.

[0102]

Table 4

[0103] Figure 2. Tumor Efficacy and Duration of H3B-6527 Treatment. Shows the duration of treatment with H3B-6527 at 300 - 1400 mg QD in HCC patients in the full analysis set. CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease, and NE = Not Evaluated.

[0104] Figure 3 shows the change rate of the total diameter of the target lesions as measured for this example.

[0105] Example 3: Further PK Analysis The PK results available at the time points after the clinical trial of Example 2 were further collected and reconciled as reflected in Table 5 below:

[0106] [Table 5]

[0107] All publications and patent documents cited in this specification are hereby incorporated by reference as if each such publication or document had been specifically and individually indicated to be incorporated by reference herein. The citation of publications and patent documents is not intended as an admission that any of them are relevant prior art, nor does it constitute any admission as to their content or date. Herein, the present invention has been described with reference to the description herein, but those skilled in the art will recognize that the present invention can be implemented in various embodiments, and that the foregoing description and the following examples are for purposes of illustration and not limitation of the following claims.

[0108] The present invention can be embodied in other specific forms without departing from its spirit or essential characteristics. Accordingly, the foregoing embodiments are to be considered in all respects as illustrative rather than restrictive of the invention described herein. Thus, the scope of the present invention is indicated not by the foregoing description, but rather by the appended claims, and all modifications that come within the meaning and range of equivalents of the claims are intended to be embraced therein.

Claims

1. i) a compound provided by formula I or a pharma- ceutically acceptable salt thereof, and ii) at least one pharma- ceutically acceptable excipient; 1. An oral dosage form comprising: The compound of formula I has the structure: 【Chemistry 1】 N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide represented by the formula: The oral dosage form, when orally administered to a human subject, has a mean C of about 10 ng / mL to about 1000 ng / mL of Formula I ｍａｘ The oral dosage form is formulated to achieve the following:

2. The average C of formula I ｍａｘ is from about 100 ng / mL to about 400 ng / mL.

3. The average C of formula I ｍａｘ is from about 100 ng / mL to about 300 ng / mL.

4. The average C of formula I ｍａｘ but, From 80% to 125% of 100 ng / mL 80% to 125% of 400 ng / mL 2. The oral dosage form of claim 1, wherein the .alpha.-

5. About 0.5 hours to about 8 hours ｍａｘ The average of t ｍａｘ The oral dosage form of any one of claims 1 to 4, formulated to achieve:

6. The mean C ｍａｘ The average of t ｍａｘ 6. The oral dosage form of claim 5, formulated to achieve:

7. The mean C ｍａｘ The average of t ｍａｘ 7. The oral dosage form of claim 6, formulated to achieve:

8. The mean C ｍａｘ The average of t ｍａｘ 8. The oral dosage form of claim 7, formulated to achieve:

9. 7. The oral dosage form of claim 6, comprising from about 300 mg to about 2000 mg of a total equivalent amount of formula I.

10. 7. The oral dosage form of claim 6 comprising about 500 to about 1400 mg of a total equivalent amount of formula I.

11. i) a compound provided by formula I or a pharma- ceutically acceptable salt thereof; and ii) at least one pharma- ceutically acceptable excipient; 1. An oral dosage form comprising: The formula I has the structure: 【Chemistry 2】 N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide represented by the formula: The oral dosage form, when orally administered to a human subject, has a mean AUC of Formula I of about 50 h·ng / mL to about 5700 h·ng / mL. ０－２４ The oral dosage form is formulated to achieve the following:

12. The average AUC ０－２４ is from about 100 h·ng / mL to about 1200 h·ng / mL.

13. The average AUC ０－２４ but, From 80% to 125% of 100h·ng / mL 80% to 125% of 1200h·ng / mL 12. The oral dosage form of claim 11, wherein the

14. 12. The oral dosage form of claim 11 comprising from about 300 mg to about 2000 mg of a total equivalent amount of formula I.

15. 12. The oral dosage form of claim 11 comprising from about 600 mg to about 1000 mg of a total equivalent amount of formula I.

16. i) a compound provided by formula I or a pharma- ceutically acceptable salt thereof, and ii) at least one pharma- ceutically acceptable excipient; 1. An oral dosage form for administration to a human subject comprising: The formula I has the structure: 【Chemistry 3】 N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide represented by the formula: The oral dosage form, when orally administered to a human subject, has an average t １／２ The oral dosage form is formulated to achieve the following:

17. The average t １／２ is from about 1 hour to about 5 hours.

18. The average t １／２ is from about 2 hours to about 3 hours.

19. 17. The oral dosage form of claim 16 comprising from about 300 mg to about 2000 mg of a total equivalent amount of formula I.

20. 17. The oral dosage form of claim 16 comprising from about 500 mg to about 1000 mg of a total equivalent amount of formula I.

21. i) a compound provided by formula I or a pharma- ceutically acceptable salt thereof, and ii) at least one pharma- ceutically acceptable excipient; 1. An oral dosage form comprising: The formula I has the structure: 【Chemistry 4】 N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide represented by the formula: The oral dosage form, when orally administered to a human subject, has a mean AUC of Formula I of about 400 h·ng / mL to about 1200 h·ng / mL. ０－１２ The oral dosage form is formulated to achieve the following:

22. The average AUC ０－１２ is from about 400 h·ng / mL to about 700 h·ng / mL.

23. The average AUC ０－１２ but, From 80% to 125% of 400h·ng / mL 80% to 125% of 1200h·ng / mL 22. The oral dosage form of claim 21, in the range of

24. 22. The oral dosage form of claim 21 comprising from about 500 mg to about 700 mg of a total equivalent amount of formula I.

25. 22. The oral dosage form of any one of claims 1, 11, 16, and 21, which is a capsule comprising an internal phase comprising Formula I or a pharma-ceutically acceptable salt thereof, lactose monohydrate, calcium carbonate, copovidone, low-substituted hydroxypropyl cellulose, colloidal silicon dioxide, and magnesium stearate.

26. 26. The oral dosage form of claim 25, wherein the capsule further comprises an external phase comprising magnesium stearate.

27. 26. The oral dosage form of claim 25, wherein the internal phase is contained in a hypromellose capsule.

28. 26. The oral dosage form of claim 25 comprising Formula I in free base form.

29. 1. A method of treating cancer in a human subject, comprising administering to the subject: i) a therapeutically effective amount of a compound provided by Formula I or a pharma- ceutically acceptable salt thereof, and ii) at least one pharma- ceutically acceptable excipient; In a method comprising administering an oral dosage form comprising The formula I has the structure: 【Chemistry 5】 N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide represented by the formula: the therapeutically effective amount being a dose in the range of about 300 mg to about 2000 mg of Formula I; and The oral dosage form has a mean C ｍａｘ The method comprising:

30. The average C of formula I ｍａｘ is from about 100 ng / mL to about 400 ng / mL.

31. The average C of formula I ｍａｘ is from about 100 ng / mL to about 300 ng / mL.

32. The average C of formula I ｍａｘ but, From 80% to 125% of 100 ng / mL 80% to 125% of 400 ng / mL 30. The method of claim 29, wherein the range is

33. The dosage form has a mean C ｍａｘ The average of t ｍａｘ The method according to any one of claims 29 to 32, comprising:

34. The dosage form has a mean C ｍａｘ The average of t ｍａｘ 34. The method of claim 33, having the following structure:

35. The dosage form has a mean C ｍａｘ The average of t ｍａｘ 35. The method of claim 34, having the following structure:

36. The dosage form has a mean C ｍａｘ The average of t ｍａｘ 36. The method of claim 35, having the following structure:

37. 34. The method of claim 33, wherein the dosage form comprises from about 500 mg to about 1000 mg of a total equivalent amount of formula I.

38. 34. The method of claim 33, wherein the dosage form comprises from about 1000 to about 1400 mg of a total equivalent amount of formula I.

39. 1. A method of treating cancer in a human subject, comprising administering to the subject: i) a therapeutically effective amount of a compound provided by Formula I or a pharma- ceutically acceptable salt thereof, and ii) at least one pharma- ceutically acceptable excipient; In a method comprising administering once daily an oral dosage form comprising The formula I has the structure: 【Chemistry 6】 N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide represented by the formula: the therapeutically effective amount being a dose in the range of about 300 mg to about 2000 mg of Formula I; and The oral dosage form has a mean AUC of Formula I of about 50 h·ng / mL to about 5700 h·ng / mL. ０－２４ The method comprising:

40. The average AUC ０－２４ is from about 100 h·ng / mL to about 1200 h·ng / mL.

41. The average AUC ０－２４ but, From 80% to 125% of 100h·ng / mL 80% to 125% of 1200h·ng / mL 40. The method of claim 39, in the range of

42. 40. The method of claim 39, wherein the dosage form comprises from about 500 mg to about 1000 mg of a total equivalent amount of Formula I.

43. 40. The method of claim 39, wherein the dosage form comprises from about 1000 mg to about 1400 mg of a total equivalent amount of formula I.

44. 1. A method of treating cancer in a human subject, comprising administering to the subject: i) a therapeutically effective amount of a compound provided by Formula I or a pharma- ceutically acceptable salt thereof, and ii) at least one pharma- ceutically acceptable excipient; In a method comprising administering an oral dosage form comprising The formula I has the structure: 【Chemistry 7】 N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide represented by the formula: the therapeutically effective amount being a dose in the range of about 300 mg to about 2000 mg of Formula I; and The oral dosage form has an average t １／２ The method comprising:

45. The average t １／２ is from about 1 hour to about 5 hours.

46. The average t １／２ is from about 2 hours to about 3 hours.

47. 45. The method of claim 44, wherein the dosage form comprises from about 500 mg to about 1000 mg of a total equivalent amount of formula I.

48. 45. The method of claim 44, wherein the dosage form comprises from about 1000 mg to about 1400 mg of a total equivalent amount of formula I.

49. 1. A method of treating cancer in a human subject, comprising administering to the subject: i) a therapeutically effective amount of a compound provided by Formula I or a pharma- ceutically acceptable salt thereof, and ii) at least one pharma- ceutically acceptable excipient; 23. A method comprising administering twice daily an oral dosage form comprising: The formula I has the structure: 【Chemistry 8】 N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide represented by the formula: the therapeutically effective amount being a dose in the range of about 500 mg to about 700 mg of Formula I; and The oral dosage form has a mean AUC of Formula I of about 400 h·ng / mL to about 1200 h·ng / mL. ０－１２ The method comprising:

50. The average AUC ０－１２ is about 400 h·ng / mL to about 700 h·ng / mL.

51. The average AUC ０－１２ but, From 80% to 125% of 400h·ng / mL 80% to 125% of 1200h·ng / mL 50. The method of claim 49, wherein the range is

52. 50. The method of any one of claims 29, 39, 44 and 49, wherein the oral dosage form is a capsule comprising an internal phase comprising Formula I or a pharma-ceutically acceptable salt, lactose monohydrate, calcium carbonate, copovidone, low-substituted hydroxypropyl cellulose, colloidal silicon dioxide, and magnesium stearate.

53. 53. The method of claim 52, wherein the capsule further comprises an external phase comprising magnesium stearate.

54. 53. The method of claim 52, wherein the internal phase is contained in a hypromellose capsule.

55. 53. The method of claim 52, comprising formula I in free base form.

56. 50. The method of any one of claims 29, 39, 44 and 49, wherein the cancer is hepatocellular carcinoma.

57. 57. The method of claim 56, wherein the cancer expresses or overexpresses FGFR4 or FGF19.

58. 50. The method of any one of claims 29, 39, 44 and 49, wherein the cancer is rhabdomyosarcoma.

59. 59. The method of claim 58, wherein the cancer expresses or overexpresses FGFR4 or FGF19.

60. 50. The method of any one of claims 29, 39, 44 and 49, wherein the oral dosage form is administered to the human in a fasted state.

61. 50. The method of any one of claims 29, 39, 44 and 49, wherein the oral dosage form is administered to the human in a fed state.

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