Administration schedule of solid dispersion of Her2 inhibitor

Abstract

The present invention relates to an administration schedule, particularly a dose and / or second-line or later administration, of a solid dispersion of a HER2 inhibitor and a pharmaceutically acceptable dispersion carrier, which is useful for the prevention and / or treatment of cancer.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to an administration schedule for a solid dispersion of a HER2 inhibitor, N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide, and a pharmaceutically acceptable dispersion carrier, which is useful for preventing and / or treating cancer. In particular, the administration schedule can be determined by the dose of the HER2 inhibitor and / or second-line or later administration.

[0002] background N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]-diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide, also referred to herein as compound (1) or zongertinib, is a HER2 (ErbB2) inhibitor described in WO 2021 / 213800. Zongertinib is a potent and selective tyrosine kinase inhibitor of wild-type and mutant HER2, sparing wild-type epidermal growth factor receptor (EGFR). Therefore, it is useful for the treatment and / or prevention of diseases and / or conditions in which inhibition of wild-type and / or mutant HER2 is therapeutically beneficial, particularly neoplastic and / or hyperproliferative diseases, such as cancer.

[0003] The solubility of compound (1) in aqueous media is limited and has been found to be strongly pH-dependent, with the solubility increasing under acidic conditions. Specifically, the solubility increases by approximately 10% between pH 1.2 and pH 6.8. 5A 2-fold decrease in absorption of Compound (1) was observed. As a result, the in vivo absorption of Compound (1) is affected by gastric pH. In particular, lower gastric pH is associated with increased absorption of Compound (1), while higher gastric pH is associated with decreased blood serum levels of Compound (1). This pH dependence is undesirable because it may reduce the bioavailability and / or bioaccessibility of Compound (1). Such a decrease may occur to different degrees in different patients due to variations in gastric pH among patients.

[0004] Furthermore, gastric pH in cancer patients can be altered by therapeutic agents in their treatment regimens, such as protein pump inhibitors (PPIs), antacids, and antihistamines. These therapeutic agents are acid-reducing agents known to increase gastric pH. These therapeutic agents are frequently administered to cancer patients, for example, to alleviate gastrointestinal side effects caused by medications, particularly those that lower gastric pH, and also to manage the effects of tumors in the gastric region. Therefore, coadministration of acid-reducing agents with Compound (1) can reduce the absorption and systemic exposure of Compound (1).

[0005] Therefore, there remains a need to reduce the pH dependence of compound (1) and improve its bioavailability and / or bioaccessibility.

[0006] Additionally, there is a need to find methods of administering Compound (1) that are therapeutically effective in the context of existing treatments, and as such are safe and tolerable. [Brief explanation of the drawings]

[0007] [Figure 1] FIG. 1 shows the powder X-ray diffraction diagrams (XRPDs) of a spray-dried amorphous solid dispersion of Compound (1) and 75 wt. % HPMCAS-M (top curve) and a spray-dried amorphous solid dispersion of Compound (1) and 50 wt. % HPMCAS-M (bottom curve) from Example 1 herein, compared to the XRPD of crystalline Compound (1). [Figure 2] FIG. 2 shows the powder X-ray diffraction diagrams (XRPDs) of a spray-dried amorphous solid dispersion of Compound (1) with 75 wt % PVP-VA (top curve) and a spray-dried amorphous solid dispersion of Compound (1) with 50 wt % PVP-VA (bottom curve) from Example 1 herein, compared with the XRPD of crystalline Compound (1). [Figure 3] FIG. 3 shows the powder X-ray diffraction diagrams (XRPDs) of a spray-dried amorphous solid dispersion of Compound (1) with 75 wt % Eudragit® L100 (top curve) and a spray-dried amorphous solid dispersion of Compound (1) with 50 wt % Eudragit® L100 (bottom curve) from Example 1 herein, compared with the XRPD of crystalline Compound (1). [Figure 4] FIG. 4 shows the powder X-ray diffraction diagrams (XRPDs) of a spray-dried amorphous solid dispersion of Compound (1) with 75 wt % HPMC HME 15LV (top curve) and a spray-dried amorphous solid dispersion of Compound (1) with 50 wt % HPMC HME 15LV (bottom curve) from Example 1 herein, compared to the XRPD of crystalline Compound (1). [Figure 5] 5 shows the powder X-ray diffraction diagrams (XRPDs) of spray-dried amorphous solid dispersions of Compound (1) obtained from Example 3.3 herein. From top to bottom curve: Sample 3.3-A (top curve), Sample 3.3-B (middle curve), and Sample 3.3-C (bottom curve). [Figure 6] 6 shows the powder X-ray diffraction diagrams (XRPDs) of spray-dried amorphous solid dispersions of Compound (1) obtained from Example 3.4 herein. From top to bottom curve: Sample 3.4-A (top curve) and Sample 3.4-B (bottom curve). [Figure 7]7 shows powder X-ray diffraction patterns (XRPD) of an amorphous solid dispersion of Compound (1) and HPMCAS-M (50 wt%:50 wt%) after exposure to 75°C / 79% relative humidity and 80°C / 76% relative humidity for 3 weeks. From top to bottom curve: unstressed sample (top), sample stressed at 75°C / 79% relative humidity (middle), and sample stressed at 80°C / 76% relative humidity (bottom). [Figure 8] FIG. 8 shows a comparison of Log solubility values ​​measured in aqueous media at various pH values: amorphous solid dispersion of Compound (1) with HPMCAS-M (50 wt%:50 wt%) (circles), crystalline Compound (1) Form III (squares), and crystalline Compound (1) Form IV (triangles). [Figure 9] Figure 9 shows the in vitro dissolution profiles of various amorphous solid dispersions with various polymers (25 wt%:75 wt% Compound (1):polymer) compared to the dissolution profile of crystalline Compound (1) in simulated intestinal fluid after transit from simulated gastric fluid in the two-stage gastric transit study of Example 5.2. From top to bottom curve (relative to first measurement point): HPMC HME 15LV, PVP-VA, HPMCAS-M, Eudragit® L100, and crystalline Compound (1). [Figure 10] Figure 10 shows the in vitro dissolution profiles of various amorphous solid dispersions with various polymers (50 wt%:50 wt% Compound (1):polymer) compared to the dissolution profile of crystalline Compound (1) in simulated intestinal fluid after transit from simulated gastric fluid in the two-stage gastric transit study of Example 5.2. From top to bottom curve (relative to first measurement point): HPMCAS-M, HPMC HME 15LV, PVP-VA, Eudragit® L100, and crystalline Compound (1). [Figure 11] FIG. 11 shows the results of a comparison of in vitro dissolution at pH 2.0 between tablets containing crystalline Compound (1) (squares) and tablets containing a solid dispersion of Compound (1) (circles). [Figure 12]FIG. 12 shows the results of a comparison of in vitro dissolution at pH 6.8 between conventional tablets (circles) containing crystalline Compound (1) and tablets containing a solid dispersion of Compound (1) (squares: Example 6.2-A, triangles: Example 6.2-C). [Figure 13] Figure 13 shows a schematic diagram of a dynamic in vitro gastrointestinal model (tiny-TIM model) for simulating physiological processes occurring in the human stomach and small intestine: A: food inlet, B: gastric body, C: proximal antrum, D: distal antrum, E: pyloric valve, F: peristaltic valve, G: small intestinal segments, H: filtration system, I: gastric secretion, J: intestinal secretion, K: pH electrode, L: level sensor. [Figure 14] Figure 14 shows the results of an in vitro time course measurement of the bioaccessibility of a solid dispersion of Compound 1 ("SDD") compared to administration of a conventional tablet of crystalline Compound 1 ("Conv."), both at a 100 mg dose, under fasting conditions (normal low gastric pH) and under simulated high gastric pH conditions following proton pump inhibitor (PPI) administration. [Figure 15] FIG. 15 shows the X-ray powder diffraction diagram (XRPD) of the formulation disclosed in Example 6.1-C. [Figure 16] FIG. 16 shows the X-ray powder diffraction diagram (XRPD) of the formulation disclosed in Example 6.2-C. [Figure 17] 17 shows the design of the dose escalation portion of a clinical trial testing various doses and schedules of Compound (1) in pretreated patients with unresectable, advanced, and / or metastatic solid tumors harboring HER2 gene aberrations, as described in Example 1. N = number of patients; BID = twice daily in die; QD = once daily in die; RP2D = recommended dose for dose escalation. [Figure 18] Figure 18 shows a swimmer plot of response assessment and treatment duration by patient and dose on the BID schedule as of March 16, 2023. Bars represent progression-free survival, not treatment duration. BID = twice daily; QD = once daily; PR = partial response; SD = stable disease; PD = progressive disease. [Figure 19] Figure 19 shows a swimmer plot of response assessment and treatment duration by patient and dose on a BID schedule as of March 16, 2023. Bars represent progression-free survival, not treatment duration. Abbreviations are defined as in Figure 2. [Figure 20] Figure 20 shows a swimmer plot of response assessments and treatment duration by patient and dose on a QD schedule as of March 16, 2023. Bars represent progression-free survival, not treatment duration. Abbreviations are defined as in Figure 2. [Figure 21] Figure 21 shows a waterfall plot of the BID vs QD schedule for best change from baseline in target lesions (RECIST v1.1) expressed as %. [Figure 22] Figure 22 shows a waterfall plot of the BID dose levels with best change from baseline in target lesions (RECIST v1.1) expressed as %. [Figure 23] Figure 23 shows a waterfall plot of QD dose levels with best change from baseline in target lesions (RECIST v1.1) expressed as %. [Figure 24] FIG. 24 shows waterfall plots of best change from baseline in target lesions (RECIST v1.1) in % for BID dose levels in (a) patients with non-small cell lung cancer and (b) patients with other tumors. [Figure 25] FIG. 25 shows waterfall plots of QD dose levels with best change from baseline in target lesions (RECIST v1.1) expressed as % in (a) patients with non-small cell lung cancer and (b) patients with other tumors.

[0008] overview According to a first aspect, there is provided a compound (1) defined below: [ka] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier, wherein the solid dispersion is for use in a method for preventing and / or treating cancer, wherein Compound (1) is administered in a daily dose of at least 30 mg. Also provided herein is a method for preventing and / or treating cancer, comprising administering to a subject in need thereof a solid dispersion comprising Compound (1) as defined herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier, wherein Compound (1) is administered in a daily dose of at least 30 mg.

[0009] According to another embodiment, compound (1) defined below: [ka]

[0013] Provided herein is a solid dispersion comprising Compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier, for use in a method for preventing and / or treating cancer, wherein Compound (1) is administered after administration of a systemic anti-cancer therapy. Also provided herein is a method for preventing and / or treating cancer, comprising administering to a subject in need thereof a solid dispersion comprising Compound (1) as defined herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier, wherein Compound (1) is administered after administration of a systemic anti-cancer therapy.

[0010] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer.

[0011] In an embodiment, the polymer is enteric or non-enteric.

[0012] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer selected from the group consisting of hydroxypropylmethylcellulose and its esters, polyvinylpyrrolidone and its copolymers, and polymethacrylates and its copolymers.

[0013] In an embodiment, the hydroxypropyl methylcellulose and its esters are selected from the group consisting of hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose, especially hot melt extrusion grade hydroxypropyl methylcellulose.

[0014] In an embodiment, the polyvinylpyrrolidone and its copolymers are polyvinylpyrrolidone-vinyl acetate copolymers.

[0015] In an embodiment, the polymethacrylate and copolymers thereof are methylacrylic acid-methylmethacrylate copolymers.

[0016] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer selected from the group of hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone-vinyl acetate copolymer, methylacrylic acid-methylmethacrylate copolymer, and hot melt extrusion grade hydroxypropyl methylcellulose.

[0017] In an embodiment, Compound (1) is amorphous.

[0018] In an embodiment, Compound (1) is present in an amount ranging from 25 wt % to 75 wt %, based on 100 wt % of the total weight of the solid dispersion.

[0019] In an embodiment, the pharmaceutically acceptable dispersion carrier is present in an amount ranging from 25 wt% to 75 wt%, based on 100 wt% of the total weight of the solid dispersion.

[0020] In an embodiment, the weight ratio of compound (1) to the pharmaceutically acceptable dispersion carrier in the solid dispersion is 1:1 to 1:3.

[0021] In an embodiment, the solid dispersion for use described herein is characterized by having a powder X-ray diffraction pattern that does not contain any diffraction peaks at a 2θ angle of 40.0° or less when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0022] Also provided herein is a pharmaceutical composition comprising a solid dispersion as defined herein and one or more pharmaceutically acceptable excipients, for use in a method for preventing and / or treating cancer, wherein Compound (1) is administered in a daily dose of at least 30 mg.

[0023] In embodiments, the one or more pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, glidants, lubricants, and coating agents.

[0024] In an embodiment, the filler is selected from the group consisting of microcrystalline cellulose, mannitol, and mixtures thereof.

[0025] In embodiments, the disintegrant is selected from the group consisting of croscarmellose sodium, sodium bicarbonate, crospovidone, sodium starch glycolate, and mixtures thereof.

[0026] In an embodiment, the glidant is colloidal silicon dioxide.

[0027] In an embodiment, the lubricant is selected from the group consisting of stearyl fumarate, magnesium stearate, and mixtures thereof.

[0028] In embodiments, the one or more pharmaceutically acceptable excipients include mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

[0029] In an embodiment, the pharmaceutical composition for use described herein comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - a solid dispersant as defined herein in the range of 25 wt% to 65 wt%, and / or - one or more fillers in the range of 25wt% to 65wt%, and / or - disintegrants in the range of 4 wt% to 10 wt%, and / or - Glidants in the range of 1 wt% to 2 wt%, and / or - lubricant in the range of 1 wt% to 2 wt%, and / or - Optionally, coating agent in the range of 2wt% to 5wt% include.

[0030] In an embodiment, the pharmaceutical compositions for the uses described herein are in the form of tablets, granules or capsules.

[0031] In an embodiment, the pharmaceutical composition for use described herein comprises: (i) a tablet core comprising a solid dispersion, as defined herein, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; (ii) film coating and Includes.

[0032] In an embodiment, the pharmaceutical composition for use described herein is characterized by having a powder X-ray diffraction pattern that does not contain any diffraction peaks at 2θ angles below 6.5° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0033] In an embodiment, the cancer is selected from the group consisting of brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colon cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0034] In an embodiment, the cancer is a HER2-overexpressing, HER2-amplified and / or HER2-mutated cancer.

[0035] In an embodiment, the cancer is an advanced or metastatic cancer.

[0036] In an embodiment, the solid dispersion or the pharmaceutical composition is administered to a subject in the fasted state.

[0037] In an embodiment, the solid dispersion or the pharmaceutical composition is administered in combination with a pharmaceutical agent that increases gastric pH.

[0038] In an embodiment, the pharmaceutical agent that increases gastric pH is selected from the group consisting of a proton pump inhibitor, an antacid, and an antihistamine.

[0039] In an embodiment, Compound (1) is administered in a daily dose of 30 mg to 600 mg.

[0040] In embodiments, Compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0041] In an embodiment, Compound (1) is administered once daily or twice daily.

[0042] In an embodiment, Compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0043] In an embodiment, Compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0044] In embodiments, the systemic anti-cancer therapy is selected from the group consisting of platinum-based chemotherapy, anti-HER2 antibody-drug conjugates, and combinations thereof.

[0045] Further embodiments are presented below.

[0046] 1) A compound (1) defined below; [ka] for use in treating cancer, wherein compound (1) is administered in a daily dose of at least 30 mg.

[0047] 2) A method for preventing and / or treating cancer, comprising: Administering compound (1) as defined herein to a subject in need thereof in a daily dose of at least 30 mg, method.

[0048] 3) The compound for use according to embodiment 1) or the method according to embodiment 2), wherein compound (1) is administered in a daily dose of 30 mg to 600 mg.

[0049] 4) The compound for use according to embodiment 1) or 3) or the method according to embodiment 2) or 3), wherein compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.

[0050] 5) The compound for use according to any one of embodiments 1) or 3) to 4) or the method according to any one of embodiments 2) or 3) to 4), wherein compound (1) is administered once a day or twice a day.

[0051] 6) The compound for use according to any one of embodiments 1) or 3) to 5) or the method according to any one of embodiments 2) or 3) to 5), wherein compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg; or compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0052] 7) The compound for use according to any one of embodiments 1) or 3) to 6) or the method according to any one of embodiments 2) or 3) to 6), wherein compound (1) is administered orally.

[0053] 8) The compound for use according to any one of embodiments 1) or 3) to 7) or the method according to any one of embodiments 2) or 3) to 7), wherein compound (1) is administered as a tablet.

[0054] 9) A compound (1) defined below: [ka] for use in treating cancer, wherein compound (1) is administered after administration of a systemic anti-cancer therapy.

[0055] 10) A method for preventing and / or treating cancer, comprising: administering compound (1) to a subject in need thereof after administration of a systemic anti-cancer therapy; method.

[0056] 11) The compound for use according to embodiment 9) or the method according to embodiment 10), wherein compound (1) is administered as defined in any embodiment herein, in particular embodiments 1) to 8).

[0057] 12) The compound for use according to embodiment 9) or 11) or the method according to embodiment 10), wherein the systemic anti-cancer therapy is selected from the group consisting of platinum-based chemotherapy, anti-HER2 antibody-drug conjugates, and combinations thereof.

[0058] 13) The compound for use according to embodiment 9), 11) or 12) or the method according to any one of embodiments 10) to 12), wherein the cancer is selected from the group consisting of brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colon cancer, endometrial cancer, skin cancer, stomach cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.

[0059] 14) A compound for use according to any one of embodiments 9) or 11) to 13) or a method according to any one of embodiments 10) to 13), wherein the cancer is HER2 overexpression, HER2 amplification and / or HER2 mutation.

[0060] 15) A compound for use according to any one of embodiments 9) or 11) to 14) or a method according to any one of embodiments 10) to 14), wherein the cancer is progressive or metastatic.

[0061] 16) A compound (1) defined below: [ka] and at least one pharmaceutically acceptable excipient, Compound (1) is administered in a daily dose of at least 30 mg. Pharmaceutical compositions.

[0062] 17) A method for preventing and / or treating cancer, comprising: administering to a subject in need thereof a pharmaceutical composition comprising Compound (1) and at least one pharmaceutically acceptable excipient; Compound (1) is administered in a daily dose of at least 30 mg. method.

[0063] 18) The pharmaceutical composition according to embodiment 16) or the method according to embodiment 17), wherein compound (1) is administered according to any one of embodiments 1) to 15).

[0064] All embodiments described herein for Compound (1) for use in treating cancer or for methods of treating patients suffering from cancer with Compound (1) are applicable to pharmaceutical compositions for use in treating cancer or for methods of treating patients suffering from cancer with pharmaceutical compositions.

[0065] Detailed Description The object of the present invention is to reduce the pH dependency of compound (1) and improve its bioavailability and / or bioaccessibility.

[0066] It has surprisingly been discovered that formulation of Compound (1) as a solid dispersion has the potential to achieve consistent bioavailability and / or bioaccessibility and overcome patient-to-patient gastric pH variability compared to administration of formulations comprising Compound (1) in crystalline form. Accordingly, the present invention provides a solid dispersion comprising Compound (1), as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable dispersion carrier.

[0067] Specifically, administration of solid dispersions of Compound (1) provides high uptake not only when administered to subjects with normal low gastric pH, but also when administered in combination with pharmaceutical agents that increase gastric pH, such as proton pump inhibitors, antacids, or antihistamines. The surprising results shown in the examples described herein, particularly the superior in vitro and in vivo performance of the solid dispersions of the present invention compared to formulations containing crystalline Compound (1), as demonstrated in Examples 5.1, 5.2, and 7.1-7.4 herein, indicate that formulations of Compound (1) as solid dispersions provide consistently high uptake that is not affected by pH fluctuations (e.g., those initiated by concomitant medications that cause elevated gastric pH levels), thereby enabling the inclusion of patient populations receiving concomitant medications (e.g., proton pump inhibitors, antacids, or antihistamines) in treatment with Compound (1).

[0068] It has also been surprisingly found that compound (1) can maintain an amorphous state, such as in a solid dispersion, even when exposed to temperature and humidity stress for extended periods of time, as demonstrated in Example 4 herein.

[0069] It is also an object of the present invention to provide a safe and effective dosing regimen for Compound (1) for use in the treatment of cancer. Surprisingly, it has been found that the dosing regimen of the present invention achieves clinical efficacy, as evidenced by a partial response with an overall response rate (ORR) of 45.8%, along with a good disease control rate (DCR) of 95.8% (excluding patients with a best overall response of "inevaluable" at the time of data cutoff).

[0070] At the same time, the side effects caused by the dosing regimen of the present invention are surprisingly few and mild, as demonstrated by the fact that only three cases of dose-limiting toxicity (DLT) were observed outside the maximum tolerated dose (MTD) observation period, and the MTD has not yet been reached. This indicates the good safety and tolerability of the medical use and treatment method of the present invention, and also indicates a low discontinuation rate. In addition, the dosing regimen of the present invention is believed to be suitable for various patients who have already received other cancer-related treatments. As used herein, the terms "dosing regimen" and "dosing schedule" are intended to be synonymous with "dosing regimen" and "dosing schedule," and thus are not necessarily limited to a specific dose, as is the case in certain aspects and embodiments related to second-line or later treatments. Thus, the terms "dosing regimen" and "dosing schedule" also include dosing regimens or schedules defined by the line of administration, but are not necessarily defined by the dose.

[0071] The positive safety profile observed with the dosing schedule of the present invention allows for the simultaneous administration of relatively large amounts of Compound (1), which in turn may have some beneficial effects, for example, on patient compliance.

[0072] The dose-effectiveness and dose-safety relationships were found to be unexpectedly flat, which may indicate the wide therapeutic window of the present invention.

[0073] Compound (1) As used herein, the term “compound (1)” refers to the compound defined below: [ka] or a pharmaceutically acceptable salt thereof.

[0074] The IUPAC name of compound (1) is N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide. In the event of a conflict between the IUPAC name and the formula shown, the formula shall prevail. Compound (1) is also known as zongertinib. Compound (1) is disclosed in WO 2021 / 213800 as Example Compound I-01. WO 2021 / 213800 describes [1,3]diazino[5,4-d]pyrimidines such as compound (1) as HER2 inhibitors and provides a method for synthesizing compound (1). The properties of compound (1) and evidence of its effectiveness in inhibiting HER2 wild-type and YVMA kinase activity while sparing EGFR are also disclosed in WO 2021 / 213800, which is incorporated herein by reference.

[0075] As used herein, the term "compound (1)" also encompasses any tautomers and pharmaceutically acceptable salts, as well as all solid forms of the compound and solvates, including hydrates and solvates, of its pharmaceutically acceptable salts.

[0076] In embodiments, Compound (1) is the free base. Thus, in any aspect or embodiment, the phrase "Compound (1) or a pharmaceutically acceptable salt thereof" can be substituted for "Compound (1)" without reference to a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutically acceptable salt of Compound (1) is used. As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissue without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0077] As used herein, a "pharmaceutically acceptable salt" of Compound (1) refers to Compound (1) that has been modified by making an acid or base salt thereof. As used herein, the term "pharmaceutically acceptable salt" generally includes both acid and base addition salts. Pharmaceutically acceptable acid addition salts refer to salts formed with inorganic or organic acids that retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts include salts derived from inorganic bases or organic non-toxic bases. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues, such as amines; alkali or organic acid salts of acidic residues, such as carboxylic acids; and the like. For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. In an embodiment, the pharmaceutically acceptable salt is selected from chloride salts and fumarate salts.

[0078] Pharmaceutically acceptable salts can be synthesized from Compound 1 by conventional chemical methods. Generally, such salts can be prepared by reacting the free base form of Compound 1 with a sufficient amount of the appropriate acid or base in water or an organic diluent or solvent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

[0079] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules with compound (1). Examples of solvents include water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, tert-butyl methyl ether, tetrahydrofuran, methyl ethyl ketone, N-methylpyrrolidone, and ethanolamine. The term "hydrate" refers to a complex where the solvent molecule is water.

[0080] solid dispersion agent In embodiments, the solid dispersions described herein consist essentially of Compound (1) or a pharmaceutically acceptable salt thereof, as defined herein, and a pharmaceutically acceptable dispersion carrier. As used herein, the terms "consists essentially of" and "consisting essentially of" have their art-defined meanings. In particular, they indicate that additional components may be present, particularly those that do not significantly affect the properties of the dispersion, composition, or formulation, respectively. Such additional components may be, for example, residual solvent.

[0081] In embodiments, the solid dispersion described herein consists of Compound (1), as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable dispersion carrier.

[0082] As used herein, the term "solid dispersion" refers to a solid-state system comprising at least two components, wherein one component, e.g., Compound (1), preferably in an amorphous state, or generally, an active pharmaceutical ingredient (API), is dispersed throughout another component, e.g., a pharmaceutically acceptable solid dispersion carrier, particularly a dispersion polymer.

[0083] As used herein, the term "dispersion carrier" refers to a carrier component through which an API, e.g., Compound (1), can be dispersed so as to form a solid dispersion. In an embodiment, Compound (1) is dispersed at a molecular level in the pharmaceutically acceptable dispersion carrier.

[0084] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer. Accordingly, the present invention provides, inter alia, a solid dispersion comprising Compound (1) or a pharmaceutically acceptable salt thereof for the uses defined herein and a polymer. A polymeric dispersion carrier may also be referred to as a "dispersion polymer." Accordingly, the present invention provides a solid dispersion comprising Compound (1) or a pharmaceutically acceptable salt thereof as defined herein and a polymer, wherein the solid dispersion is for the uses defined herein in any aspect or embodiment. Polymers are widely used in solid dispersion formulations. Different polymeric carriers result in solid dispersions with different properties in terms of physical stability, phase behavior, and rate and extent of drug release. Due to the complex nature of solid dispersion formulations, testing to find the optimal carrier for a given API is necessary. The pharmaceutically acceptable dispersion polymer is preferably a neutral or acidic polymer. In another embodiment, the pharmaceutically acceptable dispersion carrier is an enteric or non-enteric polymer, preferably an enteric polymer. In another embodiment, the polymer is an enteric or non-enteric polymer, preferably an enteric polymer. The term "enteric polymer" refers to a pH-dependent acidic polymer that is insoluble or only slightly soluble at low pH (e.g., from about pH 1 up to less than pH 3) but becomes soluble at higher pH (e.g., pH 5 or greater). In certain embodiments, the pH-dependent polymer may be soluble in a pH range of about pH 5 or greater, e.g., from about pH 6 to about pH 9, from about pH 6 to about pH 8, from about pH 5 to about pH 7, or from about pH 5 to about pH 6, which are generally less acidic than the stomach environment and roughly correspond to pH values ​​in the small intestine.Examples of enteric polymers include, but are not limited to, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate, HPMCAS), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer (Eudragit® L100), shellac, cellulose acetate trimellitate, sodium alginate, and zein. The term "non-enteric polymer" refers to a neutral polymer that does not exhibit pH-dependent solubility properties. Examples of non-enteric polymers include, but are not limited to, cellulose derivatives such as methylcellulose (MC), ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), copovidone, such as polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), poly(ethylene glycol) PEG, starch derivatives such as cyclodextrin, polyethylene glycol, Soluplus®, an amphiphilic copolymer consisting of polyvinylcaprolactam and polyvinyl acetate.

[0085] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer, or more simply, the polymer is selected from the group consisting of hydroxypropylmethylcellulose and its esters, polyvinylpyrrolidone and its copolymers, and polymethacrylate and its copolymers. The pharmaceutically acceptable dispersion carrier may contain a mixture of two or more polymers.

[0086] In an embodiment, the hydroxypropyl methylcellulose and its esters are selected from the group consisting of hydroxypropyl methylcellulose acetate (HPMCA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), carboxymethyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose acetate trimellitate (HPMCAT), and carboxymethyl cellulose acetate butyrate (CMCAB). In an embodiment, the hydroxypropyl methylcellulose and its esters are selected from the group consisting of hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose, especially hot melt extrusion grade hydroxypropyl methylcellulose.

[0087] In an embodiment, polyvinylpyrrolidone and its copolymers are selected from the group consisting of polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), polyvinyl alcohol, polyvinyl alcohol-polyvinyl acetate copolymer, and polyvinylpyrrolidone (PVP). Polyvinylpyrrolidone (PVP) is also commonly referred to as polyvidone or povidone. In an embodiment, polyvinylpyrrolidone and its copolymers are polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA).

[0088] In embodiments, the polymethacrylate and its copolymers are selected from the group consisting of methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, methyl methacrylate and methacrylic acid copolymer. Polymethacrylate and its copolymers are available, for example, under the trade name Eudragit® from Evonik Industries AG. Methacrylic acid-methyl methacrylate copolymer is available, for example, under the trade name Eudragit® L100. In certain embodiments, the polymethacrylate and its copolymer are methacrylic acid-methyl methacrylate copolymer.

[0089] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer, or more simply, the polymer is selected from the group of hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), methylacrylic acid-methyl methacrylate copolymer (e.g., Eudragit® L100), and hot melt extrusion grade hydroxypropyl methylcellulose (HPMC HME).

[0090] In a specific embodiment, the pharmaceutically acceptable dispersion carrier is hydroxypropyl methylcellulose acetate succinate (HPMCAS). HPMCAS is also known as hypromellose acetate succinate. Hypromellose acetate succinate (HPMCAS) can be obtained by introducing acetyl and succinoyl groups into the hydroxyl groups of the backbone of hydroxypropyl methylcellulose (HPMC), also known as hypromellose. This method can be carried out by known methods, for example, by treating HPMC with acetic anhydride and / or succinic anhydride. Acetic anhydride and succinic anhydride can be reacted with hydroxypropyl methylcellulose (HPMC) under controlled conditions to produce HPMCAS with different degrees of acetyl and succinoyl substitution.

[0091] HPMCAS is available in several grades (L, M, and H) that differ in the degree of acetyl and succinoyl group substitution based on the content (wt%) of acetyl and succinoyl groups in the HPMCAS molecule. Any grade of HPMCAS can be used in the solid dispersion of the present invention. Preferably, grades L, M, or H of HPMCAS are used. In certain embodiments, the pharmaceutically acceptable dispersion carrier is grade L HPMCAS. In certain embodiments, the pharmaceutically acceptable dispersion carrier is grade M HPMCAS. Grade M HPMCAS may contain 7-11 wt% acetyl content; 10-14 wt% succinoyl content; 21-25 wt% methoxyl content; and 5-9 wt% hydroxypropoxy content. Preferably, grade M HPMCAS (HPMCAS-M) is soluble at pH ≥ 6. In certain embodiments, the pharmaceutically acceptable dispersion carrier is grade H HPMCAS. Preferably, granular HPMCAS (HPMCAS-G) is used. HPMCAS-G can be used with any grade of HPMCAS, especially grade G, as can HPMCAS-MG.

[0092] In a particular embodiment, the pharmaceutically acceptable dispersion carrier is polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), a linear random copolymer obtainable by free radical polymerization of monomers in which the ratio of vinyl acetate to vinylpyrrolidone varies from 70 / 30 to 30 / 70.

[0093] In certain embodiments, the pharmaceutically acceptable dispersion carrier is a methyl acrylic acid-methyl methacrylate copolymer, such as Eudragit® L100. As used herein, "methyl acrylic acid-methyl methacrylate copolymer" is used interchangeably with "methacrylic acid-methyl methacrylate copolymer."

[0094] In a particular embodiment, the pharmaceutically acceptable dispersion carrier is hot-melt extrusion grade hydroxypropyl methylcellulose (HPMC HME). HPMC HME refers to a modified grade of hydroxypropyl methylcellulose with a low glass transition temperature and melt viscosity, and can be used to prepare solid dispersions by hot-melt extrusion. HPMC HME is a water-soluble amorphous polymer, usually provided as a white to off-white powder, and is available in three grades with different molecular weights: HPMC HME 15LV, HPMC HME 100LV, and HPMC HME 4M. Preferably, the molecular weight (M) is 100 kDa or less. W More preferably, HPMC HME 15LV having a molecular weight (M) of 200 kDa or less is used. W ) is used.

[0095] Compound (1) can be dispersed at a molecular level, for example, in a polymeric pharmaceutically acceptable dispersion carrier, thereby maintaining its amorphous state even when exposed to high temperature and / or high humidity conditions, and the solid dispersion can reliably provide Compound (1) in amorphous form. In an embodiment, Compound (1) is amorphous. The preferred feature of Compound (1) being amorphous can be applied to any of the embodiments disclosed herein to provide further embodiments of the present invention, particularly to any of the solid dispersions (including those relating to the identity of the pharmaceutically acceptable dispersion carrier, the amount of components of the solid dispersion, specific dosing regimes, etc.), pharmaceutical compositions, kits, uses, and methods described herein. As used herein, the term "amorphous" refers to a condensed phase characterized by random molecular orientation, the absence of diffraction peaks by XRPD, and the absence of any microscopic order. Amorphous solid systems can be composed of a single chemical entity or can be multi-component systems that do not have a stoichiometric composition, for example, containing an API, a polymer, and other excipients. Amorphous solids generally have crystal-like short-range molecular ordering, but lack the long-range molecular packing order found in crystalline solids. The solid form of a solid can be determined, for example, by powder X-ray diffraction ("XRPD") or modulated differential scanning calorimetry ("mDSC").

[0096] In embodiments, the solid dispersion comprises, consists essentially of, or consists of amorphous Compound (1) and a pharmaceutically acceptable dispersion carrier, wherein Compound (1) is in a substantially amorphous solid-state form. In certain embodiments, the substantially amorphous solid-state form refers to a solid dispersion comprising at least 80 wt% amorphous Compound (1), based on 100 wt% total weight of Compound (1). In certain embodiments, the substantially amorphous solid-state form refers to a solid dispersion comprising at least 85 wt% amorphous Compound (1), based on 100 wt% total weight of Compound (1). In certain embodiments, the substantially amorphous solid-state form refers to a solid dispersion comprising at least 90 wt% amorphous Compound (1), based on 100 wt% total weight of Compound (1). In certain embodiments, a substantially amorphous solid-state form refers to a solid dispersion comprising at least 95 wt% amorphous Compound (1), based on 100 wt% of the total weight of Compound (1). In certain embodiments, a substantially amorphous solid-state form refers to a solid dispersion comprising at least 96, 97, 98, or 99 wt% amorphous Compound (1), based on 100 wt% of the total weight of Compound (1). In this manner, the solid dispersion can provide Compound (1) in an amorphous or essentially amorphous state. For this reason, such solid dispersions may be referred to as amorphous solid dispersions. For this reason, in embodiments, the solid dispersion is an amorphous solid dispersion.

[0097] In one embodiment, the solid dispersion comprises a predetermined amount of Compound (1) or a pharmaceutically acceptable salt thereof, wherein the predetermined amount refers to the initial amount of Compound (1) or a pharmaceutically acceptable salt thereof used to prepare the solid dispersion.

[0098] In another embodiment, the solid dispersion comprises a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof.

[0099] In an embodiment, Compound (1) is present in an amount ranging from 5 wt% to 95 wt%, based on 100 wt% of the total weight of the solid dispersion. In an embodiment, Compound (1) is present in an amount ranging from 25 wt% to 75 wt%, based on 100 wt% of the total weight of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersion carrier is present in an amount ranging from 5 wt% to 95 wt%, based on 100 wt% of the total weight of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersion carrier is present in an amount ranging from 25 wt% to 75 wt%, based on 100 wt% of the total weight of the solid dispersion.

[0100] In an embodiment, Compound (1) is present in an amount ranging from 20 wt% to 50 wt%, based on 100 wt% of the total weight of the solid dispersion. In an embodiment, Compound (1) is present in an amount ranging from 25 wt% to 50 wt%, based on 100 wt% of the total weight of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersion carrier is present in an amount ranging from 50 wt% to 80 wt%, based on 100 wt% of the total weight of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersion carrier is present in an amount ranging from 50 wt% to 75 wt%, based on 100 wt% of the total weight of the solid dispersion.

[0101] The solid dispersion may comprise Compound (1) and a pharmaceutically acceptable dispersion carrier in approximately equal amounts by weight. In an embodiment, the solid dispersion comprises, consists of, or consists essentially of about 50 wt% Compound (1) and about 50 wt% pharmaceutically acceptable dispersion carrier, based on a total weight of 100 wt%.

[0102] In an embodiment, the solid dispersion comprises, consists of, or consists essentially of about 25 wt% or 50 wt% Compound (1) and about 75 wt% or 50 wt% pharmaceutically acceptable dispersing carrier, based on a total weight of 100 wt%. In an embodiment, the weight ratio of Compound (1) to pharmaceutically acceptable dispersing carrier in the solid dispersion is about 1:4 to 4:1, preferably 1:3 to 3:1, for example, 1:1 to 1:3. In an embodiment, the weight ratio of Compound (1) to pharmaceutically acceptable dispersing carrier in the solid dispersion is 1:1 to 1:3. In an embodiment, the weight ratio of Compound (1) to pharmaceutically acceptable dispersing carrier in the solid dispersion is about 1:1.

[0103] As used herein, the terms "approximately" and "about" mean within a statistically meaningful range of values. Such a range may be within one order of magnitude, typically within 10%, more typically within 5%, even more typically within 1%, and most typically within 0.1% of the indicated value or range. In some cases, such a range may be within the range of experimental error typical of the standard method used to measure and / or determine the given value or range.

[0104] In an embodiment, the solid dispersion comprises Compound (1): pharmaceutically acceptable dispersing carrier in a weight ratio of about 1:4 to 4:1, preferably 1:3 to 3:1, for example, 1:1 to 1:3. In an embodiment, the solid dispersion comprises Compound (1): pharmaceutically acceptable dispersing carrier in a weight ratio of 1:1 to 1:3. In an embodiment, the solid dispersion comprises Compound (1): pharmaceutically acceptable dispersing carrier in a weight ratio of about 1:1.

[0105] In an embodiment, the solid dispersion is characterized by having an X-ray powder diffraction diagram (XRPD) that does not include a diffraction peak at a 2-theta angle of 40.0° or less when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30° C. As used herein, "Cu-Kα radiation" includes Cu-Kα1 radiation and Cu-Kα1,2 radiation, wherein Cu-Kα1 radiation has a wavelength of 1.54056 Å and Cu-Kα1,2 radiation has a mean wavelength of 1.54184 Å.

[0106] In another embodiment, the solid dispersion is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks in the range of 2.0 to 40.0° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0107] In yet another embodiment, the solid dispersion is characterized by having an X-ray powder diffraction diagram (XRPD) essentially the same as that shown in Figure 5 or Figure 6 below, when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0108] In yet another embodiment, the solid dispersion is characterized by having a differential scanning calorimetry curve containing a single glass transition temperature (Tg) signal when measured by modulated differential scanning calorimetry (mDSC) with a modulation index of 1°C / min and a heating rate of 3.0°C / min. Preferably, the single glass transition temperature (Tg) signal is in the range of 90 to 190°C, preferably in the range of 110 to 120°C.

[0109] In yet another embodiment, the solid dispersion comprises: (i) a D90 value of 100 μm or less, preferably 90 μm or less, and most preferably 85 μm or less; and / or (ii) a D50 value of 50 μm or less, preferably 45 μm or less, and most preferably 40 μm or less; and / or (iii) a D10 value of 20 μm or less, preferably 15 μm or less, and most preferably 13 μm or less The particles are characterized by a particle size distribution as measured by laser diffraction having:

[0110] In yet another embodiment, the solid dispersion comprises: (i) a D90 value in the range of 50 to 100 μm, preferably in the range of 55 to 90 μm, and most preferably in the range of 60 to 85 μm; and / or (ii) a D50 value in the range of 25 to 50 μm, preferably in the range of 30 to 45 μm, and most preferably in the range of 30 to 40 μm; and / or (iii) a D10 value in the range of 1 to 20 μm, preferably in the range of 5 to 15 μm, and most preferably in the range of 10 to 13 μm; The particles are characterized by a particle size distribution as measured by laser diffraction having a particle size distribution of:

[0111] As used herein, the term "particle size distribution" refers to a list of values ​​or a mathematical function that defines the relative amount, typically mass or volume, of particles present in a sample according to size. Particle size distribution can be characterized by one or more values, for example, D90, D50, or D10. Particle size distribution can be measured by means well known to those skilled in the art, for example, laser diffraction.

[0112] As used herein, "D90" refers to the particle size value where 90% of the total volume of the particles is made up of particles no larger than the stated size.

[0113] As used herein, "D50" refers to the particle size value where 50% of the total volume of the particles is made up of particles no larger than the stated size.

[0114] As used herein, "D10" refers to the particle size value where 10% of the total volume of the particles is made up of particles no larger than the indicated size.

[0115] A further aspect relates to the use of a solid dispersion as described herein for preparing a pharmaceutical composition, wherein the pharmaceutical composition is preferably as defined below.

[0116] Pharmaceutical Composition Another aspect provides a pharmaceutical composition comprising a solid dispersion as described herein and one or more pharmaceutically acceptable excipients. Another embodiment of the invention is a pharmaceutical composition comprising a therapeutically effective amount of a solid dispersion as described herein and one or more pharmaceutically acceptable excipients.

[0117] Another embodiment of the present invention is a pharmaceutical composition comprising a predetermined amount of the solid dispersion described herein and one or more pharmaceutically acceptable excipients, in this context, the predetermined amount refers to the initial amount of the solid dispersion used in preparing the pharmaceutical composition.

[0118] The term "pharmaceutically acceptable excipient" refers to a non-toxic ingredient that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable excipients that can be used in the compositions of the present invention include fillers, disintegrants, glidants, lubricants, and coating agents. The compositions may further include pharmaceutically acceptable excipients selected from buffers, binders, dispersants, surfactants, wetting agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, processing aids, colorants, sweeteners, flavors, fragrances, diluents, and other known additives that can be used in the manufacture of pharmaceuticals.

[0119] The pharmaceutical composition may contain conventional non-toxic pharmaceutically acceptable excipients.In an embodiment, one or more pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, glidants, lubricants and coating agents.In an embodiment, the pharmaceutical composition comprises fillers, disintegrants, glidants and lubricants.In an embodiment, the pharmaceutical composition comprises fillers, disintegrants, glidants, lubricants and coating agents.It should be understood that the pharmaceutical composition may comprise one or more excipients for each function, for example, one or more fillers, one or more disintegrants, one or more glidants, one or more lubricants, one or more coating agents.

[0120] In an embodiment, the filler is selected from the group consisting of microcrystalline cellulose, mannitol, and mixtures thereof. In an embodiment, the disintegrant is selected from the group consisting of cross-linked sodium carboxymethylcellulose, also known as croscarmellose sodium, sodium bicarbonate, crospovidone, sodium starch glycolate, and mixtures thereof. In a particular embodiment, the disintegrant is croscarmellose sodium. In an embodiment, the glidant is colloidal silicon dioxide. In an embodiment, the lubricant is selected from the group consisting of stearyl fumarate, magnesium stearate, and mixtures thereof. In a particular embodiment, the lubricant is sodium stearyl fumarate.

[0121] In embodiments, the one or more pharmaceutically acceptable excipients include mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

[0122] In an embodiment, the pharmaceutical composition comprises, consists of, or consists essentially of Compound (1), as defined herein, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, a solid dispersion comprising mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

[0123] In certain embodiments, the pharmaceutical composition comprises a coating agent, for example, when formulated as a film-coated tablet. In an embodiment, the coating agent comprises a film-forming agent, for example, polyvinyl alcohol, which may be partially hydrolyzed, an anti-tacking agent, for example, talc, a pigment, for example, titanium dioxide, glyceryl mono- and dicaprylocaprate (GMDCC), and iron oxide, for example, iron oxide yellow, and a lubricant, for example, sodium lauryl sulfate. Coating agents are, for example, commercially available under the trade name Opadry®, for example, Opadry® AMB II yellow. In a preferred embodiment, the coating agent does not contain titanium dioxide, for example, is titanium dioxide-free.

[0124] In an embodiment, the pharmaceutical composition comprises: (i) a tablet core comprising a solid dispersion as described herein, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; (ii) film coating.

[0125] In an embodiment, the pharmaceutical composition comprises: (i) a tablet core comprising, consisting of, or consisting essentially of a solid dispersion as described herein, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; (ii) consisting of or consisting essentially of a film coating.

[0126] In certain embodiments, the film coating is a non-functional film coating. In one embodiment, the film coating does not contain titanium dioxide.

[0127] In an embodiment, the pharmaceutical composition comprises a solid dispersion described herein in an amount ranging from 25 wt% to 65 wt%, preferably 35 wt% to 60 wt%, or 25 wt% to 35 wt%, or 27 wt% to 31 wt%, more preferably about 30 wt%, based on 100 wt% total weight of the pharmaceutical composition.

[0128] In an embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - in the range of 25 wt% to 65 wt% of a solid dispersion as described herein, and / or - one or more fillers in the range of 25wt% to 65wt%, and / or - disintegrants in the range of 4 wt% to 10 wt%, and / or - Glidants in the range of 1 wt% to 2 wt%, and / or - lubricant in the range of 1 wt% to 2 wt%, and / or Optionally, a coating agent is included in the range of 2 wt% to 5 wt%.

[0129] In any of the present and following embodiments referring to wt % of ingredients of the pharmaceutical composition, it is to be understood that the sum of the ranges or amounts of all ingredients does not exceed 100 wt %.

[0130] In a further embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - a solid dispersion as described herein in the range of 30 wt% to 60 wt%, preferably 35 wt% to 60 wt%, and / or one or more fillers in the range of 30 wt% to 60 wt%, preferably 35 wt% to 60 wt%, and / or - disintegrants in the range of 4 wt% to 7 wt%, and / or - Glidants in the range of 1 wt% to 1.5 wt%, and / or - lubricants in the range of 1 wt% to 1.5 wt%, and / or Optionally, a coating agent is included in the range of 3 wt% to 5 wt%.

[0131] In a further embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - a solid dispersion as described herein in the range of 25 wt% to 35 wt%, and / or - one or more fillers in the range of 55wt% to 65wt%, and / or - disintegrants in the range of 4 wt% to 7 wt%, and / or - Glidants in the range of 1 wt% to 2 wt%, and / or - lubricant in the range of 1 wt% to 2 wt%, and / or Optionally, a coating agent is included in the range of 3 wt% to 5 wt%.

[0132] In an embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - a solid dispersion as described herein in the range of 28 wt% to 30 wt%, and / or - one or more fillers in the range of 57wt% to 62wt%, and / or - disintegrants in the range of 4 wt% to 5 wt%, and / or - Glidants in the range of 1.4wt% to 1.5wt%, and / or - lubricant in the range of 1.4wt% to 1.5wt%, and / or Optionally, about 4 wt % of a coating agent.

[0133] In this embodiment, preferably, the lower limits of the ranges for solid dispersion agent, filler, disintegrant, glidant, and lubricant refer to pharmaceutical compositions that include a coating, while the upper limits of the same ranges refer to pharmaceutical compositions that do not include a coating.

[0134] In an embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - in the range of 25 wt% to 65 wt% of a solid dispersion as described herein, - one or more fillers in the range of 25 wt% to 65 wt%; - a disintegrant in the range of 4 wt% to 10 wt%; - Glidants in the range of 1wt% to 2wt% and - consisting essentially of or consisting of lubricants in the range of 1 wt% to 2 wt%, where the total range of all ingredients does not exceed 100 wt%.

[0135] In a further embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - 30 wt% to 60 wt%, preferably 35 wt% to 60 wt%, of a solid dispersion as described herein, - one or more fillers in the range of 30wt% to 60wt%, preferably 35wt% to 60wt%, - a disintegrant in the range of 4 wt% to 7 wt%; - Glidants in the range of 1wt% to 1.5wt% and - consisting essentially of or consisting of lubricants in the range of 1 wt% to 1.5 wt%, where the total range of all ingredients does not exceed 100 wt%.

[0136] In a further embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition: - in the range of 25 wt% to 35 wt% of a solid dispersion as described herein, - 55wt% to 65wt% of one or more fillers, - a disintegrant in the range of 4 wt% to 7 wt%; - Glidants in the range of 1wt% to 2wt% and - consisting essentially of or consisting of lubricants in the range of 1 wt% to 2 wt%, where the total range of all ingredients does not exceed 100 wt%.

[0137] In one embodiment, the pharmaceutical composition contains Compound (1) in an amount ranging from 10 to 20 wt%, based on 100 wt% of the total weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition contains Compound (1) in an amount of about 15 wt%, based on 100 wt% of the total weight of the pharmaceutical composition.

[0138] In certain embodiments, the pharmaceutical composition comprises, consists essentially of, or consists of about 15 wt% Compound (1), about 15 wt% hypromellose acetate succinate, about 36 wt% microcrystalline cellulose, about 24 wt% mannitol, about 7 wt% croscarmellose sodium, about 1.5 wt% colloidal silicon dioxide, and about 1.5 wt% sodium stearyl fumarate, based on 100 wt% total weight of the pharmaceutical composition.

[0139] In certain embodiments, the pharmaceutical composition comprises, consists essentially of, or consists of about 15 wt% Compound (1), about 15 wt% hypromellose acetate succinate, about 20 wt% microcrystalline cellulose, about 42 wt% mannitol, about 5 wt% croscarmellose sodium, about 1.5 wt% colloidal silicon dioxide, and about 1.5 wt% sodium stearyl fumarate, based on 100 wt% total weight of the pharmaceutical composition.

[0140] In certain embodiments, the pharmaceutical composition comprises, consists essentially of, or consists of about 14 wt% Compound (1), about 43 wt% hypromellose acetate succinate, about 19 wt% microcrystalline cellulose, about 24 wt% mannitol, about 7 wt% croscarmellose sodium, about 1.5 wt% colloidal silicon dioxide, and about 1.5 wt% sodium stearyl fumarate, based on 100 wt% total weight of the pharmaceutical composition.

[0141] In certain embodiments, the pharmaceutical composition comprises, consists essentially of, or consists of about 17.5 wt% Compound (1), about 17.5 wt% hypromellose acetate succinate, about 30 wt% microcrystalline cellulose, about 25 wt% mannitol, about 7 wt% croscarmellose sodium, about 1.5 wt% colloidal silicon dioxide, and about 1.5 wt% sodium stearyl fumarate, based on 100 wt% total weight of the pharmaceutical composition.

[0142] In certain embodiments, the pharmaceutical composition comprises, consists essentially of, or consists of about 15 wt% Compound (1), about 47 wt% hypromellose acetate succinate, about 15 wt% microcrystalline cellulose, about 15 wt% mannitol, about 5 wt% croscarmellose sodium, about 1 wt% colloidal silicon dioxide, and about 1 wt% sodium stearyl fumarate, based on 100 wt% total weight of the pharmaceutical composition.

[0143] In one embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of about 15 mg Compound (1), about 15 mg hypromellose acetate succinate, about 36 mg microcrystalline cellulose, about 24 mg mannitol, about 7 mg croscarmellose sodium, about 1.5 mg colloidal silicon dioxide, and about 1.5 mg sodium stearyl fumarate.

[0144] In one embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of about 15 mg Compound (1), about 15 mg hypromellose acetate succinate, about 20 mg microcrystalline cellulose, about 42 mg mannitol, about 5 mg croscarmellose sodium, about 1.5 mg colloidal silicon dioxide, and about 1.5 mg sodium stearyl fumarate.

[0145] In one embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of about 60 mg Compound (1), about 60 mg hypromellose acetate succinate, about 80 mg microcrystalline cellulose, about 168 mg mannitol, about 20 mg croscarmellose sodium, about 6 mg colloidal silicon dioxide, and about 6 mg sodium stearyl fumarate.

[0146] In an embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks at a 2-theta angle of 10.0° or less when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0147] In another embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks at a 2-theta angle of 9.0° or less when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20-30°C.

[0148] In yet another embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks at a 2-theta angle of 6.5° or less when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20-30°C.

[0149] In another embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks in the range of 2.0 to 10.0° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0150] In yet another embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks in the range of 2.0 to 9.0° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0151] In one embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks in the range of 2.0 to 6.5° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0152] In another embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not contain any diffraction peaks in the range of 2.0 to 10.0° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C.

[0153] In yet another embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not include a diffraction peak at a 2-theta angle of (5.9±0.2)° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20-30°C.

[0154] In a further embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) that does not include a diffraction peak at a 2-theta angle of (6.2±0.2)° when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20-30°C.

[0155] In another embodiment, the pharmaceutical composition is characterized by having an X-ray powder diffraction diagram (XRPD) essentially the same as that shown in Figure 15 or Figure 16 below, when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20-30°C.

[0156] For use in treatment, the solid dispersion or the pharmaceutical composition may be contained or formulated into a suitable dosage unit for easy administration. Thus, the solid dispersion or the pharmaceutical composition can be formulated into a dosage unit suitable for each administration route. Typical pharmaceutical dosage units include, for example, tablets, pills, capsules, suppositories, lozenges, troches, liquids, particularly infusion solutions, elixirs, syrups, sachets, emulsions or dispersible powders. Dosage forms and formulations of active ingredients are known in the art, and dosage forms can generally be prepared by any conventional method.

[0157] The solid dispersion or the pharmaceutical composition can be preferably administered orally and can be formulated into a suitable dosage unit formulation. The pharmaceutical composition can be administered as a tablet, hard or soft gelatin capsule, pill, granule, or suspension. In an embodiment, the pharmaceutical composition is in the form of a tablet, granule, or capsule. In a preferred embodiment, the pharmaceutical composition is in the form of a film-coated tablet. Suitable tablets can be obtained, for example, by mixing the solid dispersion with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders, and / or lubricants. Tablets can be compressed from the solid dispersion, a mixture of the solid dispersion and excipients, or pellets thereof. In another embodiment, the solid dispersion, a mixture of the solid dispersion and excipients, or pellets thereof can be filled into capsules.

[0158] From the viewpoint of compliance, oral administration may be preferred, but the route of administration is not limited to oral administration, and the solid dispersion or the pharmaceutical composition may be administered parenterally, for example, by intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection or implant, or by enteral, nasal, vaginal, rectal or topical administration.

[0159] The solid dispersion or pharmaceutical composition can be administered or included in a dosage form in a therapeutically effective amount. A therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result, such as the minimum amount necessary to prevent, ameliorate, or treat a disease or disorder, or an amount in which any toxic or adverse effects of the compound are outweighed by the therapeutically beneficial effects. As used herein, the terms "active ingredient," "active pharmaceutical ingredient," "active substance," and "API" refer to the component intended to provide pharmacological activity or other direct effect, e.g., Compound (1).

[0160] The pharmaceutical composition preferably contains a therapeutically effective amount of Compound (1). In embodiments, a therapeutically effective amount of Compound (1) can be divided into one or more individual dosage unit formulations, such that multiple individual dosage unit formulations may contain portions of a therapeutically effective amount of Compound (1). In embodiments, a tablet, a portion of a granule, or a capsule may contain 5 mg to 100 mg of Compound (1). In embodiments, a tablet, a portion of a granule, or a capsule may contain 15 mg to 80 mg of Compound (1). In embodiments, a tablet, a portion of a granule, or a capsule may contain 15 mg to 30 mg of Compound (1). In embodiments, a tablet, a portion of a granule, or a capsule may contain about 15, 30, or 60 mg of Compound (1).

[0161] For storage, the solid dispersion or the pharmaceutical composition can be packaged in a suitable container (i.e., a means for containing the solid dispersion or pharmaceutical composition). Such a container can be selected from a bag, a blister, a bottle, an ampule, and a vial. The container can be made from a suitable packaging material.

[0162] Typical packaging materials are selected from glass, polyethylene, polypropylene, polystyrene, polymethyl methacrylate, low-density polyethylene (LDPE), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), cyclic olefin copolymer (COC), cyclic olefin polymer (COP), polyethylene terephthalate (PET), glycol-modified polyethylene terephthalate (PETg), aluminum, polyamide, and any combination thereof. In certain embodiments, the solid dispersion is packaged in a double low-density polyethylene (LDPE) bag. In yet another embodiment, the pharmaceutical composition is packaged in a high-density polyethylene (HDPE) bottle. Preferably, the HDPE bottle further contains a desiccant. Typical desiccants can be selected from activated alumina, aerogel, benzophenone (as anion), bentonite clay, calcium chloride, calcium oxide, calcium sulfate, cobalt(II) chloride, copper(II) sulfate, lithium chloride, lithium bromide, magnesium chloride hexahydrate, magnesium sulfate, magnesium perchlorate, molecular sieves, phosphorus pentoxide, potassium carbonate, potassium hydroxide, rice, silica gel, sodium chlorate, sodium chloride, sodium hydroxide, sodium sulfate, sucrose, and sulfuric acid. In a preferred embodiment, the desiccant is silica gel.

[0163] A further embodiment of the present invention comprises a solid dispersion or a pharmaceutical composition as described herein; - a means for containing said solid dispersion or pharmaceutical composition, preferably a high density polyethylene bottle; - refers to a kit optionally including a desiccant, preferably silica gel.

[0164] Use for the treatment and / or prevention of neoplastic and / or hyperproliferative disorders In embodiments, provided is Compound (1) in the dosing regimens described herein for use in treating and / or preventing cancer. Additionally, further aspects relate to Compound (1) and the dosing regimens described herein for use in treating and / or preventing cancer, wherein the patient has previously undergone one or more anti-cancer treatments or therapies.

[0165] A further embodiment provides Compound (1) for use in treating and / or preventing cancer, wherein the patient has already received a different first-line, second-line, or later treatment. The different treatment includes administration of an anti-cancer therapy, drug, or agent that is different from and does not include Compound (1). The prior first-line, second-line, or later treatment is unrelated to the administration of Compound (1), and the prior first-line, second-line, or later treatment is completed or terminated before the treatment including administration of Compound (1) is administered.

[0166] A further aspect relates to a method for treating and / or preventing cancer, comprising administering Compound (1) to a patient in a dosage regimen described herein. In one embodiment, such a method comprises administering to a human in need of such treatment a therapeutically effective amount of Compound (1) disclosed herein. A further aspect relates to a method for treating and / or preventing cancer, comprising administering Compound (1) to a patient in a dosage regimen described herein, wherein the patient has already received a different first-line, second-line, or later treatment. In one embodiment, such a method comprises administering to a human in need of such treatment a therapeutically effective amount of Compound (1) disclosed herein, wherein the patient has already received a different first-line, second-line, or later treatment.

[0167] An embodiment relates to the use of Compound (1), in the dosing regimens described herein, in the manufacture of a medicament for treating and / or preventing cancer.

[0168] The solid dispersions and pharmaceutical compositions described herein can be used as medicaments in the dosage regimens described herein. In particular, the solid dispersions and pharmaceutical compositions described herein can be used in the dosage regimens described herein for the treatment and / or prevention of neoplastic and / or hyperproliferative disorders, in particular for anti-cancer therapy.

[0169] According to an aspect, there is provided a solid dispersion as described herein for use as a medicament, in the dosing regimen described herein. According to another aspect, there is provided a pharmaceutical composition as described herein for use as a medicament, in the dosing regimen described herein. Another embodiment of the invention is a solid dispersion or pharmaceutical composition for treating or preventing a disease, in the dosing regimen described herein.

[0170] According to an aspect, there is provided a solid dispersion as described herein for use as an anti-cancer medicament, in the dosing regimen described herein. According to another aspect, there is provided a pharmaceutical composition as described herein for use as an anti-cancer medicament, in the dosing regimen described herein.

[0171] In embodiments, there is provided a solid dispersion as described herein for use in treating and / or preventing a disease or disorder modulated by HER2, particularly a neoplastic and / or hyperproliferative disease, in the dosing regimen described herein. A further embodiment provides a pharmaceutical composition as described herein for use in treating and / or preventing a disease or disorder modulated by HER2, particularly a neoplastic and / or hyperproliferative disease, in the dosing regimen described herein. Another aspect refers to a solid dispersion as described herein or a pharmaceutical composition as described herein for use in a method for treating and / or preventing a disease or disorder modulated by HER2, particularly a neoplastic or hyperproliferative disease, in the dosing regimen described herein.

[0172] A further aspect relates to methods for treating and / or preventing diseases or disorders modulated by HER2, in particular neoplastic and / or hyperproliferative diseases, comprising administering to a patient a solid dispersion as described herein or a pharmaceutical composition as described herein in a dosing regimen as described herein. In an embodiment, such methods comprise administering to a human in need of such treatment a therapeutically effective amount of a solid dispersion or pharmaceutical composition as described herein.

[0173] A related aspect relates to the use of a solid dispersion as described herein or a pharmaceutical composition as described herein, in a dosing regimen as described herein, in the manufacture of a medicament. An embodiment relates to the use of a solid dispersion as described herein or a pharmaceutical composition as described herein, in a dosing regimen as described herein, in the manufacture of a medicament for the treatment and / or prevention of a disease or disorder modulated by HER2, in particular a neoplastic disease and / or a hyperproliferative disease.

[0174] In one aspect, there is provided a solid dispersion or pharmaceutical composition as described herein for use in the dosing regimens described herein for treating and / or preventing diseases and / or conditions where inhibition of wild-type and / or mutant HER2 is therapeutically beneficial, particularly diseases and / or conditions where inhibition of HER2 exon 20 mutant proteins is therapeutically beneficial, in the dosing regimens described herein. Examples of such diseases and / or conditions include, but are not limited to, neoplastic diseases and / or hyperproliferative diseases, such as cancer.

[0175] One aspect relates to a solid dispersion as described herein for use in treating and / or preventing neoplastic and / or hyperproliferative disorders, in the dosing regimens described herein. A further aspect relates to a pharmaceutical composition as described herein for use in treating and / or preventing neoplastic and / or hyperproliferative disorders, in the dosing regimens described herein.

[0176] As used herein, the term "hyperproliferative disorder" refers to a condition in which cell proliferation is greater than normal. Hyperproliferative disorders include malignant disorders, e.g., cancer, and non-malignant disorders. In a preferred embodiment, the hyperproliferative disorder is cancer. As used herein, the term "neoplastic disorder" refers to a disease or condition associated with cancer or a cancer indication. Cancers can be classified by the type of tissue from which they arise (histological type) and the primary site, or location in the body where the cancer first develops.

[0177] In an embodiment, the neoplastic and / or hyperproliferative disease is cancer.

[0178] In embodiments, there is provided a solid dispersion as described herein for use in treating and / or preventing cancer, in the dosing regimen described herein. A further embodiment provides a pharmaceutical composition as described herein for use in treating and / or preventing cancer, in the dosing regimen described herein. Another aspect refers to a solid dispersion as described herein or a pharmaceutical composition as described herein for use in a method of treating and / or preventing cancer, in the dosing regimen described herein.

[0179] Additionally, a further aspect relates to a solid dispersion or pharmaceutical composition as described herein for use in treating and / or preventing cancer, in the dosing regimen described herein, wherein the patient has already received one or more prior anti-cancer treatments or therapies. A further embodiment provides a solid dispersion or pharmaceutical composition as described herein for use in treating and / or preventing cancer, in the dosing regimen described herein, wherein the patient has already received a different first-line, second-line or subsequent treatment.

[0180] A further aspect is a method of treating and / or preventing cancer, comprising administering to a patient a solid dispersion described herein or a pharmaceutical composition described herein in a dosing regimen described herein. In an embodiment, such a method comprises administering to a human in need of such treatment a therapeutically effective amount of Compound (1) as disclosed herein.

[0181] A further aspect relates to a method of treating and / or preventing cancer, comprising administering a solid dispersion described herein or a pharmaceutical composition described herein in a dosing regimen described herein to a patient, wherein the patient has already received a different first-line, second-line, or later treatment. In an embodiment, such a method comprises administering a therapeutically effective amount of Compound (1) described herein to a human in need of such treatment, wherein the patient has already received a different first-line, second-line, or later treatment.

[0182] One embodiment relates to the use of a solid dispersion as described herein, or a pharmaceutical composition as described herein, in the dosing regimen as described herein, in the manufacture of a medicament for the treatment and / or prevention of cancer.

[0183] In an embodiment, the cancer is HER2 overexpression, HER2 amplification, and / or HER2 mutation. In an embodiment, the cancer is a HER2 exon 20 mutation cancer. In an embodiment, the neoplastic disease and / or hyperproliferative disease is a HER2 overexpression, HER2 amplification, and / or HER2 mutation cancer.

[0184] As used herein, "HER2 overexpression" refers to a cancer in which the cells of the cancer or tumor express HER2 at levels detectable by immunohistochemistry (e.g., IHC2+ and IHC3+) and / or methods that assay for ERBB2 messenger RNA.

[0185] As used herein, "HER2 amplified" refers to a cancer in which the cancer or tumor cells display two or more copies of the HER2 gene ERBB2, particularly 3, 4, 5, 6, 7, 8, 9 or 10 or more copies, preferably 6 or more copies.

[0186] HER2 expression, gene copy number, and amplification can be measured, for example, by nucleic acid sequencing (e.g., sequencing of genomic DNA or cDNA), measuring mRNA expression, measuring protein abundance, or a combination thereof. HER2 testing methods include immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), chromogenic in situ hybridization (CISH), RNA quantification using techniques such as ELISA and RT-PCR, microarray analysis, and next-generation sequencing (NGS). HER2 expression in or on cancer sample cells can be compared with reference cells. The reference cells can be non-cancerous cells obtained from the same subject as the sample cells. The reference cells can be non-cancerous cells obtained from a different subject or population of subjects.

[0187] If HER2 is overexpressed and / or amplified in or on the cells of a cancer, the cancer may be said to be "HER2 positive."

[0188] As used herein, "HER2 mutation" refers to a cancer having at least one mutation, i.e., a change in the nucleic acid sequence of the HER2 gene and / or a change in the amino acid sequence of the HER2 protein. Such mutations include, but are not limited to, those listed below. Mutations can be detected by any method known to those skilled in the art, for example, molecular diagnostic methods, including (but not limited to) polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE), heteroduplex analysis, restriction fragment length polymorphism (RFLP), next-generation sequencing (NGS), and whole-exome sequencing.

[0189] As used herein, "cancer with a HER2 exon 20 mutation" or "HER2 exon 20 mutant cancer" refers to a cancer in which the cancer or tumor cells have at least one HER2 exon 20 mutation, including (but not limited to) the mutations listed below.

[0190] Exon 20 of ERBB2 (HER2) encodes part of the kinase domain, spanning amino acids 769 to 835. Any mutation, insertion, duplication, or deletion within this region is defined as an exon 20 mutation, including the following mutations: p.A772_G773insMMAY; p.Y772_A775_dup(YVMA); p.A775_G776insYVMA; p.Y772insYVMA; p.M774delinsWLV; p.A775_G776insSVMA; p.A775_G776insVVMA; p.A775_G776insYV MS;p.A775_G776insC;p.A776_delinsVC;p.A776_delinsLC;p.A776_delinsVV;p.A776_delinsAVGC;p.A776_delinsIC;p.A776_V777delinsCVC;p.V777_insE;p.G778_P780dup(GSP);p.G776_delinsVC ("p." refers to the HER2 protein).

[0191] In addition, tumorigenic HER2 mutations exist outside of exon 20 and include the following mutations: p.S310F; p.R678Q; p.L755S; p.L755A; p.L755P; p.S310Y; p.S310A; p.V842I; p.D769Y; p.D769H; p.R103Q; p.G1056S; p.I767M; p.L869R; p.L869R; p.T733I; p.T862A; p.V697L; p.V777L; p.V777M; p.R929W; p.D277H; p.D277Y; p.G660D ("p." refers to the HER2 protein).

[0192] In embodiments, the neoplastic and / or hyperproliferative disease or cancer is, but is not limited to, one of the following cancers, tumors or other proliferative diseases:

[0193] Cancers / tumors / carcinomas of the head and neck: for example, tumors / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lips, gums, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, and buccal mucosa), oropharynx (including base of tongue, tonsils, tonsillar pillars, soft palate, tonsillar fossa, and pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, and vocal cords), hypopharynx, and salivary glands (including minor salivary glands);

[0194] Lung cancers / tumors / carcinomas: e.g., non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchoalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, combined oat cell carcinoma);

[0195] Mediastinal neoplasms: for example, neurogenic tumors (including neurofibroma, schwannoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, nonseminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangioleiomyoma);

[0196] Cancers / tumors / carcinomas of the gastrointestinal (GI) tract: e.g., esophagus, stomach (gastric cancer), pancreas, liver and biliary tract (including hepatocellular carcinoma (HCC), e.g., childhood HCC, fibrolamellar HCC, complex HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcomatous HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocellular carcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatzkin's tumor), gallbladder, extrahepatic bile duct, small intestine (including duodenum, jejunum, ileum) ), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stromal tumor (GIST)), genitourinary system (kidney, e.g., including renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), renal epithelioma, Grawitz's tumor), ureter, bladder (e.g., urachal carcinoma, urothelial carcinoma), urethra, e.g., distal, bulbomembranous, prostate, prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), penis), appendix tumors / carcinomas;

[0197] Cancer / tumor / carcinoma of the testis: e.g., seminoma, nonseminoma;

[0198] Gynecological cancers / tumors / carcinomas: for example, tumors / cancers / cancers of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, and uterine body (including endometrium and fundus);

[0199] Breast cancer / tumor / cancer type: for example, breast cancer (infiltrating ductal, colloid, lobular infiltrating, tubular, glandular cystic, papillary, medullary, mucinous), hormone receptor positive breast cancer (estrogen receptor positive breast cancer, progesterone receptor positive breast cancer), HER2 positive breast cancer, triple negative breast cancer, Paget's disease of the breast;

[0200] Cancers / tumors / carcinomas of the endocrine system: for example, tumors / carcinomas / cancers of the endocrine glands, thyroid gland (thyroid cancer / tumors; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid cancer / tumors), adrenal cortex (adrenocortical cancer / tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, carotid body, islet cell tumors, paraganglia, pancreatic endocrine tumors (PET; non-functional (nonfluorine unctional) PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors;

[0201] Sarcomas of soft tissues: e.g., fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of the tendon sheath, solitary fibrous tumor of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, dysplastic small cell tumor;

[0202] Sarcomas of bone: e.g., myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, and mesenchymal chondrosarcomas), osteosarcoma (including parosteal, periosteal, high-grade superficial, small cell, radiation-induced osteosarcoma, and Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, and chondroblastoma;

[0203] Mesothelioma: e.g., pleural mesothelioma, peritoneal mesothelioma;

[0204] Cancers of the skin: e.g., basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentigo, nodular, and intraocular melanoma), actinic keratosis, and eyelid cancer;

[0205] Neoplasms of the central nervous system and brain: for example, astrocytomas (cerebral, cerebellar, diffuse, fibrous, anaplastic, pilocytic, protoplasmic, round cell), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, ganglioneuroma, neuroblastoma, retinoblastoma, schwannoma (e.g., acoustic), supinal axis tumor;

[0206] peripheral nervous system cancer;

[0207] Lymphomas and leukemias: for example, B-cell non-Hodgkin's lymphoma (NHL) (small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt lymphoma (BL)), T-cell non-Hodgkin's lymphoma (anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma ( ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (BchlorineL), chronic T-cell lymphocytic leukemia (TchlorineL), B-cell small lymphocytic lymphoma (B-SLL) , cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte-predominant HD (NLPHD), nodular sclerosing HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-predominant classical HD, and lymphopenic HD (LDHD)), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), / myeloid leukemia (AML), acute lymphocytic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous / myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML);

[0208] Carcinoma of unknown primary site (CUP).

[0209] All cancers / tumors / carcinomas referred to above that are characterized by a particular location / origin within the body are meant to include both the primary tumor and metastatic tumors derived therefrom. Preferably, cancers as defined herein (including, for example, in any embodiment that refers to a type of cancer) are metastatic, advanced, and / or unresectable.

[0210] All the above mentioned cancers / tumors / carcinomas can be further differentiated by histopathological classification.

[0211] Epithelial carcinomas, such as squamous cell carcinoma (SCC) (in situ carcinoma, superficial invasive carcinoma, verrucous carcinoma, pseudosarcoma, undifferentiated carcinoma, transitional cell carcinoma, lymphoepithelial carcinoma), adenocarcinoma (AC) (well-differentiated carcinoma, mucinous carcinoma, papillary carcinoma, pleomorphic giant cell carcinoma, tubular carcinoma, small cell carcinoma, signet ring cell carcinoma, spindle cell carcinoma, clear cell carcinoma, oat cell carcinoma, colloid carcinoma, adenosquamous carcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma), mucinous cystadenocarcinoma, spiculated cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid);

[0212] Non-epithelial cancers, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed carcinomas, and undifferentiated carcinomas.

[0213] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is manifested by at least one solid tumor.

[0214] In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, endocrine cancer, gastrointestinal cancer, gynecological cancer, head and neck cancer, lung cancer, nervous system cancer, and skin cancer.

[0215] Preferably, the brain tumor is a glioblastoma or a glioma.

[0216] Preferably, the breast cancer is lobular breast cancer. Additionally or alternatively, the breast cancer is preferably metastatic.

[0217] Preferably, the endocrine cancer is a nerve sheath tumor, more preferably a HER2-mutated nerve sheath tumor.

[0218] Preferably, the gastrointestinal cancer is selected from the group consisting of anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colon cancer, esophagogastric cancer, stomach cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, and small intestine cancer. Additionally or alternatively, the gastrointestinal cancer may be a gastrointestinal neuroendocrine tumor, preferably a HER2 mutant type. More preferably, the gastrointestinal cancer is selected from the group consisting of gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, and esophageal adenocarcinoma, in particular, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, and metastatic esophageal adenocarcinoma.

[0219] Preferably, the gynecological cancer is selected from the group consisting of cervical cancer, uterine cancer, endometrial cancer and ovarian cancer.

[0220] Preferably, the head and neck tumor is a salivary gland cancer or tumor.

[0221] Preferably, the lung cancer is non-small cell lung cancer (NSCLC).

[0222] Preferably, the nervous system cancer is a peripheral nervous system cancer, more preferably a HER2-amplified peripheral nervous system cancer.

[0223] Preferably, the skin cancer is not melanoma, ie, a non-melanoma skin cancer.

[0224] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, nerve sheath tumor, anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colon cancer, esophagogastric cancer, stomach cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small intestine cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non-small cell lung cancer (NSCLC), peripheral nervous system cancer, and non-melanoma skin cancer.

[0225] In some embodiments, the cancer is a HER2-overexpressing, HER2-amplified, and / or HER2-mutated (particularly HER2 exon 20 mutated) cancer selected from the group consisting of glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, nerve sheath tumor, anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colon cancer, esophagogastric cancer, stomach cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small intestine cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non-small cell lung cancer (NSCLC), peripheral nervous system cancer, and non-melanoma skin cancer.

[0226] In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colon cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0227] In some embodiments, the cancer is a HER2-overexpressing, HER2-amplified and / or HER2-mutated (particularly a HER2 exon 20 mutation) cancer selected from the group consisting of brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colon cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.

[0228] In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colon cancer, endometrial cancer, skin cancer, stomach cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0229] In an embodiment, the cancer is a HER2-overexpressing, HER2-amplified and / or HER2-mutated (particularly a HER2 exon 20-mutated) cancer selected from brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colon cancer, endometrial cancer, skin cancer, stomach cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.

[0230] In other embodiments, the cancer is selected from the group consisting of breast cancer, bladder cancer, colon cancer, gastrointestinal cancer, esophageal cancer, or lung cancer. In a further embodiment, the cancer is selected from lung cancers / tumors / carcinomas, such as non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchoalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, complex oat cell carcinoma). In a further embodiment, the cancer is NSCLC. In a further embodiment, the cancer is HER2 exon 20 mutant NSCLC. In a further embodiment, the cancer is unresectable. In a further embodiment, the cancer is unresectable HER2 exon 20 mutant NSCLC.

[0231] In a preferred embodiment, the cancer is progressive or metastatic. In a further preferred embodiment, the cancer is both progressive and metastatic. In a further preferred embodiment, when the cancer is metastatic, metastases are present in the lungs, lymph nodes, or bone. In a further preferred embodiment, the cancer is a progressive cancer comprising metastases, and the metastases are present in the lungs, lymph nodes, or bone.

[0232] Additionally or alternatively, the cancer may be unresectable.

[0233] In a preferred embodiment, the cancer is an unresectable, advanced cancer, including solid tumors and solid metastases, where the metastases are in the lung, lymph node tissue or bone.

[0234] In a preferred embodiment, the cancer is advanced NSCLC, including solid, unresectable tumors and metastases, the metastases being in the lung, lymph node tissue or bone.

[0235] In a preferred embodiment, the cancer is HER2 exon 20 mutated advanced NSCLC, including solid unresectable tumors and metastases, which are present in lung or lymph node tissue or bone.

[0236] In one embodiment, the cancer is advanced, unresectable, or metastatic NSCLC with a HER2 mutation, wherein the HER2 mutation is in the tyrosine kinase domain. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a first line of treatment. More preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a second or subsequent line of treatment.

[0237] In one embodiment, the cancer is HER2-positive metastatic breast cancer. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a first line of treatment. More preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a second or subsequent line of treatment.

[0238] In an embodiment, the cancer is HER2-positive metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, or metastatic esophageal adenocarcinoma. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a first line of treatment. Even more preferably, in this embodiment, the solid dispersion or pharmaceutical composition described herein is administered as a second or subsequent line of treatment.

[0239] A further aspect relates to Compound (1), a solid dispersion or a pharmaceutical composition for use as a medicament, in particular for treating and / or preventing neoplastic and / or hyperproliferative disorders, such as cancer, in the dosing regimen described herein, wherein Compound (1), the solid dispersion or the pharmaceutical composition comprises: - in subjects in a fasting state, and / or in combination with medicines that increase gastric pH, preferably proton pump inhibitors (PPIs), antacids or antihistamines, and / or - administered to a subject with a gastric pH in the range of about 1-7, preferably a subject with a gastric pH in the range of about 1-5.

[0240] In embodiments, the solid dispersions described herein or the pharmaceutical compositions described herein are administered in a dosage regimen described herein: - in subjects in a fasting state, and / or - administered in combination with a medication that increases gastric pH, preferably a proton pump inhibitor (PPI), an antacid or an antihistamine.

[0241] Another aspect relates to compound (1) as defined above for use in treating and / or preventing neoplastic and / or hyperproliferative diseases, wherein compound (1) is administered in the dosage regimen described herein: - in subjects in a fasting state, and / or - Administered in combination with medications that increase gastric pH.

[0242] In an embodiment, Compound (1), the solid dispersion, or the pharmaceutical composition is administered to a subject in the fasted state according to a dosing regimen described herein.

[0243] As used herein, the term "subject" refers to a human, for example, a human who has, is at risk of having, or may have cancer.

[0244] In an embodiment, Compound (1), the solid dispersion, or the pharmaceutical composition is administered in combination with a pharmaceutical agent that increases gastric pH, preferably a proton pump inhibitor (PPI), an antacid, or an antihistamine, in a dosing regimen described herein.

[0245] In an embodiment, Compound (1), the solid dispersion, or the pharmaceutical composition is administered in a dosing regimen described herein to a subject in a fasted state in combination with a pharmaceutical agent that increases gastric pH, preferably a proton pump inhibitor (PPI), an antacid, or an antihistamine.

[0246] In an embodiment, Compound (1), the solid dispersion, or the pharmaceutical composition is administered to a subject having a gastric pH in the range of about 1-7 at a dosing regimen described herein.

[0247] In an embodiment, Compound (1), the solid dispersion, or the pharmaceutical composition is administered to a subject having a gastric pH in the range of about 1-5 at a dosing regimen described herein.

[0248] As used herein, a "fasted subject" refers to a subject who has not eaten for at least 8 hours, preferably at least 10 hours, typically overnight, before administering the solid dispersion or pharmaceutical composition or dosage form thereof. A fasted subject may conveniently be administered Compound (1), the solid dispersion, the pharmaceutical composition or dosage form thereof with water after fasting for at least 8 or 10 hours. After that, the subject cannot eat for, for example, 4 hours, but can drink a small amount of water after administration of the pharmaceutical agent, for example, 2 hours later.

[0249] In embodiments, a subject in a fasted state is a subject who has not eaten for at least 2 hours prior to administration of a solid dispersion or pharmaceutical composition described herein and / or a subject who has not eaten for at least 1 hour after administration of a solid dispersion or pharmaceutical composition described herein.

[0250] In embodiments, a fasted subject is one who has not eaten for about 2 hours before administration of a solid dispersion or pharmaceutical composition described herein and a subject who has not eaten for about 1 hour after administration of a solid dispersion or pharmaceutical composition described herein. In these embodiments, a fasted subject may be referred to as a "modified fasted subject."

[0251] "Drugs that increase gastric pH" refer to a class of drugs that neutralize gastric acid. Drugs that neutralize gastric acid may reduce pepsin activity. In an embodiment, the drug that increases gastric pH is a proton pump inhibitor. The term "proton pump inhibitor" (PPI) refers to a class of drugs that cause a fundamental and sustained reduction in gastric acid production. In an embodiment, they are suppressors of gastric acid secretion. In an embodiment, PPIs that may be administered in combination with Compound (1), the solid dispersion, or the pharmaceutical composition include, but are not limited to, rabeprazole, omeprazole, pantoprazole, esomeprazole, lansoprazole, dexlansoprazole, and ilaprazole. Rabeprazole is a proton pump inhibitor indicated for diseases in which gastric pH is elevated, such as reflux esophagitis.

[0252] In an embodiment, the pharmaceutical agent that increases gastric pH is an antacid. The term "antacid" refers to a class of pharmaceutical agents that neutralize gastric acid. In an embodiment, antacids that may be administered in combination with Compound (1), the solid dispersion, or the pharmaceutical composition include, but are not limited to, aluminum, calcium, magnesium, or sodium salts, such as aluminum hydroxide, magnesium hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate, and sodium bicarbonate.

[0253] In an embodiment, the pharmaceutical agent that increases gastric pH is an antihistamine, particularly an H2 receptor antagonist. The term "H2 receptor antagonist" refers to a class of pharmaceutical agents that block the action of histamine in the stomach. In an embodiment, antihistamines that may be administered in combination with Compound (1), the solid dispersion, or the pharmaceutical composition include, but are not limited to, cimetidine, ranitidine, famotidine, nizatidine, roxatidine, lafutidine, lavortidine, and niperotidine.

[0254] The compound (1), the solid dispersion, the pharmaceutical composition, or dosage form thereof, and the pharmaceutical agent that increases gastric pH can be administered simultaneously, concurrently, sequentially, or consecutively. The term "simultaneous" refers to administration of both compounds / compositions at substantially the same time. The term "concurrent" refers to administration of the active ingredients within the same general period, e.g., on the same day, but not necessarily simultaneously. The term "sequential" administration includes administration of one active ingredient using one or more doses during a first period, e.g., over several hours, days, or a week, followed by administration of the other active ingredient using one or more doses during a second period, e.g., over several hours, days, or a week. Overlapping schedules can also be used, including administration of the active ingredients on different days throughout the treatment period, not necessarily in a regular order. The term "sequential" administration alternatively refers to administration in which the administration of the first compound is completed immediately followed by a second administration step. Variations on these general administration forms can also be used.

[0255] In an embodiment, Compound (1), the solid dispersion, the pharmaceutical composition, or a dosage form thereof is administered in a dosing regimen described herein after a pharmaceutical agent that increases gastric pH, preferably a proton pump inhibitor (PPI), an antacid, or an antihistamine.

[0256] In another aspect, the present invention relates to a solid dispersion or a pharmaceutical composition as described herein for use in treating and / or preventing a neoplastic disease and / or a hyperproliferative disease as defined herein, wherein said solid dispersion or said pharmaceutical composition is administered in combination with a cytostatic and / or cytotoxic active substance and / or in combination with radiation therapy and / or immunotherapy in a dosing regimen as described herein.

[0257] In another aspect, the present invention relates to a combination of a solid dispersion or a pharmaceutical composition as described herein, in the dosing regimen as described herein, with a cytostatic and / or cytotoxic agent and / or radiation therapy and / or immunotherapy, for use in treating and / or preventing cancer.

[0258] The solid dispersions or pharmaceutical compositions described herein can be used alone or in combination with one or more other pharmacologically active agents, such as state-of-the-art or standard of care compounds, such as cell growth inhibitors, anti-angiogenic agents, steroids or immune modulators / checkpoint inhibitors.

[0259] Pharmacologically active substances that may be administered in combination with the solid dispersions or pharmaceutical compositions described herein include hormones, hormone analogs and antihormones (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g., anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane, etc.), LHRH agonists and antagonists (e.g., goserelin acetate, leuprolide), inhibitors of growth factors and / or their corresponding receptors (growth factors, e.g., platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), etc.), and the like. ), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, e.g., HER2, HER3, HER4) and hepatocyte growth factor (HGF) and / or their corresponding receptors, etc.), such as (anti) growth factor antibodies, (anti) growth factor receptor antibodies and tyrosine kinase inhibitors (e.g., cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab, anti-metabolites (e.g., antifolates, e.g., methotrexate, raltitrexed, pyrimidine analogs, e.g., 5-fluorouracil, ribonucleoside and deoxyribonucleoside analogs, capecitabine and gemcitabine, purine and adenosine analogs, e.g., mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (arabinose),C), fludarabine); antitumor antibiotics (e.g., anthracyclines, e.g., doxorubicin, Doxil (pegylated liposomal doxorubicin hydrochloride, Myoset (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); Alkylating agents (e.g., estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as carmustine and lomustine, thiotepa, etc.); antimitotic agents (e.g., vinca alkaloids such as vinblastine, vindesine, vinorelbine, and vincristine, etc. and taxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g., tasquinimod), tubulin inhibitors; DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins, e.g., etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone, etc.), serine / threonine kinase inhibitors (e.g., PDK1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR / PI3K inhibitors, STK33 inhibitors, AKT inhibitors, PLK1 inhibitors, CDK inhibitors, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g., IAP activators, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, KRAS inhibitors (e.g., KRASG12C inhibitors), signal transduction pathway inhibitors (e.g., SOS1 inhibitors), FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors, Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs (e.g., everolimus, temsirolimus, ladaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors, immunotherapeutic agents, for example, immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LA G3 and TIM3 binding molecules / immunoglobulins such as ipilimumab, nivolumab, pembrolizumab, etc.), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T cell engagers (e.g., bispecific T cell engagers (BiTE®), e.g., CD3×BCMA, CD3×CD33, CD3×CD19, PSMA×CD3, etc.), tumor vaccines, and various chemotherapeutic agents such as amifostine, anagrelide, clodronat, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer.

[0260] Dosage and Administration Schedule of Compound (1) An object of the present invention is to provide a safe and effective dosing regimen for administering Compound (1) or a pharmaceutical composition comprising Compound (1) in the described dosing regimen. This dosing regimen is particularly useful for use in the treatment of cancer. Additionally, this dosing regimen for Compound (1) or a pharmaceutical composition comprising Compound (1) is particularly useful in methods of treating patients suffering from cancer. Additionally, this dosing regimen is believed to be suitable as a second-line or later treatment in patients who have already undergone one or more prior cancer treatments.

[0261] As used herein, "daily dose" or "total daily dose" refers to the amount of active agent, i.e., Compound (1), administered to a patient within a 24-hour time frame, which does not necessarily begin at noon or midnight.

[0262] Surprisingly, as described above and in the Examples below, it has been discovered that the use of Compound (1) in the treatment of cancer at daily doses of at least 30 mg is safe and effective.

[0263] In a preferred embodiment, Compound (1) is administered in a daily dose of at least 60 mg. Alternatively, the method of treating a patient suffering from cancer described above comprises administering Compound (1) in a daily dose of at least 60 mg.

[0264] In a preferred embodiment, Compound (1) is administered in a daily dose of at least 80 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of at least 80 mg.

[0265] In a preferred embodiment, Compound (1) is administered in a daily dose of at least 120 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of at least 120 mg.

[0266] In a preferred embodiment, Compound (1) is administered in a daily dose of at least 180 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of at least 180 mg.

[0267] In a preferred embodiment, Compound (1) is administered in a daily dose of at least 200 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of at least 200 mg.

[0268] In a preferred embodiment, Compound (1) is administered in a daily dose of at least 240 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of at least 240 mg.

[0269] In a preferred embodiment, Compound (1) is administered in a daily dose of at least 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of at least 300 mg.

[0270] In a preferred embodiment, Compound (1) is administered in a daily dose of 30 mg to 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 30 mg to 600 mg.

[0271] In a preferred embodiment, Compound (1) is administered in a daily dose of 60 mg to 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 60 mg to 600 mg.

[0272] In a preferred embodiment, Compound (1) is administered in a daily dose of 80 mg to 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 80 mg to 600 mg.

[0273] In a preferred embodiment, Compound (1) is administered in a daily dose of 120 mg to 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 120 mg to 600 mg.

[0274] In a more preferred embodiment, Compound (1) is administered in a daily dose of 30 mg to 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 30 mg to 300 mg.

[0275] In a more preferred embodiment, Compound (1) is administered in a daily dose of 60 mg to 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 60 mg to 300 mg.

[0276] In a more preferred embodiment, Compound (1) is administered in a daily dose of 80 mg to 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 80 mg to 300 mg.

[0277] In a more preferred embodiment, Compound (1) is administered in a daily dose of 120 mg to 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 120 mg to 300 mg.

[0278] In a preferred embodiment, Compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0279] In a preferred embodiment, Compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0280] In a preferred embodiment, Compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, or 300 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, or 300 mg.

[0281] In a preferred embodiment, Compound (1) is administered in a daily dose of 30 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 30 mg.

[0282] In a preferred embodiment, Compound (1) is administered in a daily dose of 60 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 60 mg.

[0283] In a preferred embodiment, Compound (1) is administered in a daily dose of 120 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 120 mg.

[0284] In a preferred embodiment, Compound (1) is administered in a daily dose of 180 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 180 mg.

[0285] In a preferred embodiment, Compound (1) is administered in a daily dose of 200 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 200 mg.

[0286] In a preferred embodiment, Compound (1) is administered in a daily dose of 240 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 240 mg.

[0287] In a preferred embodiment, Compound (1) is administered in a daily dose of 300 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 300 mg.

[0288] In a preferred embodiment, Compound (1) is administered in a daily dose of 360 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 360 mg.

[0289] In a preferred embodiment, Compound (1) is administered in a daily dose of 400 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 400 mg.

[0290] In a preferred embodiment, Compound (1) is administered in a daily dose of 420 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 420 mg.

[0291] In a preferred embodiment, Compound (1) is administered in a daily dose of 480 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 480 mg.

[0292] In a preferred embodiment, Compound (1) is administered in a daily dose of 500 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 500 mg.

[0293] In a preferred embodiment, Compound (1) is administered in a daily dose of 540 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 540 mg.

[0294] In a preferred embodiment, Compound (1) is administered in a daily dose of 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) in a daily dose of 600 mg.

[0295] Within preferred embodiments, Compound (1) is administered once or twice daily, meaning that the daily dose is either administered in a single dose or the daily dose is divided into two separate doses, each administered at a different time within the day, i.e., 24 hours.

[0296] In a preferred embodiment, Compound (1) is administered once daily. In a preferred embodiment, Compound (1) is administered as a single dose within a 24 hour period.

[0297] In a preferred embodiment, Compound (1) is administered twice daily. In a preferred embodiment, Compound (1) is administered twice within a 24 hour period.

[0298] In a preferred embodiment, each of the two daily doses of Compound (1) corresponds to half of the daily dose. By administering the required daily dose of Compound (1) in two doses containing the same amount, a simple and reliable application scheme can be provided.

[0299] In a further preferred embodiment, Compound (1) is administered for at least 21 consecutive days. In a further preferred embodiment, Compound (1) is administered for X times 21 days, where X is a natural number equal to or greater than 1. Additionally, the overall cancer treatment may include administration-free intervals during treatment periods involving administration of Compound (1).

[0300] In certain embodiments, Compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg; or Compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg, or Compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0301] In certain embodiments, Compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg; or Compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg, or Compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0302] In certain embodiments, Compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg, or Compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg, or Compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg.

[0303] In some embodiments, Compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0304] In some embodiments, Compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0305] In some embodiments, Compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg.

[0306] In a preferred embodiment, Compound (1) is administered once daily at a daily dose of 60 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 60 mg.

[0307] In a preferred embodiment, Compound (1) is administered once daily at a daily dose of 120 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 120 mg.

[0308] In a preferred embodiment, Compound (1) is administered once daily at a daily dose of 180 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 180 mg.

[0309] In a preferred embodiment, Compound (1) is administered once daily at a daily dose of 240 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 240 mg.

[0310] In a preferred embodiment, Compound (1) is administered once daily at a daily dose of 300 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 300 mg.

[0311] In a preferred embodiment, Compound (1) is administered once daily at a daily dose of 360 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 360 mg.

[0312] In a preferred embodiment, Compound (1) is administered once daily at a daily dose of 400 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 400 mg.

[0313] In a preferred embodiment, Compound (1) is administered once daily at a daily dose of 420 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 420 mg.

[0314] In a preferred embodiment, Compound (1) is administered once daily at a daily dose of 480 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 480 mg.

[0315] In a preferred embodiment, Compound (1) is administered once daily at a daily dose of 500 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 500 mg.

[0316] In a preferred embodiment, Compound (1) is administered once daily at a daily dose of 540 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 540 mg.

[0317] In a preferred embodiment, Compound (1) is administered once daily at a daily dose of 600 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) once daily at a daily dose of 600 mg.

[0318] In some embodiments, Compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0319] In some embodiments, Compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0320] In some embodiments, Compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg.

[0321] In a preferred embodiment, Compound (1) is administered twice daily at a daily dose of 30 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 30 mg. Preferably, in these embodiments, each of the twice daily doses is 15 mg.

[0322] In a preferred embodiment, Compound (1) is administered twice daily at a daily dose of 60 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 60 mg. Preferably, in these embodiments, each of the twice daily doses is 30 mg.

[0323] In a preferred embodiment, Compound (1) is administered twice daily at a daily dose of 120 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 120 mg. Preferably, in these embodiments, each of the twice daily doses is 60 mg.

[0324] In a preferred embodiment, Compound (1) is administered twice daily at a daily dose of 200 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 200 mg. Preferably, in these embodiments, each of the twice daily doses is 100 mg.

[0325] In a preferred embodiment, Compound (1) is administered twice daily at a daily dose of 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 300 mg. Preferably, in these embodiments, each of the twice daily doses is 150 mg.

[0326] In a preferred embodiment, Compound (1) is administered twice daily at a daily dose of 360 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 360 mg. Preferably, in these embodiments, each of the twice daily doses is 180 mg.

[0327] In a preferred embodiment, Compound (1) is administered twice daily at a daily dose of 400 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 400 mg. Preferably, in these embodiments, each of the twice daily doses is 200 mg.

[0328] In a preferred embodiment, Compound (1) is administered twice daily at a daily dose of 420 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 420 mg. Preferably, in these embodiments, each of the twice daily doses is 210 mg.

[0329] In a preferred embodiment, Compound (1) is administered twice daily at a daily dose of 480 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 480 mg. Preferably, in these embodiments, each of the twice daily doses is 240 mg.

[0330] In a preferred embodiment, Compound (1) is administered twice daily at a daily dose of 500 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 500 mg. Preferably, in these embodiments, each of the twice daily doses is 250 mg.

[0331] In a preferred embodiment, Compound (1) is administered twice daily at a daily dose of 540 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 540 mg. Preferably, in these embodiments, each of the twice daily doses is 270 mg.

[0332] In a preferred embodiment, Compound (1) is administered twice daily at a daily dose of 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering Compound (1) twice daily at a daily dose of 600 mg. Preferably, in these embodiments, each of the twice daily doses is 300 mg.

[0333] In one embodiment, Compound (1) is administered orally, preferably as a tablet, once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0334] In one embodiment, Compound (1) is administered orally, preferably as a tablet, once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0335] In one embodiment, Compound (1) is administered orally, preferably as a tablet, once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg.

[0336] In one embodiment, Compound (1) is administered orally, preferably as a tablet, at a daily dose of 60 mg once daily. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, at a daily dose of 60 mg once daily.

[0337] In one embodiment, Compound (1) is administered orally, preferably as a tablet, at a daily dose of 120 mg once daily. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, at a daily dose of 120 mg once daily.

[0338] In one embodiment, Compound (1) is administered orally, preferably as a tablet, at a daily dose of 180 mg once daily. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, at a daily dose of 180 mg once daily.

[0339] In one embodiment, Compound (1) is administered orally, preferably as a tablet, at a daily dose of 240 mg once daily. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, at a daily dose of 240 mg once daily.

[0340] In one embodiment, Compound (1) is administered orally, preferably as a tablet, at a daily dose of 300 mg once daily. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, at a daily dose of 300 mg once daily.

[0341] In one embodiment, Compound (1) is administered orally, preferably as a tablet, at a daily dose of 360 mg once daily. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, at a daily dose of 360 mg once daily.

[0342] In one embodiment, Compound (1) is administered orally, preferably as a tablet, at a daily dose of 400 mg once daily. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, at a daily dose of 400 mg once daily.

[0343] In one embodiment, Compound (1) is administered orally, preferably as a tablet, once daily at a daily dose of 420 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, once daily at a daily dose of 420 mg.

[0344] In one embodiment, Compound (1) is administered orally, preferably as a tablet, at a daily dose of 480 mg once daily. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, at a daily dose of 480 mg once daily.

[0345] In one embodiment, Compound (1) is administered orally, preferably as a tablet, at a daily dose of 500 mg once daily. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, at a daily dose of 500 mg once daily.

[0346] In one embodiment, Compound (1) is administered orally, preferably as a tablet, at a daily dose of 540 mg once daily. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, at a daily dose of 540 mg once daily.

[0347] In one embodiment, Compound (1) is administered orally, preferably as a tablet, at a daily dose of 600 mg once daily. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, at a daily dose of 600 mg once daily.

[0348] In one embodiment, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0349] In one embodiment, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0350] In one embodiment, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg.

[0351] In some embodiments, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 30 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 30 mg. Preferably, in these embodiments, each of the twice daily doses is 15 mg.

[0352] In some embodiments, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 60 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 60 mg. Preferably, in these embodiments, each of the twice daily doses is 30 mg.

[0353] In some embodiments, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 120 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 120 mg. Preferably, in these embodiments, each of the twice daily doses is 60 mg.

[0354] In some embodiments, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 200 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 200 mg. Preferably, in these embodiments, each of the twice daily doses is 100 mg.

[0355] In some embodiments, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 300 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 300 mg. Preferably, in these embodiments, each of the twice daily doses is 150 mg.

[0356] In some embodiments, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 360 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 360 mg. Preferably, in these embodiments, each of the twice daily doses is 180 mg.

[0357] In some embodiments, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 400 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 400 mg. Preferably, in these embodiments, each of the twice daily doses is 200 mg.

[0358] In some embodiments, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 420 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 420 mg. Preferably, in these embodiments, each of the twice daily doses is 210 mg.

[0359] In some embodiments, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 480 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 480 mg. Preferably, in these embodiments, each of the twice daily doses is 240 mg.

[0360] In some embodiments, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 500 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 500 mg. Preferably, in these embodiments, each of the twice daily doses is 250 mg.

[0361] In some embodiments, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 540 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 540 mg. Preferably, in these embodiments, each of the twice daily doses is 270 mg.

[0362] In some embodiments, Compound (1) is administered orally, preferably as a tablet, twice daily at a daily dose of 600 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering Compound (1) orally, preferably as a tablet, twice daily at a daily dose of 600 mg. Preferably, in these embodiments, each of the twice daily doses is 300 mg.

[0363] In a preferred embodiment, the dosing regimens defined above for Compound (1) can be combined, and the daily dose can be varied during the course of treatment. Thus, for example, treatment can be initiated by administering a daily dose of 30 mg (once or twice daily), and then switched to a higher or lower daily dose (applied once or twice daily).

[0364] The dosing regimens described in this section are also applicable when the patient has already undergone one or more systemic anti-cancer treatments or therapies.

[0365] Dosage and Administration Regimen of Solid Dispersions and Pharmaceutical Compositions An object of the present invention is to provide a safe and effective dosing regimen for administering a solid dispersion comprising Compound (1) in the described dosing regimen. This dosing regimen is particularly useful for use in the treatment of cancer. In addition, this dosing regimen for a solid dispersion comprising Compound (1) is particularly useful in methods for treating patients suffering from cancer. In addition, this dosing regimen is also believed to be suitable for treating patients who have already received one or more prior cancer treatments.

[0366] Surprisingly, as described above and in the Examples below, it has been discovered that the use of solid dispersions comprising Compound (1) described herein, at a daily dose of Compound (1) of at least 30 mg, is safe and effective for the treatment of cancer.

[0367] In a preferred embodiment, the solid dispersion is administered in a daily dose of at least 60 mg of Compound (1). Alternatively, the method of treating a patient suffering from cancer described above comprises administering the solid dispersion, wherein Compound (1) is administered in a daily dose of at least 60 mg.

[0368] In a preferred embodiment, the solid dispersion is administered in a daily dose of at least 80 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered in a daily dose of at least 80 mg.

[0369] In a preferred embodiment, the solid dispersion is administered in a daily dose of at least 120 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered in a daily dose of at least 120 mg.

[0370] In a preferred embodiment, the solid dispersion is administered in a daily dose of at least 180 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered in a daily dose of at least 180 mg.

[0371] In a preferred embodiment, the solid dispersion is administered in a daily dose of at least 200 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered in a daily dose of at least 200 mg.

[0372] In a preferred embodiment, the solid dispersion is administered in a daily dose of at least 240 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered in a daily dose of at least 240 mg.

[0373] In a preferred embodiment, the solid dispersion is administered in a daily dose of at least 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered in a daily dose of at least 300 mg.

[0374] In a preferred embodiment, the solid dispersion provides a daily dose of 30 mg to 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered in a daily dose of 30 mg to 600 mg.

[0375] In a preferred embodiment, the solid dispersion is administered at a daily dose of 60 mg to 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 60 mg to 600 mg.

[0376] In a preferred embodiment, the solid dispersion is administered at a daily dose of 80 mg to 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 80 mg to 600 mg.

[0377] In a preferred embodiment, the solid dispersion is administered at a daily dose of 120 mg to 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 120 mg to 600 mg.

[0378] In a further preferred embodiment, the solid dispersion is administered at a daily dose of 30 mg to 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 30 mg to 300 mg.

[0379] In a further preferred embodiment, the solid dispersion is administered at a daily dose of 60 mg to 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 60 mg to 300 mg.

[0380] In a further preferred embodiment, the solid dispersion is administered at a daily dose of 80 mg to 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 80 mg to 300 mg.

[0381] In a further preferred embodiment, the solid dispersion is administered at a daily dose of 120 mg to 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 120 mg to 300 mg.

[0382] In a preferred embodiment, the solid dispersion is administered at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0383] In a preferred embodiment, the solid dispersion is administered at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0384] In a preferred embodiment, the solid dispersion is administered at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, or 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, or 300 mg.

[0385] In a preferred embodiment, the solid dispersion is administered at a daily dose of 30 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 30 mg.

[0386] In a preferred embodiment, the solid dispersion is administered at a daily dose of 60 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 60 mg.

[0387] In a preferred embodiment, the solid dispersion is administered at a daily dose of 120 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 120 mg.

[0388] In a preferred embodiment, the solid dispersion is administered at a daily dose of 180 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 180 mg.

[0389] In a preferred embodiment, the solid dispersion is administered at a daily dose of 200 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 200 mg.

[0390] In a preferred embodiment, the solid dispersion is administered at a daily dose of 240 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 240 mg.

[0391] In a preferred embodiment, the solid dispersion is administered at a daily dose of 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 300 mg.

[0392] In a preferred embodiment, the solid dispersion is administered at a daily dose of 360 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 360 mg.

[0393] In a preferred embodiment, the solid dispersion is administered at a daily dose of 400 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 400 mg.

[0394] In a preferred embodiment, the solid dispersion is administered at a daily dose of 420 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 420 mg.

[0395] In a preferred embodiment, the solid dispersion is administered at a daily dose of 480 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 480 mg.

[0396] In a preferred embodiment, the solid dispersion is administered at a daily dose of 500 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 500 mg.

[0397] In a preferred embodiment, the solid dispersion is administered at a daily dose of 540 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 540 mg.

[0398] In a preferred embodiment, the solid dispersion is administered at a daily dose of 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein Compound (1) is administered at a daily dose of 600 mg.

[0399] Within preferred embodiments, the solid dispersion is administered once or twice daily.

[0400] In a preferred embodiment, the solid dispersion is administered once daily. In a preferred embodiment, the solid dispersion is administered in a single dose within a 24 hour period.

[0401] In a preferred embodiment, the solid dispersion is administered twice daily. In a preferred embodiment, the solid dispersion is administered twice within a 24 hour period.

[0402] In a preferred embodiment, each of the two daily doses of the solid dispersion corresponds to half of the daily dose of Compound (1). By administering the required daily dose of Compound (1) in two doses containing the same amount, an easy and error-free application scheme can be provided.

[0403] In a further preferred embodiment, the solid dispersion is administered for at least 21 consecutive days. In a further preferred embodiment, the solid dispersion is administered for X times 21 days (X is a natural number equal to or greater than 1). In addition, the overall cancer treatment may include a time interval during which no administration is performed during the treatment period that includes administering the solid dispersion.

[0404] In certain embodiments, the solid dispersion provides a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg of Compound (1), administered once daily, or a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg of Compound (1), administered twice daily. Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg, or Compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0405] In certain embodiments, the solid dispersion provides a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg of Compound (1), administered once daily, or a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg of Compound (1), administered twice daily. Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg, or Compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0406] In certain embodiments, the solid dispersion is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg of Compound (1), or twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily and Compound (1) is administered at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg, or Compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg.

[0407] In certain embodiments, the solid dispersion is administered once daily to provide a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0408] In certain embodiments, the solid dispersion is administered once daily to provide a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0409] In certain embodiments, the solid dispersion is administered once daily to provide a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg.

[0410] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 60 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered at a daily dose of 60 mg.

[0411] In a preferred embodiment, the solid dispersion is administered once daily to provide a daily dose of 120 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered at a daily dose of 120 mg.

[0412] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 180 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered at a daily dose of 180 mg.

[0413] In a preferred embodiment, the solid dispersion is administered once daily to provide a daily dose of 240 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered at a daily dose of 240 mg.

[0414] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered at a daily dose of 300 mg.

[0415] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 360 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered at a daily dose of 360 mg.

[0416] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 400 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered at a daily dose of 400 mg.

[0417] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 420 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered at a daily dose of 420 mg.

[0418] In a preferred embodiment, the solid dispersion is administered once daily to provide a daily dose of 480 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered at a daily dose of 480 mg.

[0419] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 500 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered at a daily dose of 500 mg.

[0420] In a preferred embodiment, the solid dispersion is administered once daily to provide a daily dose of 540 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered at a daily dose of 540 mg.

[0421] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion once daily, wherein Compound (1) is administered at a daily dose of 600 mg.

[0422] In certain embodiments, the solid dispersion is administered twice daily to provide a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0423] In certain embodiments, the solid dispersion is administered twice daily to provide a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0424] In certain embodiments, the solid dispersion is administered twice daily to provide a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg.

[0425] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 30 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 30 mg. Preferably, in these embodiments, each of the twice daily doses is 15 mg.

[0426] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 60 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 60 mg. Preferably, in these embodiments, each of the twice daily doses is 30 mg.

[0427] In preferred embodiments, the solid dispersion is administered twice daily to provide a daily dose of 120 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 120 mg. Preferably, in these embodiments, each of the twice-daily doses is 60 mg.

[0428] In preferred embodiments, the solid dispersion is administered twice daily at a daily dose of 200 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 200 mg. Preferably, in these embodiments, each of the twice daily doses is 100 mg.

[0429] In preferred embodiments, the solid dispersion is administered twice daily at a daily dose of 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 300 mg. Preferably, in these embodiments, each of the twice daily doses is 150 mg.

[0430] In preferred embodiments, the solid dispersion is administered twice daily to provide a daily dose of 360 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 360 mg. Preferably, in these embodiments, each of the twice-daily doses is 180 mg.

[0431] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 400 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 400 mg. Preferably, in these embodiments, each of the twice daily doses is 200 mg.

[0432] In preferred embodiments, the solid dispersion is administered twice daily to provide a daily dose of 420 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 420 mg. Preferably, in these embodiments, each of the twice-daily doses is 210 mg.

[0433] In preferred embodiments, the solid dispersion is administered twice daily to provide a daily dose of 480 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 480 mg. Preferably, in these embodiments, each of the twice-daily doses is 240 mg.

[0434] In preferred embodiments, the solid dispersion is administered twice daily at a daily dose of 500 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 500 mg. Preferably, in these embodiments, each of the twice daily doses is 250 mg.

[0435] In preferred embodiments, the solid dispersion is administered twice daily to provide a daily dose of 540 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 540 mg. Preferably, in these embodiments, each of the twice daily doses is 270 mg.

[0436] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion twice daily, wherein Compound (1) is administered at a daily dose of 600 mg. Preferably, in these embodiments, each of the twice daily doses is 300 mg.

[0437] In certain embodiments, the solid dispersion is administered orally, preferably as a tablet, once daily, to provide a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, to provide a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg of Compound (1).

[0438] In certain embodiments, the solid dispersion is administered orally, preferably as a tablet, once daily, to provide a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, wherein Compound (1) is administered in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0439] In certain embodiments, the solid dispersion is administered orally, preferably as a tablet, once daily, to provide a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, wherein Compound (1) is administered at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg.

[0440] In one embodiment, the solid dispersion is administered orally, preferably as a tablet, once daily, to provide a daily dose of 60 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, wherein Compound (1) is administered at a daily dose of 60 mg.

[0441] In one embodiment, the solid dispersion is administered orally, preferably as a tablet, once daily, to provide a daily dose of 120 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, wherein Compound (1) is administered at a daily dose of 120 mg.

[0442] In one embodiment, the solid dispersion is administered orally, preferably as a tablet, once daily, to provide a daily dose of 180 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, wherein Compound (1) is administered at a daily dose of 180 mg.

[0443] In one embodiment, the solid dispersion is administered orally, preferably as a tablet, once daily, to provide a daily dose of 240 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, wherein Compound (1) is administered at a daily dose of 240 mg.

[0444] In one embodiment, the solid dispersion is administered orally, preferably as a tablet, once daily, at a daily dose of 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, wherein Compound (1) is administered at a daily dose of 300 mg.

[0445] In one embodiment, the solid dispersion is administered orally, preferably as a tablet, once daily, to provide a daily dose of 360 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, wherein Compound (1) is administered at a daily dose of 360 mg.

[0446] In one embodiment, the solid dispersion is administered orally, preferably as a tablet, once daily, to provide a daily dose of 400 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, wherein Compound (1) is administered at a daily dose of 400 mg.

[0447] In one embodiment, the solid dispersion is administered orally, preferably as a tablet, once daily, to provide a daily dose of 420 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, wherein Compound (1) is administered at a daily dose of 420 mg.

[0448] In one embodiment, the solid dispersion is administered orally, preferably as a tablet, once daily, to provide a daily dose of 480 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, wherein Compound (1) is administered at a daily dose of 480 mg.

[0449] In one embodiment, the solid dispersion is administered orally, preferably as a tablet, once daily, at a daily dose of 500 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, wherein Compound (1) is administered at a daily dose of 500 mg.

[0450] In one embodiment, the solid dispersion is administered orally, preferably as a tablet, once daily, to provide a daily dose of 540 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, wherein Compound (1) is administered at a daily dose of 540 mg.

[0451] In one embodiment, the solid dispersion is administered orally, preferably as a tablet, once daily, to provide a daily dose of 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, once daily, wherein Compound (1) is administered at a daily dose of 600 mg.

[0452] In one embodiment, the solid dispersion is administered orally, preferably as a tablet, twice daily, to provide a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg of Compound (1). Alternatively, the method comprises administering the solid dispersion orally, preferably as a tablet, twice daily, wherein Compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0453] In one embodiment, the solid dispersion is administered orally, preferably as a tablet, twice daily, to provide a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg of Compound (1). Alternatively, the method comprises administering the solid dispersion orally, preferably as a tablet, twice daily, wherein Compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0454] In certain embodiments, the solid dispersion is administered orally, preferably as a tablet, twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg. Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, twice daily, and Compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg.

[0455] In some embodiments, the solid dispersion is administered orally, preferably as a tablet, twice daily, at a daily dose of 30 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, twice daily, wherein Compound (1) is administered at a daily dose of 30 mg. Preferably, in these embodiments, each of the twice daily doses is 15 mg.

[0456] In some embodiments, the solid dispersion is administered orally, preferably as a tablet, twice daily, at a daily dose of 60 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, twice daily, wherein Compound (1) is administered at a daily dose of 60 mg. Preferably, in these embodiments, each of the twice daily doses is 30 mg.

[0457] In some embodiments, the solid dispersion is administered orally, preferably as a tablet, twice daily, to provide a daily dose of 120 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, twice daily, wherein Compound (1) is administered at a daily dose of 120 mg. Preferably, in these embodiments, each of the twice-daily doses is 60 mg.

[0458] In some embodiments, the solid dispersion is administered orally, preferably as a tablet, twice daily, at a daily dose of 200 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, twice daily, wherein Compound (1) is administered at a daily dose of 200 mg. Preferably, in these embodiments, each of the twice daily doses is 100 mg.

[0459] In some embodiments, the solid dispersion is administered orally, preferably as a tablet, twice daily, at a daily dose of 300 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, twice daily, wherein Compound (1) is administered at a daily dose of 300 mg. Preferably, in these embodiments, each of the twice-daily doses is 150 mg.

[0460] In some embodiments, the solid dispersion is administered orally, preferably as a tablet, twice daily, to provide a daily dose of 360 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, twice daily, wherein Compound (1) is administered at a daily dose of 360 mg. Preferably, in these embodiments, each of the twice-daily doses is 180 mg.

[0461] In some embodiments, the solid dispersion is administered orally, preferably as a tablet, twice daily, to provide a daily dose of 400 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, twice daily, wherein Compound (1) is administered at a daily dose of 400 mg. Preferably, in these embodiments, each of the twice-daily doses is 200 mg.

[0462] In some embodiments, the solid dispersion is administered orally, preferably as a tablet, twice daily, to provide a daily dose of 420 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, twice daily, wherein Compound (1) is administered at a daily dose of 420 mg. Preferably, in these embodiments, each of the twice-daily doses is 210 mg.

[0463] In some embodiments, the solid dispersion is administered orally, preferably as a tablet, twice daily, to provide a daily dose of 480 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, twice daily, wherein Compound (1) is administered at a daily dose of 480 mg. Preferably, in these embodiments, each of the twice-daily doses is 240 mg.

[0464] In some embodiments, the solid dispersion is administered orally, preferably as a tablet, twice daily, at a daily dose of 500 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, twice daily, wherein Compound (1) is administered at a daily dose of 500 mg. Preferably, in these embodiments, each of the twice daily doses is 250 mg.

[0465] In some embodiments, the solid dispersion is administered orally, preferably as a tablet, twice daily, to provide a daily dose of 540 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, twice daily, wherein Compound (1) is administered at a daily dose of 540 mg. Preferably, in these embodiments, each of the twice-daily doses is 270 mg.

[0466] In some embodiments, the solid dispersion is administered orally, preferably as a tablet, twice daily, at a daily dose of 600 mg of Compound (1). Alternatively, a method of treating a patient suffering from cancer comprises administering the solid dispersion orally, preferably as a tablet, twice daily, wherein Compound (1) is administered at a daily dose of 600 mg. Preferably, in these embodiments, each of the twice daily doses is 300 mg.

[0467] In a preferred embodiment, the dosing regimens defined above for the solid dispersions can be combined, and the daily dose of Compound (1) can be varied during the course of treatment. Thus, for example, treatment can be initiated by administering a daily dose of 30 mg of Compound (1) (once or twice daily), and then switching to a higher or lower daily dose (applied once or twice daily).

[0468] The doses and administration regimens described in this section are also applicable when the patient has already received one or more systemic anti-cancer drug treatments or therapies.

[0469] The doses and dosing regimens described in this section are also applicable to the pharmaceutical compositions described herein. Accordingly, there are provided herein embodiments corresponding to those mentioned in this section, in which the term "solid dispersion" is replaced by the term "pharmaceutical composition."

[0470] Second-line and later administration It has surprisingly been discovered that the use of compound (1), a solid dispersion described herein, or a pharmaceutical composition described herein following cancer treatment with at least one systemic anti-cancer therapy may improve or stabilize clinical outcomes.

[0471] In a preferred embodiment, at least one additional therapeutic agent is administered in a line of treatment prior to or before administration of Compound (1) at the doses and dosing schedules described herein. Alternatively, the above-described methods of treating a patient suffering from cancer comprise administering Compound (1) in a line of treatment at the doses and dosing schedules described herein after or following administration of at least one additional therapeutic agent.

[0472] In a preferred embodiment, at least one additional therapeutic agent is administered in a line of treatment prior to or prior to administering the solid dispersion described herein, or the pharmaceutical composition described herein, at the doses and dosing schedules described herein. Alternatively, the above-described methods of treating a patient suffering from cancer comprise administering the solid dispersion described herein, or the pharmaceutical composition described herein, at the doses and dosing schedules described herein, in a line of treatment after or subsequent to the administration of the at least one additional therapeutic agent.

[0473] In a preferred embodiment, the additional therapeutic agent administered in a line of treatment prior to administration of Compound (1), a solid dispersion described herein, or a pharmaceutical composition described herein is selected from the group consisting of chemotherapeutic agents and systemic anti-cancer therapeutic agents. The additional therapeutic agent can be used in the treatment of cancer in addition to the administration of Compound (1).

[0474] In a preferred embodiment, a systemic anti-cancer therapeutic agent is administered prior to or prior to Compound (1) in a line of treatment. In particular, one or more systemic anti-cancer therapeutic agents can be administered prior to Compound (1) in a line of treatment. That is, Compound (1) is preferably used to treat cancer in a line of treatment following or after the administration of a line of treatment comprising one or more systemic anti-cancer therapeutic agents. These systemic anti-cancer therapeutic agents can be administered as separate lines of treatment or in combination with each other in the same line of treatment. Additionally or alternatively, a systemic anti-cancer agent administered prior to Compound (1) in a line of treatment can be used in combination with any other anti-cancer agent treatment different from Compound (1), whether systemic or not. This means that Compound (1) can be administered as a second-line treatment (where only one line of treatment including at least one systemic anti-cancer therapy is administered prior to Compound (1)) or later (where two or more lines of treatment including at least one systemic anti-cancer therapy are administered prior to Compound (1)). In this embodiment, Compound (1) is preferably administered in the solid dispersions, doses, and dosing schedules described herein.

[0475] In a preferred embodiment, a systemic anticancer therapy is administered in a line of treatment prior to or before the solid dispersion described herein or the pharmaceutical composition described herein. In particular, one or more systemic anticancer therapy agents can be administered in a line of treatment prior to the solid dispersion described herein or the pharmaceutical composition described herein. That is, the solid dispersion described herein or the pharmaceutical composition described herein is preferably used to treat cancer in a line of treatment following or after the administration of a selective treatment comprising the administration of one or more systemic anticancer therapy agents. These systemic anticancer therapy agents can be administered in combination with each other as separate lines of treatment or in the same line of treatment. Additionally or alternatively, the systemic anticancer therapy administered in a line of treatment prior to the solid dispersion described herein or the pharmaceutical composition described herein can be used in combination with any other anticancer therapy, whether systemic or not, different from Compound (1). This means that the solid dispersions described herein, or the pharmaceutical compositions described herein, can be administered as a second-line treatment (when only one line of treatment comprising at least one systemic anti-cancer therapy is administered prior to the solid dispersions described herein, or the pharmaceutical compositions described herein) or subsequent treatments (when two or more lines of treatment comprising at least one systemic anti-cancer therapy are administered prior to the solid dispersions described herein, or the pharmaceutical compositions described herein). In this embodiment, the solid dispersion can be as defined herein in any aspect or embodiment. In this embodiment, Compound (1) is preferably administered at the doses and dosing schedules described herein.

[0476] In this context, the terms "after" and "consequently" mean that an additional therapeutic agent, particularly a chemotherapeutic agent or systemic anti-cancer therapy, is administered in one or more doses during a first period, e.g., over a period of hours, days, or a week or more, in a first-line or prior-line treatment, followed by administration of Compound (1), optionally as a solid dispersion or pharmaceutical composition described herein, in one or more doses during a second period, e.g., over a period of hours, days, or a week or more, in a second-line or subsequent treatment, provided that there is no overlap between the first and second periods.

[0477] The systemic anti-cancer therapy or chemotherapeutic agent and Compound (1) are not administered on the same day. In particular, once Compound (1) is administered, administration of the single systemic anti-cancer therapy or chemotherapeutic agent is not resumed at the same dose (of said single systemic anti-cancer therapy or chemotherapeutic agent).

[0478] The systemic anti-cancer therapy or chemotherapeutic agent and the solid dispersion described herein or the pharmaceutical composition described herein are not administered on the same day. In particular, once the solid dispersion described herein or the pharmaceutical composition described herein is administered, the administration of the single systemic anti-cancer therapy or chemotherapeutic agent is not resumed at the same dose (of said single systemic anti-cancer therapy or chemotherapeutic agent).

[0479] The terms "after" and "consequently" do not require that Compound (1), a solid dispersion described herein, or a pharmaceutical composition described herein be administered in a line of therapy immediately following or immediately following a line of treatment with a systemic anti-cancer therapy. Thus, another prior therapy may be administered between the systemic anti-cancer therapy or chemotherapy and Compound (1), optionally formulated in a solid dispersion or pharmaceutical composition described herein, so long as the systemic anti-cancer therapy or chemotherapy is administered in a line of treatment prior to Compound (1), optionally formulated in a solid dispersion or pharmaceutical composition described herein. Preferably, the systemically detectable dose of the anti-cancer therapy in the prior anti-cancer therapy is below the therapeutically effective amount established before Compound (1) is administered. In a further preferred embodiment, the selected daily amount and daily application schedule of Compound (1), optionally formulated in a solid dispersion or pharmaceutical composition described herein, can also be selected as a function of one or all prior treatments with a systemic anti-cancer therapy.

[0480] Those skilled in the art will recognize that the terms "before," "prior to," "after," and "following" are used herein to refer to different and / or separate lines of treatment. That is, a reference to administration of Compound (1), the solid dispersion, or the pharmaceutical composition after or following systemic anti-cancer therapy or chemotherapy is equivalent to a reference to administration of Compound (1), the solid dispersion, or the pharmaceutical composition as a second or subsequent line of treatment following administration of systemic anti-cancer therapy or chemotherapy, even if not explicitly stated.

[0481] As used herein, "second-line or later" and its grammatical variations have the meaning known in the art. In particular, "second-line or later" and its grammatical variations can refer to the administration of Compound (1), optionally formulated in a solid dispersion or pharmaceutical composition described herein, at the discretion of the attending physician after or subsequent to a first-line or prior line of therapy that has failed, become ineffective, become less effective, experienced intolerable side effects, or was only partially successful (particularly where the first-line or prior line of therapy is not administered again to the patient). The phrase "second-line or later administration" can be read as "second-line or later administration."

[0482] As used herein, a "systemic anti-cancer therapy" may exist and be administered in the form of a single drug compound or a single active ingredient. Alternatively, the drug may exist and be administered in the form of a combination of two or more drug compounds or active ingredients. Drug compounds may include small or large molecules, chemical elements, e.g., Pt, biologics, and combinations thereof.

[0483] As used herein, the term "systemic anti-cancer therapy" includes the administration of at least one systemic anti-cancer therapeutic agent, alone or in combination with another pharmaceutical compound or active ingredient.

[0484] As used herein, a "chemotherapy agent" or "chemotherapeutic agent" may exist and be administered in the form of a single drug compound or active ingredient alone, or it may exist and be administered in the form of a combination of two or more drug compounds or active ingredients.

[0485] As used herein, the term "chemotherapy" includes the administration of at least one chemotherapeutic agent, alone or in combination with another pharmaceutical compound or active ingredient.

[0486] Preferably, the chemotherapy is administered systemically, ie, systemic chemotherapy.

[0487] In a preferred embodiment, the chemotherapeutic agent or systemic anticancer therapy is selected from the group consisting of platinum-based chemotherapy, anti-HER2 antibody-drug conjugates, taxanes, antimetabolites, immunotherapeutics, and combinations thereof. Preferably, the term "combination thereof" may include the separate administration of two or more members of the list at different time intervals or at different times as different lines of treatment, or the combined administration of two or more members of the list in the same line of treatment. This combination may include, for example, first-line treatment with a platinum-based chemotherapy agent prior to treatment based on compound (1), followed by second-line treatment based on an ADC, preferably an anti-HER2 ADC, or vice versa. This combination may be performed in a planned sequence or as a function of treatment outcome.

[0488] Preferred platinum-based chemotherapy includes carboplatin and / or cisplatin. Preferred anti-HER2 antibody-drug conjugates include trastuzumab deruxtecan and / or trastuzumab emtansine. Preferred taxanes include docetaxel and / or paclitaxel. Preferred antimetabolites include gemcitabine, pemetrexed, and / or tegafur. Preferred immunotherapeutic agents include pembrolizumab, durvalumab, atezolizumab, nivolumab, ipilimumab, tremelimumab, and / or ramucirumab.

[0489] As used herein, the term "antibody drug conjugate" (also abbreviated herein as "ADC") is well known in the art and refers to a group of therapeutic agents that combine the specificity of tumor targeting binders, such as antibodies, with the potency of highly cytotoxic drugs. ADCs are well known in the art and have been reviewed, for example, in Dumontet et al. 2023 (Dumontet, C., Reichert, JM, Senter, PD et al. Antibody-drug conjugates come of age in oncology. Nat Rev Drug Discov 22, 641-661 (2023)).

[0490] In particular, as used herein, "anti-HER2 antibody-drug conjugate" refers to an ADC in which the tumor-targeting binder is an antibody that is directed against, targets, and / or binds to HER2, e.g., trastuzumab.

[0491] In preferred embodiments, the chemotherapeutic agent or systemic anti-cancer therapy is selected from the group consisting of carboplatin, cisplatin, trastuzumab deruxtecan, trastuzumab emtansine, pemetrexed, docetaxel, paclitaxel, gemcitabine, pembrolizumab, durvalumab, tremelimumab, ramucirumab, atezolizumab, tegafur, nivolumab, and ipilimumab.

[0492] In a further preferred embodiment, compound (1) is defined as follows: [ka] is for use in treating cancer, wherein Compound (1) is administered as a line of treatment following administration of a chemotherapeutic agent or systemic anti-cancer therapy. Alternatively, in a preferred embodiment, a method of treating a patient suffering from cancer comprises administering Compound (1), wherein Compound (1) is administered as a line of treatment following administration of a chemotherapeutic agent or systemic anti-cancer therapy. Preferably, in these embodiments, Compound (1) is administered according to the doses and dosing regimens described above. Additionally or alternatively, in these embodiments, the cancer and / or systemic anti-cancer therapy can be as defined herein. Preferably, the systemic anti-cancer therapy is a specific anti-HER2 systemic anti-cancer therapy, e.g., an anti-HER2 antibody-drug conjugate.

[0493] In a preferred embodiment, Compound (1) can be used to treat cancer at least 21 days after the last administration of a chemotherapeutic agent or systemic anti-cancer therapy. Alternatively, in a preferred embodiment, a method of treating a patient suffering from cancer comprises administering Compound (1), wherein Compound (1) is administered at least 21 days after the last administration of a chemotherapeutic agent or systemic anti-cancer therapy.

[0494] In a further preferred embodiment, a solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof as defined herein and a pharmaceutically acceptable dispersion carrier is for use in the treatment of cancer, wherein the solid dispersion is administered in a line of treatment following administration of a chemotherapeutic agent or a systemic anti-cancer therapy. Alternatively, in a preferred embodiment, a method of treating a patient suffering from cancer comprises administering a solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof as defined herein and a pharmaceutically acceptable dispersion carrier, wherein the solid dispersion is administered in a line of treatment following administration of a chemotherapeutic agent or a systemic anti-cancer therapy. Preferably, in these embodiments, the solid dispersion is administered according to the doses and dosing regimens described above. Additionally or alternatively, in these embodiments, the cancer and / or systemic anti-cancer therapy may be as defined herein. Preferably, the systemic anti-cancer therapy is a specific anti-HER2 systemic anti-cancer therapy, such as an anti-HER2 antibody-drug conjugate.

[0495] In a preferred embodiment, a solid dispersion comprising Compound (1) or a pharmaceutically acceptable salt thereof as defined herein and a pharmaceutically acceptable dispersion carrier can be used to treat cancer at least 21 days after the last day of administration of a chemotherapeutic agent or systemic anti-cancer therapy. Alternatively, in a preferred embodiment, a method of treating a patient suffering from cancer comprises administering a solid dispersion comprising Compound (1) or a pharmaceutically acceptable salt thereof as defined herein and a pharmaceutically acceptable dispersion carrier, wherein Compound (1) is administered at least 21 days after the last day of administration of a chemotherapeutic agent or systemic anti-cancer therapy.

[0496] Method for producing a solid dispersion The solid dispersions of the present invention can be prepared by any method known in the art for this purpose, for example, as disclosed in SV Bhujbal et al., Acta Pharmaceutica Sinica B 2021;11(8):2505e2536, which is incorporated herein by reference. In accordance with the present invention, solid dispersions are generally prepared by dissolving the active agent and a pharmaceutically acceptable dispersion carrier in a solvent or mixture of solvents to form a feed solution, and then removing the solvent from the feed solution, such as by spray drying, to form the solid dispersion.

[0497] In embodiments, there is provided a method of making a solid dispersion described herein, the method comprising: a) providing a mixture of compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier, and adding a solvent to obtain a solution or suspension; b) removing the solvent from the solution or suspension to form a solid dispersion as described herein.

[0498] The method may further comprise the step of drying the solid dispersion obtained in step b).

[0499] In embodiments, there is provided a method of making a solid dispersion described herein, the method comprising: a) providing a solution or suspension comprising Compound (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, and at least one solvent; b) removing the solvent from the solution or suspension to form a solid dispersion as described herein; c) optionally drying the solid dispersion obtained in b); Includes.

[0500] The solution or suspension of step a) according to any of the methods described above may be referred to as a feed solution.

[0501] In an embodiment, the removal of the solvent in step b) of the above defined process is carried out by spray drying, freeze drying, rotary evaporation, distillation, drum drying and / or vacuum drying. In a preferred embodiment, the removal of the solvent in step b) is carried out by spray drying.

[0502] As used herein, the term "spray drying" is used conventionally and broadly to generally refer to any process involving atomizing a solution, suspension, slurry, or emulsion containing one or more components of a desired product into droplets, followed by rapid evaporation of the atomized droplets with hot air at a specific temperature and pressure to a solid powder. Spray drying is a process known to those skilled in the art.

[0503] Spray drying is generally carried out by dissolving Compound (1) and a pharmaceutically acceptable dispersion carrier in a solvent to prepare a feed solution. The feed solution can be delivered to a drying chamber through an atomizer. The feed solution can be atomized by conventional means known in the art, such as a two-fluid ultrasonic nozzle, a pressure nozzle, a rotary nozzle, and a two-fluid non-ultrasonic nozzle. The solvent is then removed in the drying chamber to form the solid dispersion. In a typical drying chamber, hot gas, such as forced air, nitrogen, nitrogen-enriched air, or argon, is used to dry the particles. The size of the drying chamber can be adjusted to achieve particle characteristics or processing capacity.

[0504] The solid dispersions are preferably prepared by conventional spray drying techniques, although other techniques known in the art can be used, such as melt extrusion, freeze drying, rotary evaporation, co-precipitation, KinetiSol® Dispersing Technology (KSD), fluidized bed techniques, drum drying, vacuum drying, or other solvent removal processes.

[0505] The above-described method for producing the solid dispersions described herein may comprise an additional step between step a) and step b) of spraying the solution or suspension obtained in step a) onto an inert excipient core. This process belongs to the fluidized bed technique, in particular the fluidized bed granulation technique.

[0506] In embodiments, there is provided a method of making a solid dispersion described herein, the method comprising: (a) providing a solution or suspension comprising Compound (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, and at least one solvent; (a') spraying the solution or suspension provided in (a) onto an inert excipient core; (b') removing the solvent from the inert excipient cores; (c') optionally drying the excipient cores containing the solid dispersion obtained in (c'); Includes.

[0507] The spraying in step (a') can be carried out in a fluidized bed coater, for example as top spray, bottom spray, Wurster spray, tangential spray or side rotor spray.

[0508] Any solvent or mixture of solvents in which compound (1) is at least partially soluble can be used. Examples of suitable solvents that can be used individually or as a mixture include water, alcohols such as methanol ("MeOH"), ethanol ("EtOH"), n-propanol, isopropanol, and butanols, such as n-butanol, 2-butanol, isobutanol, and tert-butanol; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as methyl acetate, ethyl acetate, and propyl acetate, isopropyl acetate, n-butyl acetate, and isobutyl acetate, as well as various other solvents such as dichloromethane (DCM), chloroform, tetrahydrofuran, acetonitrile, toluene, and 1,1,1-trichloroethane. In an embodiment, the solvent referred to in any of the above-described methods and embodiments thereof is selected from the group consisting of water, alcohols, ketones, esters, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, toluene, 1,1,1-trichloroethane, and mixtures thereof. In an embodiment, the solvent referred to in any of the above-described methods and embodiments thereof is selected from the group consisting of alcohols (especially methanol, ethanol, n-propanol, isopropanol, and butanol, such as n-butanol, 2-butanol, isobutanol, and tert-butanol), ketones (especially acetone, methyl ethyl ketone, and methyl isobutyl ketone), esters (especially methyl acetate, ethyl acetate, and propyl acetate, isopropyl acetate, n-butyl acetate, and isobutyl acetate), dichloromethane (DCM), tetrahydrofuran, acetonitrile, toluene, and 1,1,1-trichloroethane. Mixtures of solvents with water can also be used.

[0509] In an embodiment, the solvent is a mixture of dichloromethane (DCM) and methanol (MeOH). The relative amounts of DCM and MeOH in the mixture can be varied. Preferably, the mixture contains at least 25 wt% MeOH, based on 100 wt% of the total weight of the mixture. In an embodiment, the mixture contains excess DCM. More preferably, the weight:weight ratio of DCM:MeOH ranges from 25:75 to 95:5 (w / w). Preferably, DCM and MeOH are in a weight:weight ratio of about 25:75, 50:50, 70:30, 75:25, 80:20, 85:15, or 90:10. It has been advantageously found that a solvent mixture of DCM:MeOH in a ratio of about 90:10 (w / w) allows for higher throughput for spray drying.

[0510] In an embodiment, the solids concentration in the feed solution (particularly the suspension or solution defined in step a) above) is in the range of about 1 to 20 wt %, based on 100 wt % of the total weight of the feed solution. Preferably, the solids concentration in the feed solution is in the range of about 5 to 15 wt %, more preferably in the range of about 8 to 12 wt %, based on 100 wt % of the total weight of the feed solution. For example, the solids concentration in the feed solution is about 8 wt % or 10 wt %, based on 100 wt % of the total weight of the feed solution.

[0511] After removing the solvent by spray drying, the resulting solid dispersion is optionally subjected to a drying process to reduce the residual solvent content. In an embodiment, drying is carried out at a temperature ranging from about room temperature to 100°C, preferably about 30 to 60°C, and more preferably about 35 to 45°C. For example, drying is carried out at a temperature of about 40°C. In another embodiment, drying is carried out under ambient pressure and / or reduced pressure. For example, drying is carried out at ambient pressure or at a pressure of about 900 mbar or less, more preferably about 100 mbar or less, and most preferably about 50 mbar or less, e.g., about 20 mbar or less. In yet another embodiment, drying is carried out for a period ranging from about 6 to 72 hours, preferably about 12 to 48 hours.

[0512] Another aspect is the following: a) providing a mixture of the compound (1) or a pharmaceutically acceptable salt thereof as defined above with a pharmaceutically acceptable dispersion carrier, and adding a solvent to obtain a solution or suspension; b) removing the solvent from the solution or suspension to form the solid dispersion, wherein preferably the removal of the solvent in step b) is accomplished by spray drying; The present invention relates to a solid dispersion obtainable by a process comprising the steps of:

[0513] Another aspect is the following: a) providing a solution or suspension comprising Compound (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, and at least one solvent; b) removing the solvent from the solution or suspension to form a solid dispersion as described herein; c) optionally drying the solid dispersion obtained in b); The present invention relates to a solid dispersion obtainable by a process comprising the steps of:

[0514] Another aspect is the following: (a) providing a solution or suspension comprising Compound (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, and at least one solvent; (a') spraying the solution or suspension provided in (a) onto an inert excipient core; (b') removing the solvent from the inert excipient cores; (c') optionally drying the excipient cores containing the solid dispersion obtained in (c'); The present invention relates to a solid dispersion obtainable by a process comprising the steps of:

[0515] In these embodiments relating to a solid dispersion obtainable by the process, the process steps may be carried out as described above in relation to the process for producing the solid dispersion.

[0516] Pharmaceutical compositions, such as tablets, preferably film-coated tablets, can be prepared according to conventional methods known to those skilled in the art. In an embodiment, the preparation method may include the following steps: 1) preparing a solid dispersion, for example, by spray drying as described herein; 2) dry-granulating the solid dispersion with one or more suitable excipients; 3) blending the granules with suitable disintegrants and / or lubricants and / or glidants; 4) compressing the blend into tablet cores; and 5) optionally film-coating the tablet cores.

[0517] In the present invention, any aspect or embodiment that refers to a feature (e.g., that Compound (1) is amorphous in the solid dispersion) may be combined with any one or more aspects or embodiments that refer to (other) features (e.g., that the weight ratio of Compound (1) to the pharmaceutically acceptable dispersing carrier in the solid dispersion is 1:1 and / or that the pharmaceutically acceptable dispersing carrier is HPMCAS) to provide further aspects or embodiments of the present invention, such as: 1) A solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier (wherein compound (1) is amorphous, and the weight ratio of compound (1) to the pharmaceutically acceptable dispersion carrier in the solid dispersion is 1:1); 2) a solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier, wherein compound (1) is amorphous and the pharmaceutically acceptable dispersion carrier is HPMCAS; 3) A solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersing carrier, wherein compound (1) is amorphous, the weight ratio of compound (1) to the pharmaceutically acceptable dispersing carrier in the solid dispersion is 1:1, and the pharmaceutically acceptable dispersing carrier is HPMCAS. can be provided.

[0518] The phrases "defined herein," "disclosed herein," "described herein," "as used herein," and variations thereof, at each instance where they occur, include all aspects, embodiments, subaspects, subembodiments, etc. of the feature or term to which they refer.

[0519] In certain embodiments, numerical values ​​may be stated as part of a range, and such numerical values ​​should be considered as approximate values ​​even if the term "about" or "approximately" is not explicitly stated.

[0520] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0521] The following examples are intended to illustrate the present invention in more detail, but are not intended to limit the same.

[0522] Example 1 - Preparation of solid dispersions containing compound (1) and various dispersing polymers In this example, solid dispersions were prepared containing 25 wt % or 50 wt % Compound (1) and 75 wt % or 50 wt % of the dispersion carrier HPMCAS-M (Shin-Etsu AQOAT), PVP-VA, Eudragit® L100, or HPMC HME 15LV, respectively.

[0523] The solid dispersion of this example can be prepared according to the following protocol. The solid dispersion is spray dried from a spray solution composition (solids content 8 wt% total solids) containing Compound (1), a dispersion carrier, and a DCM:MeOH (1:1 (w / w)) solvent system. The solid dispersion is spray dried using a two-fluid nozzle type and 1.0 mm / 1.0 mm nozzle cap / tip dimensions, an inlet temperature of 85-90°C, an outlet temperature of 45-50°C, atomization at 3.0 bar, and a drying gas air flow rate of 0.50 m / s. 3The dispersion is prepared using a Procept 4M8TRX spray dryer with a solution feed rate of approximately 15 g / min. Secondary drying of the dispersion is carried out in a collection vessel in a tray dryer type vacuum dryer at 40° C. for 22.5 hours.

[0524] The spray drying yield results obtained following the protocol in the preceding paragraph are summarized in Table 1, where gA represents grams API (active pharmaceutical ingredient, i.e., Compound (1)).

[0525] [Table 1]

[0526] Example 2 - Characterization of solid dispersions by X-ray powder diffraction (XRPD) and modulated differential scanning calorimetry (mDSC) 2.1 X-ray powder diffraction (XRPD) XRPD can be obtained according to the following protocol: XRPD analysis is performed using a Rigaku Miniflex 600 diffractometer. For example, a solid dispersion of Compound (1) and a dispersing carrier, such as HPMCAS-M, PVP-VA, Eudragit® L100, or HPMC HME 15LV, in an amount of approximately 10 mg, is placed on a zero background sample disk and inserted into the autosampler of the Rigaku Miniflex 600. The sample is analyzed using the instrument parameters listed in Table 2 below.

[0527] [Table 2]

[0528] XRPDs obtained for various solid dispersions prepared in Example 1 according to the protocol described above are shown in Figures 1-4. In these figures, comparison with the XRPD of crystalline Compound (1) indicates the absence of crystalline material in the samples. Specifically, XRPDs for solid dispersions of 25 wt% or 50 wt% Compound (1) with the dispersion carriers HPMCAS-M, PVP-VA, Eudragit® L100, or HPMC HME 15LV showed the absence of sharp peaks and the presence of an amorphous halo. The absence of sharp diffraction peaks indicates that the solid dispersions are consistent with the amorphous form of Compound (1).

[0529] 2.2 Modulated Differential Scanning Calorimetry (mDSC) Solid dispersions of compound (1) of Example 1 with the dispersion carriers HPMCAS-M, PVP-VA, Eudragit® L100, or HPMC HME 15LV were characterized by mDSC to determine the glass transition temperature (Tg).

[0530] mDSC can be performed according to the following protocol. mDSC analysis is performed using a Thermal Analysis DSC 2500 and a Thermal Analysis Refrigerated Cooling System 90. 2-5 mg samples are placed in a non-hermetic pan. A Tzero non-hermetic lid is attached to the pan, and the sample is analyzed in modulated mode with a scan range of 20-250°C (unless otherwise specified), a modulation depth of 1°C / min, and a ramp rate (heating rate) of 3.0°C / min.

[0531] A summary of the glass transition temperatures (Tg) obtained following the protocol described above is shown in Table 3.

[0532] [Table 3]

[0533] As can be seen from Table 3, all solid dispersions exhibited a single glass transition temperature. This indicates a homogeneous dispersion with no evidence of phase separation. The glass transition temperature values ​​showed the expected trends with respect to the polymer and compound (1) loading. In the case of Eudragit® L100, which has a higher glass transition temperature than amorphous compound (1), the glass transition temperature decreased with increasing drug loading. In the case of polymers HPMCAS-M, PVP-VA, and HPMC HME 15LV, which have glass transition temperatures lower than that of compound (1), the glass transition temperature increased with increasing drug loading. All solid dispersions provided sufficiently high glass transition temperatures.

[0534] Example 3 - Preparation of solid dispersions using various process parameters Solid dispersions of Compound (1) were tested under various spray drying conditions, such as solvents, inlet temperatures, and spray drying parameters.

[0535] 3.1 Solvent Selection The solubility of compound (1) was measured in a solvent blend of dichloromethane (DCM):methanol.

[0536] To this end, the following protocol can be followed: A solution of compound (1) is prepared at a high concentration and then diluted with solvent until compound (1) dissolves or the concentration drops to less than 1 wt %. Solubility is determined by visual observation.

[0537] The solubility data for compound (1) obtained according to this protocol are shown in Table 4 below.

[0538] [Table 4]

[0539] Therefore, a 90:10 DCM:methanol solvent blend provides high solubility of compound (1) and potentially the highest throughput due to the lower methanol concentration in the solvent system compared to higher DCM:methanol solvent blends.

[0540] 3.2 Inlet temperature Solid dispersions containing 50 wt% Compound (1) and 50 wt% HPMCAS-M or 25 wt% Compound (1) and 75 wt% HPMC HME 15LV were prepared on a larger scale using lower inlet temperatures than in Example 1.

[0541] To this end, the following protocol can be followed: The solid dispersion is spray-dried from a spray solution composition containing Compound (1) and HPMCAS-M or HPMC HME 15LV using a DCM:MeOH (1:1 (w / w)) solvent system (solids content 8 wt% total solids). The solid dispersion is spray-dried using a two-fluid nozzle type and 1.0 mm / 1.0 mm nozzle cap / tip dimensions, an inlet temperature of 55-70°C, an outlet temperature of 45-50°C, atomization at 3.0 bar, and a drying gas air flow rate of 0.50 m / s. 3 The dispersion is prepared using a Procept 4M8TRX spray dryer with a solution feed rate of about 10-15 g / min. Secondary drying of the dispersion is carried out in a collection vessel in a tray dryer type vacuum dryer at 40°C for about 24 hours.

[0542] Spray drying yield results obtained following this protocol are summarized in Table 5, where gA represents grams API (active pharmaceutical ingredient, i.e., Compound (1)). mDSC results (unsealed pan, heating 3°C / min, modulation 1°C / min) are summarized in Table 6.

[0543] [Table 5]

[0544] [Table 6]

[0545] 3.3 Spray drying parameters The effects of flow rate (liquid feed rate), dryer outlet temperature, and drying environment on spray-dried solid dispersions were tested. A composition containing 50 wt% Compound (1) and 50 wt% dispersion carrier HPMCAS-M was used for this study. This composition was spray-dried from a spray solution composition containing Compound (1) and HPMCAS-M using a solvent ratio of 90:10 (w / w) DCM:MeOH and a solids content of 10 wt% total solids. Solid dispersions were produced using an open-loop, custom-developed spray dryer, SD-90, equipped with an SK 79-16 atomization system nozzle. Liquid feed rates of 291 to 317 g / min and outlet temperatures of 35 to 45°C were tested. The process parameters are summarized in Table 7 below.

[0546] [Table 7]

[0547] Yield improved from the first lot sprayed (3.3-A) to the last lot sprayed (3.3-C). Yield for lot A was low due to retention losses. Smaller batch sizes had lower yields compared to larger batches due to retention losses, and yield improved as the lots were sprayed due to reduced carryover from earlier lots and the impact of retention losses on later lots.

[0548] The solid dispersions of Samples 3.3-A, 3.3-B, and 3.3-C were characterized using X-ray powder diffraction (XRPD), modulated differential scanning calorimetry (mDSC), and particle size distribution (PSD). PSD was measured by laser diffraction.

[0549] XRPD can be obtained according to the following protocol: XRPD analysis is performed using a Rigaku Miniflex 600 diffractometer. Approximately 10 mg quantities of Samples 3.3-A, 3.3-B, and 3.3-C are loaded onto a zero background sample disk and placed in the autosampler of the Rigaku Miniflex 600. The samples are analyzed using the instrument parameters listed in Table 8 below.

[0550] [Table 8]

[0551] The XRPDs obtained for solid dispersions Samples 3.3-A, 3.3-B, and 3.3-C according to the protocol described above are shown in Figure 5. The lack of sharp peaks and the presence of an amorphous halo suggest that all samples contain amorphous compound (1).

[0552] This protocol can be used for mDSC measurements. Samples 3.3-A, 3.3-B, and 3.3-C (2-5 mg each) are placed in Tzero pans. A Tzero non-hermetic lid is attached to the pan, and the samples are analyzed in modulation mode over a scan range of 0-250 °C with a modulation depth of 1 °C / min, a modulation period of 60 seconds, and a ramp rate (heating rate) of 3 °C / min. The glass transition temperatures are summarized in Table 9.

[0553] [Table 9]

[0554] For all solid dispersions, Samples 3.3-A, 3.3-B, and 3.3-C, the thermograms obtained according to the protocol described above showed a single glass transition at around 116°C and no obvious melting or recrystallization phenomenon, indicating that the solid dispersions were single-phase containing amorphous Compound (1).

[0555] The particle size distribution (PSD) for the solid dispersions of Samples 3.3-A, 3.3-B, and 3.3-C can be measured by laser diffraction of the dry dispersion powder using a Sympatec HELOS laser diffraction system and a RODOS dry powder delivery system. The system can be operated using an R4 lens and a dispersion pressure of 3 bar. The results from this method are summarized in Table 10.

[0556] [Table 10]

[0557] 3.4 Spray drying parameters Spray drying parameters were further tested for larger batch sizes. A mixture containing 50 wt% Compound (1) and 50 wt% dispersion carrier HPMCAS-M was used for this test. This mixture was spray dried from a spray solution composition using a solvent ratio of 90:10 (w / w) DCM:MeOH and a solids loading of 10 wt%. Solid dispersions were produced using an open-loop, custom-developed SD-90 spray dryer equipped with an SK 79-16 atomization system nozzle. Feed rates of 300 and 325 g / min and outlet temperatures of 44 and 40°C were tested. The process parameters are summarized in Table 11 below.

[0558] [Table 11]

[0559] The lower yield of sample 3.4-A is likely due to solids losses resulting from the small batch size. Solids losses are independent of batch size, but are higher in smaller batches. Therefore, sample 3.4-B had a higher yield due to the larger batch size. Both samples were characterized using XRPD, mDSC, and PSD. PSD was measured by laser diffraction.

[0560] XRPD scans of Samples 3.4-A and 3.4-B were performed as described in Example 3.3 above. Diffractograms for the solid dispersions of Samples 3.4-A and 3.4-B are shown in Figure 6, which shows an amorphous halo without sharp peaks, suggesting that Compound (1) was in an amorphous state in both samples.

[0561] For mDSC measurements, 2-5 mg amounts of Samples 3.4-A and 3.4-B were placed in Tzero pans and the measurements were performed as described in Example 3.3 above, except that a scan range of 0-200 °C was used for Sample 3.4-B. A summary of the glass transition temperatures is shown in Table 12 below.

[0562] [Table 12]

[0563] The thermograms of the solid dispersions of Samples 3.4-A and 3.4-B showed a single glass transition, indicating a single-phase amorphous material; the mDSC thermograms did not show any obvious peaks that would indicate crystalline material. The difference in glass transition temperature compared to Sample 3.3 may be due to the different lots of Compound (1) used in the preparation of the SDD and / or noise in the measurement equipment.

[0564] The mDSC results are consistent with the XRPD results, demonstrating by two orthogonal methods that the solid dispersion contains compound (1) in amorphous form.

[0565] The particle size distribution (PSD) for the solid dispersions of Samples 3.4-A and 3.4-B can be measured by laser diffraction of the dry dispersion powder using a Sympatec HELOS laser diffraction system and a RODOS dry powder delivery system. The system can be operated using an R4 lens and a dispersion pressure of 3 bar. The results from this method are summarized in Table 13.

[0566] [Table 13]

[0567] Example 4 - Physical Stability of Amorphous Solid Dispersants 4.1 Stress stability test under accelerated stress conditions The physical stability of amorphous solid dispersion formulations of Compound (1), corresponding to Samples 3.3-A, 3.3-B, and 3.3-C obtained in Example 3.3, was evaluated using accelerated stability testing. Each sample was incubated in an open vial at (i) ambient temperature / ambient humidity, (ii) ambient temperature / 60% relative humidity, (iii) 40°C / ambient humidity, and (iv) 40°C / 75% relative humidity. Relative humidity (RH) was achieved using saturated salt solutions (sodium bromide for approximately 60% RH at ambient temperature and sodium chloride for 75% RH at 40°C). After 2 and 4 weeks, samples were removed for analysis and characterized by XRPD to assess the possibility of recrystallization.

[0568] No changes in physical properties were observed: the diffraction patterns of all amorphous solid dispersions were consistent with the amorphous form of Compound (1) after 4 weeks at all storage conditions.

[0569] 4.2 Stress stability test under severe stress conditions An amorphous solid dispersion (50 wt%:50 wt% Compound (1):HPMCAS-M, prepared, for example, according to the procedure in Example 1) was exposed to 75°C / 79% relative humidity and 80°C / 76% relative humidity in an open container for three weeks. The XRPDs for each are shown in Figure 7. No morphological changes were observed even after three weeks of exposure to these extreme stress conditions.

[0570] Example 5 - pH-dependent solubility and in vitro solubility 5.1 Comparative solubility tests in biologically relevant media and aqueous media at various pH levels The solubilities of an amorphous solid dispersion of Compound (1) and HPMCAS-M (50 wt%:50 wt%) and crystalline Compound (1) (prepared, for example, according to Reference Examples 1 and 2 below) were measured in various aqueous media at room temperature and in biorelevant media at 37° C. The media used in the solubility assays are listed in Table 14 below.

[0571] [Table 14]

[0572] The following protocol was used to prepare samples for solubility measurements. A suitable amount of crystalline compound (1) or amorphous solid dispersant of compound (1) is weighed out to achieve the desired target concentration. Add the selected vehicle at room temperature to reach the selected target concentration. Protect from light and orbital mix at room temperature or vortex mix at 37°C for 24 hours. The soluble and insoluble fractions are separated by centrifugation (18,000 rpm for 15 minutes) followed by filtration through a 0.45 μm PTFE membrane. The first 3.5 mL is discarded, and then three aliquots (approximately 0.5 mL) are collected for analysis. Quantitate 3 aliquots by UPLC-UV-MS and appropriate calibration curve.

[0573] UPLC-UV-MS method Instrument: Waters Acquity H-Class equipped with PDA and QDa detectors Column: Waters Acquity BEH C18, 17 μm, 2.1 × 50 mm Flow rate: 0.65mL / min UV detection: 254nm or 410nm Column temperature: 40°C ± 2°C Sample temperature: 23°C ± 2°C Injection volume: 0.4 μL (for concentrations of 1 to 500 μg / mL) and 9 μL (for concentrations of 0.050 to 1 μg / mL) Mobile phase: gradient with solutions A and B prepared as follows: [Table 15] Ionization mode: ESI+ / ESI- Source temperature: 600℃ Capillary voltage: 0.8 kV Cone voltage: +20V / -20V

[0574] Two calibration curves (chromatographic UV peak area vs. concentration) are established in DMSO at 254 nm or 410 nm for each solid form and solid dispersion, one from 0.025 or 0.050 μg / mL to 1 μg / mL (injection volume = 9 μL) and the other from 1 μg / mL to 500 μg / mL (injection volume = 0.4 μL). The calibration curves are linear over the entire concentration range investigated.

[0575] The results of the solubility assay obtained according to the protocol in the previous section are summarized in Table 15 and shown in Figure 8.

[0576] [Table 16]

[0577] Both crystalline forms of Compound 1 were found to be soluble in strongly acidic media, but solubility decreased at pH ≥ 5. Additionally, the solubility of the crystalline forms of Compound 1 was low in biorelevant fasted and fed simulated intestinal fluids (FaSSIF and FeSSIF). When Compound 1 was formulated as an amorphous solid dispersion with HPMCAS-M, the solubility of Compound 1 was found to be significantly improved at pH ≥ 5 and in biorelevant media.

[0578] 5.2 In vitro solubility of amorphous solid dispersions of compound (1) vs. crystalline compound (1) The kinetic solubilities of various amorphous solid dispersion formulations (25 wt%:75 wt% and 50 wt%:50 wt% Compound (1):polymer) prepared according to the procedure disclosed in Example 1 using crystalline Compound (1) and polymers selected from HPMCAS-M, HPMC HME 15LV, PVP-VA, and Eudragit® L100 were measured in biorelevant media during pH-shift non-sinking dissolution tests.

[0579] To this end, the following protocol can be used: First, the sample is transferred to simulated gastric fluid (SGF) and then, through a series of dilution steps, to simulated intestinal fluid (SIF). The test is performed at 3 mg / mL in 0.01 N HCl SGF (step 1), followed by a 3-fold dilution after 30 minutes in FaSSIF pH 6.5 (+33 mM sodium phosphate for additional buffering capacity) to a target of 1 mg / mL. "Total drug" and "dissolved drug" are assessed. Total drug is measured by sampling the supernatant of the non-settled (saturated) sample after benchtop centrifugation (approximately 19,000 rcf, 3-5 minutes). Total drug includes free drug, bile salt micelles (in SIF), and colloidal species formed by drug-polymer interactions. Dissolved drug is measured by filtering the total drug supernatant through a 0.22 μm filter to remove larger colloidal species. Dissolved drug includes free drug and bile salt micelles.

[0580] Following this protocol, all formulations were completely dissolved at 3 mg / mL in simulated gastric fluid (data not shown), but the amorphous solid dispersion formulations demonstrated significantly more dissolved drug compared to the crystalline API in simulated intestinal fluid (see Figures 9 and 10). It should be noted that for a given polymer, increasing drug loading in an amorphous solid dispersion formulation is typically expected to either be unaffected or degrade performance as assessed by increasing dissolved drug and / or colloidal species formation. However, for the Compound (1):HPMCAS-M SDD formulation, increasing drug loading consistently increased dissolved drug.

[0581] Example 6 - Pharmaceutical Composition 6.1 Methods for Producing Tablets Containing a Spray-Dried Solid Dispersion of Compound (1) Film-coated tablets containing a solid dispersion of Compound (1) were prepared generally according to the following scheme unless otherwise noted.

[0582] Step 1: Preparation of solid dispersions by spray drying Compound (1) and HPMCAS-MG (hydroxypropyl methylcellulose acetate succinate-MG) are dissolved in a solvent mixture of dichloromethane (DCM) and methanol (MeOH) to produce a spray-dried solution. Alternative dispersion carriers can be used in place of or in addition to HPMCAS-MG. This solution is spray-dried using a suitable spray dryer to produce a spray-dried solid dispersion. This spray-drying process can be carried out as detailed in Examples 1 and 3. The spray-dried solid dispersion is then further dried in a suitable dryer to remove residual solvent, as detailed in Examples 1 and 3.

[0583] Step 2: Dry granulation of solid dispersion and excipients The dry solid dispersion is mixed with microcrystalline cellulose, mannitol, croscarmellose sodium, and a portion of colloidal silicon dioxide, and then this mixture of solid dispersion and filler, disintegrant, and glidant is pre-blended and screened / delumped. Sodium stearyl fumarate is added to this pre-blend as a lubricant. The intragranular blend is then granulated using a roller compactor equipped with a 1.0 mm screen. The screened dry granules are collected for subsequent final blending.

[0584] Step 3: Blending The granules are blended in a blender with a pre-screened extragranular mixture of croscarmellose sodium and colloidal silicon dioxide. Sodium stearyl fumarate is added and blended to produce the final blend.

[0585] Step 4: Tablet compression The final blend is then compressed into tablet cores.

[0586] Steps 1 to 4 were performed for the ingredients shown in Table 16 below.

[0587] [Table 17]

[0588] 6.2 Manufacture of film-coated tablets containing 15 mg or 60 mg of Compound (1) Steps 1 to 4 can be followed by an optional film coating step, which can be carried out as outlined below.

[0589] Process 5: Film coating The film-coating mixture Opadry® AMB II yellow is dispersed in water for injection using a stirrer and a container. The tablet cores are coated with the film-coating suspension in a suitable pan coater to obtain film-coated tablets containing a solid dispersion of Compound (1) and a dispersing carrier. Step 5 is optional. An alternative film-coating mixture can be used instead of Opadry® AMB II yellow.

[0590] Film-coated tablets containing a spray-dried solid dispersion of Compound (1) and HPMCAS-MG (hypromellose acetate succinate, where MG refers to the grade soluble at pH ≥ 6.0 and is a granular, free-flowing powder) were prepared as described in Example 6.1, followed by step 5 above. The ingredients are summarized in Table 17 below.

[0591] [Table 18]

[0592] The film-coated tablets contained 15 mg or 60 mg of Compound (1). Dichloromethane and methanol were used as solvents, and nitrogen was used as the drying gas for the solid dispersion, but was removed during the process and therefore not included in the final product. Additionally, water for injection was used as the solvent for the film-coating mixture, but was also removed during drying and therefore not analyzed.

[0593] The film coating mixture used was Opadry® AMB II yellow 88A120087, which contains partially hydrolyzed polyvinyl alcohol as a film former, talc as an anti-tack agent, sodium lauryl sulfate as a lubricant, and titanium dioxide, glyceryl mono- and dicaprylocaprate (GMDCC), and iron oxide yellow as pigments.

[0594] 6.3 Preparation of tablets containing 400 mg or 200 mg of Compound (1) Uncoated tablet formulations containing spray-dried solid dispersions of Compound (1) and HPMCAS-M at 25:75 wt% or 50:50 wt% were prepared as described in Example 6.1 above, with the ingredients summarized in Tables 18 and 19 below.

[0595] [Table 19]

[0596] [Table 20]

[0597] 6.4 Preparation of tablets containing a solid dispersion of compound (1) and HPMC Solid dispersion formulations containing non-enteric polymers, such as HPMC, are known to be prone to gelation when formulated as tablets, resulting in slow disintegration. Understanding this potential challenge, an initial feasibility study was completed on a solid dispersion containing a spray-dried solid dispersion of 25 wt% Compound (1) and 75 wt% HPMC HME 15LV. The starting ingredients are summarized in Table 20 below.

[0598] [Table 21]

[0599] The formulations listed in Table 20 did not disintegrate as expected. A formulation approach to improve disintegration involved increasing the amount of microcrystalline cellulose and mannitol (24 wt% each), diluting the intragranular blend of Table 20 by 50%, and using only 2 wt% croscarmellose sodium, resulting in a tablet structure that utilized both granular and extragranular components. The final formulation contained 50 mg of Compound (1) per 700 mg tablet.

[0600] 6.5 Characterization of tablet cores and film-coated tablets by X-ray powder diffraction (XRPD) The tablet cores (Example 6.1-C) and film-coated tablets (Example 6.2-C) were investigated by XRPD to confirm the absence of crystalline Compound (1), e.g., Forms III and IV. To this end, the following protocol can be followed: Samples are prepared by slightly crushing the tablet cores or film-coated tablets in a mortar with a pestle, followed by homogeneous mixing of the resulting powder with a spatula. The resulting powder is then measured by XRPD using an X'pert PRO diffractometer with the following settings and measurement parameters:

[0601] [Table 22]

[0602] The XRPDs of the tablet cores of Example 6.1-C and the film-coated tablets of Example 6.2-C obtained according to the procedures in the previous section are shown in Figures 15 and 16. Both formulations contain crystalline excipients mixed with an amorphous solid dispersion containing Compound (1). The diffraction peaks present in the XRPD are attributable to these excipients. The absence of Form IV is indicated, for example, by the absence of a peak at (5.8±0.2)°, and the absence of Form III is indicated, for example, by the absence of a peak at (6.2±0.2)°.

[0603] Example 7 - Determination of the properties of tablets containing a spray-dried solid dispersion of Compound (1) 7.1 In vitro dissolution profile in phosphate buffer pH 2.0 A dissolution study comparison was conducted comparing a conventional film-coated tablet containing a total of 15 mg crystalline Compound (1) with a film-coated tablet containing 15 mg Compound (1) as a spray-dried solid dispersion with HPMCAS-MG from Example 6.2-B.

[0604] A comparative film-coated tablet containing crystalline Compound (1) contained 5 mg of Compound (1), 64.5 mg of silicified microcrystalline cellulose composed of colloidal silicon dioxide and microcrystalline cellulose as a filler, 21 mg of anhydrous lactose as a filler, 3 mg of sodium starch glycolate type A as a disintegrant, 5 mg of hydroxypropyl cellulose as a binder, 0.5 mg of colloidal silicon dioxide as a glidant, 1 mg of vegetable-derived magnesium stearate as a lubricant, and 4.5 mg of a film coating mixture (e.g., Opadry® yellow 03B120053). Three 5 mg tablets were used in this study.

[0605] The following protocol can be used to conduct dissolution comparisons. Dissolution tests are performed in 20 mM phosphate buffer (NaH2PO4) pH 2.0 at 37°C using an Agilent 708-DS instrument equipped with an 850-DS sampling station. A 15 mg tablet containing Compound (1) as a solid dispersion equivalent to Sample 6.2-B and three 5 mg tablets containing Compound (1) in crystalline form (total weight of 15 mg) are suspended in the buffer solution. The dissolution profile is evaluated under the following conditions: shaft rotation speed 50 rpm, medium volume 900 mL, sample volume 3 mL. The amount of Compound (1) in the buffer is measured by HPLC at regular intervals over a 60-minute period. The % solubility is calculated using the following equation (A): % solubility=((A smp ×C S1 ×DF smp ) / (A S1 ×LC))×100 (A) [In the formula, Asmp is the peak area of ​​the sample, C S1 is the concentration of standard 1, 0.017 mg / mL compound (1), Defender smp is the sample dilution factor, 900 mL, A S1 is the average peak area response from the first five standard 1 injections, LC is as stated on the tablet label and is 15 mg]

[0606] The results of an in vitro dissolution comparison between conventional tablets and solid dispersion tablets in a buffer pH 2.0 obtained according to the protocol described in the previous section are shown in Figure 11. As can be seen, the tablets containing the solid dispersion exhibited a faster initial drug release than the tablets containing crystalline Compound (1).

[0607] 7.2 In vitro dissolution profile in phosphate buffer pH 6.8 containing 0.1% SDS Comparative dissolution studies were performed comparing a conventional film-coated tablet containing 60 mg (3 x 20 mg) total of crystalline Compound 1, a film-coated tablet containing 60 mg (4 x 15 mg) total of Compound 1 as a spray-dried solid dispersion with HPMCAS-MG according to Example 6.2-A, and a film-coated tablet containing 60 mg Compound 1 as a spray-dried solid dispersion with HPMCAS-M according to Example 6.2-C.

[0608] A conventional film-coated tablet containing crystalline Compound (1) contained 20 mg of Compound (1), 49.5 mg of silicified microcrystalline cellulose composed of colloidal silicon dioxide and microcrystalline cellulose as a filler, 21 mg of anhydrous lactose as a filler, 3 mg of sodium starch glycolate type A as a disintegrant, 5 mg of hydroxypropyl cellulose as a binder, 0.5 mg of colloidal silicon dioxide as a glidant, 1 mg of vegetable-derived magnesium stearate as a lubricant, and 4.5 mg of a film-coating mixture (e.g., Opadry® yellow 03B120053). Three 20 mg tablets were used in this study.

[0609] Dissolution testing was performed under the conditions outlined in Table 22.

[0610] [Table 23]

[0611] The % dissolution% (same as % dissolved) was calculated as described above in Example 7.1. The results of an in vitro dissolution comparison between conventional tablets and solid dispersion tablets in a buffer pH 6.8 are shown in Figure 12. As can be seen, the tablets containing the solid dispersion have similar dissolution profiles and exhibit a faster initial drug release than the tablets containing crystalline Compound (1). In addition, in contrast to the tablets containing crystalline Compound (1), the tablets containing the solid dispersion dissolve completely.

[0612] 7.3 In vitro measurement of bioaccessibility Bioavailability in humans was assessed using tiny-TIM, a dynamic in vitro gastrointestinal model designed to simulate the physiological processes occurring in the human stomach and small intestine.

[0613] A conventional tablet of crystalline Compound (1) (conventional formulation) and a tablet containing a solid dispersion of Compound (1) (SDD formulation) were tested in the tiny-TIM model.

[0614] The conventional formulation contained 100 mg Compound (1), 247.5 mg silicified microcrystalline cellulose and 105 mg anhydrous lactose as fillers, 25 mg hydroxypropyl cellulose as a binder, 15 mg sodium starch glycolate as a disintegrant, 2.5 mg colloidal silicon dioxide as a glidant, and 5 mg magnesium stearate as a lubricant.

[0615] The SDD formulation tested in the tiny-TIM model corresponds to Example 6.2-A, as shown in Table 17.

[0616] tiny-TIM Test Protocol Food matrix in the tiny-TIM setup To simulate fasting conditions, one glass of water (240 mL) is presented to the tiny-TIM system.

[0617] tiny-TIM test system This study is carried out in a TNO dynamic multicompartment in vitro system of the stomach and small intestine (tiny-TIM).

[0618] The tiny-TIM system consists of a stomach compartment and one small intestine compartment (Figure 13). The compartments are composed of two glass units with a flexible silicone inner wall surrounding a lumen material. The space between the inner and outer walls is filled with water. Peristaltic mixing of the chyme results from alternating compression and relaxation of the flexible inner wall. The compartments are connected by a peristaltic valve pump, which opens and closes continuously, allowing chyme to pass through the compartment over time. In this way, the oral dosage form / API is locally altered and exposed to physiologically relevant conditions in the stomach and small intestine for the tiny-TIM.

[0619] The tiny-TIM system mimics intraluminal pH, enzyme activity, bile salt concentrations, peristalsis, and gastrointestinal transit of contents. The set points of the gastrointestinal simulation are controlled and monitored by a specific computer program. Released and dissolved drug molecules are removed from the intestinal lumen by a semipermeable membrane unit connected to the small intestinal segment. This allows the evaluation of the so-called bioabsorption rate, i.e., the proportion of drug available for small intestinal absorption.

[0620] Simulation of gastrointestinal conditions Experiments in tiny-TIM are performed under simulation of average physiological conditions in the gastrointestinal tract, as described for fasting humans. These conditions include, in particular, the kinetics of gastric emptying and pH drop, intestinal transit time, housekeeper waves, gastric and intestinal pH values ​​(Tables 23 and 24), and the composition and activity of secretions. Digested soluble (small molecule) compounds are continuously removed from the intestinal compartment via a specialized membrane system.

[0621] Before each experiment, secretory fluids (e.g., gastric juice containing enzymes, electrolytes, bile, and pancreatic juice) are freshly prepared, pH electrodes are calibrated, and semipermeable membrane (hollow fiber) units are installed.

[0622] [Table 24]

[0623] [Table 25]

[0624] Housekeeper Waves A housekeeper wave (HKW) is simulated after 60 minutes by automatic transfer of residue from the gastric compartment to the intestinal compartment.

[0625] experiment This experiment is performed in duplicate. All experiments are performed under yellow light to prevent decomposition of compound (1).

[0626] sampling Filtrate Filtration of released, dissolved, or solubilized drug molecules from the intestinal lumen through a semipermeable membrane unit (Fresenius plasmaFlux® P1dry) allows for the assessment of the so-called bioabsorption rate, i.e., the proportion of drug available for small intestinal absorption. Filtrate was collected at time intervals of 0-30 min, 30-60 min, 60-90 min, 90-120 min, 120-180 min, 180-240 min, and 240-300 min (Figure 13, sampling spot H). Analysis of these samples generated data on the bioaccessibility and availability of compound (1) for absorption. The amount collected at each time point was measured, and subsamples were taken, immediately diluted with organic solvent, and stored at 2-10°C, protected from light, until analysis.

[0627] residue At the end of each experiment, the retentate in the stomach and small intestinal compartments plus filter units is collected, measured, and analyzed. These retentate samples represent the non-bioabsorption rate. The rinses are pooled with the retentate samples from the same compartments, the volume is measured, and the rinses are stored at 2-10°C, protected from light, until analysis.

[0628] Saving backup samples The backup sample will be stored protected from light at -18°C or below for one month after the research report is finalized, after which the sample will be discarded.

[0629] Sample analysis The collected samples are analyzed for the concentration of compound (1).

[0630] Calculating the results The absolute amount of API in the sample is calculated by multiplying the analytical concentration in the sample by the collected volume (Equation 1).

number

[0631] The recovery of API is determined by summing the total amount recovered in the intestinal filtrate fraction and the gastric and intestinal retentate and rinse fractions, plus the drug product. Total recovery is expressed as % added dose (Equation 2).

number

[0632] Bioaccessibility (% uptake) is calculated by expressing the amount of API recovered from the filtrate as % uptake (Equation 3).

number

[0633] Results of duplicate experiments are expressed as mean ± SD. For SD, the STDEVP function in Microsoft® Excel® was used (Equation 4).

number

[0634] statistics No statistical analysis was performed in this study.

[0635] result Bioaccessibility profiles obtained from the tiny-TIM protocol described above are shown in Figure 14 for both the conventional (conv.) and SDD formulations under two conditions: fasted and simulated PPI conditions, i.e., high gastric pH. Under low gastric pH (fasted, 3.0-1.8 for 30 minutes), comparable bioaccessibility was observed between the conv. and SDD formulations. Under PPI conditions (fasted, gastric pH 5), the conventional tablet showed an approximately five-fold decrease in bioaccessibility, while the SDD tablet was unaffected. Thus, in contrast to the conventional tablet, the performance of the SDD formulation is not pH-dependent. Tablets from Examples 6.2-B and 6.2-C, listed in Table 17, were tested using the same tiny-TIM testing protocol and showed comparable results.

[0636] 7.4 In vivo relative bioavailability clinical trials A clinical trial was conducted to evaluate the relative bioavailability of Compound 1 in two different oral formulations: a conventional tablet containing the crystalline form of Compound 1 and a tablet containing a solid dispersion of Compound 1 of the present invention. In addition, the effects of food and multiple doses of the protein pump inhibitor (PPI), rabeprazole, on the pharmacokinetics of a single dose of Compound 1 after oral administration of the above-mentioned solid dispersion formulation in healthy male subjects were investigated.

[0637] 7.4.1 Protocol 18-45 years old (inclusive) and 18.5-29.9 kg / m 2 Sixteen healthy male subjects with a body mass index (BMI) of 100 mg / kg were enrolled in this study. The study design was an open-label, randomized, four-way crossover trial. The primary endpoint was the area under the plasma concentration-time curve (AUC) from time 0 (t0), corresponding to the time of drug administration of compound (1), to time z (tz), corresponding to the last quantifiable time point. 0-tz ) and maximum plasma concentration (C max) The secondary endpoint was the area under the plasma concentration-time curve (AUC) of compound (1) extrapolated from t0 to infinity. 0-∞ )

[0638] Therefore, the objectives of this trial are to investigate the following:

[0639] Study 1: Relative bioavailability under fasted conditions of two different tablet formulations of Compound (1) in crystalline form and Compound (1) as a solid dispersion.

[0640] Study 2: Relative bioavailability of Compound (1) formulated as a solid dispersion under fasted and fed conditions and

[0641] Study 3: Relative bioavailability of Compound (1) formulated as a solid dispersion when administered alone and in combination with rabeprazole under fasted conditions.

[0642] Test 1: Comparative film-coated tablets containing crystalline Compound (1) were prepared using 5 mg or 20 mg Compound (1) and colloidal silicon dioxide and microcrystalline cellulose as fillers. Each tablet contains 64.5 mg or 49.5 mg silicified microcrystalline cellulose, 21 mg anhydrous lactose as a filler, 3 mg type A sodium starch glycolate as a disintegrant, 5 mg hydroxypropyl cellulose as a binder, 0.5 mg colloidal silicon dioxide as a glidant, 1 mg vegetable-derived magnesium stearate as a lubricant, and 4.5 mg film coating mixture (e.g., Opadry® yellow 03B120053).

[0643] Test Article 2: Film-coated tablets containing 15 mg Compound (1) as a solid dispersion spray-dried with HPMCAS-MG as defined in Example 6.2-A.

[0644] Test Article 3: PARIET® 20 mg strength rabeprazole gastroresistant tablets, a proton pump inhibitor

[0645] The reference treatment (R or TF1) consisted of a total dose of 30 mg crystalline Compound (1) in the form of Test Article 1 (one 20 mg tablet and two 5 mg tablets), administered orally with 240 mL of water on Day 1 after an overnight fast of at least 10 hours.

[0646] Test Treatment 1 (T1 or NF1) consisted of a total dose of 30 mg Compound (1) (two 15 mg tablets) in the form of a solid dispersion as Test Article 2, administered orally with 240 mL of water on Day 1 after an overnight fast of at least 10 hours.

[0647] Test Treatment 2 (T2) consisted of a total dose of 30 mg Compound (1) (two 15 mg tablets) in the form of a solid dispersion as Test Article 2, administered under fed conditions on Day 1 after a high-fat, high-calorie breakfast. The total calorie content of the high-fat, high-calorie breakfast was provided approximately as follows: 150 kcal protein, 250 kcal carbohydrate, and 500-600 kcal fat; Ingredients: 2 whole eggs for scrambled eggs (192 kcal), 10 g butter for frying scrambled eggs (75 kcal), 35 g fried bacon (186 kcal), 2 slices of wheat bread toast (130 kcal), 15 g butter for toast slices (113 kcal), 115 g hash brown potatoes (132 kcal), and 240 mL whole milk (3.5% fat) (156 kcal), for a total of 984 kcal.

[0648] Test Treatment 3 (T3) consists of a total dose of 30 mg Compound (1) in the form of a solid dispersion (two 15 mg tablets) as Test Article 2, administered under fasting conditions. Subjects in T3 also receive Test Article 3, total dose of 200 mg rabeprazole, at a daily dose of 40 mg once daily (two 20 mg tablets) 4 days before and on the day of Compound (1) administration.

[0649] Blood samples were collected for all treatments up to 118 hours after administration of Compound (1) to analyze the plasma concentration of Compound (1). Plasma concentration-time profiles were evaluated by non-compartmental analysis to calculate each PK parameter. Relative bioavailability was estimated by the ratios of geometric means (T1 / R, T2 / T1, and T3 / T1) for the primary and secondary endpoints. Furthermore, their two-sided 90% confidence intervals (CI) were provided. This method is equivalent to two one-sided t-tests at a 5% significance level. Because the primary focus is on estimation, not testing, formal hypothesis testing and associated tolerance limits were not specified. The statistical model was an analysis of variance (ANOVA) on a logarithmic scale, including the effects of sequence, subject nested within the sequence, period, and treatment. CIs were calculated based on the residuals from the ANOVA. Descriptive statistics were calculated for all endpoints. Pharmacokinetic analysis was performed on the pharmacokinetic parameter analysis set (PKS), and safety analysis was performed on the treatment set (TS). Formal interim analyses were not planned or performed.

[0650] 7.4.2 Results Of the 16 subjects planned for inclusion in this clinical trial, 13 completed the study. Treatment comparisons included 12 subjects evaluable for the relative bioavailability comparison between T1 and R, 9 subjects for food effect evaluation (T2 vs. T1), and 11 subjects for drug-drug interaction evaluation between Compound (1) and rabeprazole (T3 vs. T1). Relative bioavailability comparisons demonstrated that tablets containing a solid dispersion of Compound (1) (T1) exhibited reduced variability compared with tablets containing crystalline Compound (1) (R). Exposure to T1 resulted in an average increase of 3% (Cmax) and 35% (AUC0-tz) compared with R. Food effect evaluations demonstrated an average decrease of -46% in Cmax and -26% in AUC0-tz under fed conditions (T2) compared with fasted conditions (T1). Pretreatment with rabeprazole did not significantly alter the exposure of tablets containing the solid dispersion of Compound 1 (mean Cmax -13% and AUC0-tz -3%), suggesting no relevant DDIs between Compound 1 and proton pump inhibitors or other pH-raising co-medications.

[0651] The trial results are discussed in more detail below.

[0652] Clinical trial subjects and protocol compliance A total of 13 subjects received the study drug and completed the scheduled observation period. No serious protocol violations were reported. Of the 13 healthy male subjects treated in this study, 12 subjects (92.3%) were Caucasian and 1 subject (7.7%) was Black or African American. The mean age of the subjects was 34.8 years (standard deviation [SD] = 5.8 years), with an age range of 25 to 45 years. The mean BMI was 25.49 kg / m 2 (SD=3.03 kg / m 2 ) and BMI is 20.7-29.5 kg / m 2 Treatment groups were similar with respect to demographics and baseline characteristics.

[0653] Twelve subjects were randomized to receive Reference Treatment (R), 12 subjects to receive Test Treatment 1 (T1), 9 subjects to receive Test Treatment 2 (T2), and 11 subjects to receive Test Treatment 3 (T3), with a washout period of at least 14 days between administration of Compound (1) and subsequent treatments.

[0654] The relative bioavailability of formulations NF(T1) and TF1(R) under fasting conditions is shown in Table 25. The adjusted geometric mean ratios for the primary and secondary endpoints in subjects receiving treatment T1 / R ranged from 129.1% to 139.3%, with 90% CIs ranging from 87.7% to 221.3% (Table 25). The pharmacokinetic (PK) parameter, C max (geometric coefficient of variation [gCV] 93.1%), AUC0-tz (gCV 52.7%) and AUC 0-∞ (gCV 52.7%), the variation of C max (gCV 37.3%), AUC 0-tz (gCV 18.8%) and AUC 0-∞ The gCV was higher in subjects on treatment R compared to subjects on treatment T1 (gCV 19.2%). Although the trend toward improved oral bioavailability of NF was not consistently observed in all subjects, an overall trend toward improved oral bioavailability was demonstrated.

[0655] [Table 26]

[0656] The ANOVA results comparing the primary and secondary endpoints of the NF formulations fasted (T1) or after ingestion of a high-fat, high-calorie meal (T2) are shown in Table 26. The adjusted g mean ratios for the primary and secondary endpoints in subjects receiving treatment T2 / T1 ranged from 53.5% to 74.9%, with 90% CIs ranging from 40.5% to 81.7% (Table 26). max , AUC 0-tz and AUC 0-∞The values ​​of β-glucan were lower in subjects treated under fed conditions, indicating a negative effect of diet.

[0657] [Table 27]

[0658] ANOVA results comparing the primary and secondary endpoints of the NF formulation without (T1) and with (T3) co-administration of the proton pump inhibitor (PPI), rabeprazole, at a defined fasting state are shown in Table 27. The adjusted geometric mean (g-mean) ratios of the endpoints in subjects treated T3 / T1 ranged from 87.0% to 97.1%, with 90% CIs ranging from 66.8% to 113.2% (Table 27). PK parameters and profiles for T1 and T3 were similar, except for the time from the (last) dose to the maximum measured concentration of the analyte in plasma (t max ) appeared to be delayed in the presence of rabeprazole. Collectively, these results suggest that rabeprazole does not interfere with the PK of compound (1).

[0659] [Table 28]

[0660] Example 8 - Open-Label Phase I Dose-Escalation Study with Dose Confirmation and Expansion of Compound (1) as Monotherapy in Patients with Advanced or Metastatic Solid Tumors with HER2 Abnormalities 8.1 Protocol This study is a first-in-human dose-escalation and expansion study to determine the maximum tolerated dose (MTD) and explore initial signs of safety, pharmacokinetics, pharmacodynamics, and efficacy of compound (1) as monotherapy in patients with HER2-aberrant, advanced and / or metastatic solid tumors.

[0661] The dose escalation portion of this trial (also referred to as Phase Ia) involves sequential cohorts of patients treated with escalating doses of Compound (1).

[0662] 8.1.1 Purpose The objectives of the dose escalation portion of this trial are to:

[0663] - To investigate the safety, tolerability, and pharmacokinetics (PK) of compound (1) administered orally twice daily (BID) or once daily (QD) at escalating doses as monotherapy in patients with HER2-abnormal, advanced and / or metastatic solid tumors.

[0664] For each study design, determine the MTD and / or recommended Phase II dose (RP2D) of compound (1) administered orally as monotherapy.

[0665] 8.1.2 Endpoints The primary endpoints of the dose escalation portion of this trial are:

[0666] - MTD: Defined as the highest dose in any study design that results in less than a 25% risk of a true dose-limiting toxicity (DLT) rate of 33% or greater during the MTD evaluation period.

[0667] - Number of patients experiencing DLT during the MTD evaluation period.

[0668] The MTD evaluation period is defined as 21 days after the start of treatment (first cycle).

[0669] Secondary endpoints of the dose escalation portion of this trial are:

[0670] - Number of patients experiencing DLTs during the entire treatment period.

[0671] - the following PK parameters of Compound (1) after initial and multiple doses of the compound on Day 1 and Day 15 (if available): C max : the maximum measured concentration of compound (1) in plasma; AUC 0-t2 : Area under the concentration-time curve of compound (1) in plasma.

[0672] The following endpoints will be further evaluated, if evaluable and applicable:

[0673] - Number of patients experiencing adverse events (AEs) during treatment.

[0674] - Best overall response defined as objective response (OR), complete response (CR), or partial response (PR), where best overall response is determined according to RECIST version 1.1 as assessed by the investigator from the first treatment administration until disease progression, death, or last evaluable tumor assessment before initiation of subsequent anti-cancer therapy, loss to follow-up, or withdrawal of consent, whichever occurs first.

[0675] - Best overall response, defined as disease progression (DC), complete response (CR), partial response (PR), or stable disease (SD), where best overall response is defined according to RECIST version 1.1 as assessed by the investigator up to disease progression, death, or the last evaluable tumor assessment before initiation of subsequent anticancer therapy, loss to follow-up, or withdrawal of consent, whichever occurs first.

[0676] Duration of objective response (DoR), defined as the time from the first documented complete response (CR) or partial response (PR) to the earliest disease progression or death among patients with an objective response.

[0677] - Time to disease control (DoDC), defined as the time from first treatment administration to earliest disease progression or death among patients who achieved disease control.

[0678] - If data are available, PK parameters to be calculated for compound (1) as monotherapy include the following: AUC 0-∞: area under the plasma concentration-time curve over the time interval extrapolated from 0 to infinity, AUC 0-tz : 0 to the last measurement time point (t z ) the area under the plasma concentration-time curve over the time interval C min : minimum measurable plasma concentration in plasma, · t 1 / 2 : the terminal half-life of the analyte in plasma, · t max :C in plasma from administration max Time until.

[0679] 8.1.3 Dose Escalation Dose escalation will be performed according to an open-label design. Data from this trial will be used to determine an MTD estimate based on a Bayesian logistic regression model (BLRM) with overdose constraints (Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med. 2008; 27:2420-2439). The BLRM estimates the MTD by taking into account updated DLT information from both schedules and updating the estimate of the probability of observing a DLT during the MTD evaluation period for each dose level in the trial as patient information becomes available. Dose escalation that does not meet the principles of overdose constraints (EWOC) will not be permitted at any time during the trial. Dose escalation will be limited to a maximum of 100% increase from the previous dose. Dose escalation and cohort size will be based on decisions of the Dose Escalation Committee (DEC) in accordance with the BLRM.

[0680] The dose escalation portion of this study will test two different dosing schedules for Compound (1) within one BLRM using a covariate (which will distinguish between BID and QD). In the BID schedule, cycles are 3 weeks in duration and Compound (1) is administered twice daily (BID). In contrast, in the QD schedule, cycles are 3 weeks in duration and Compound (1) is administered once daily (QD). The study will begin with the BID schedule, and after the DEC determines that the next dose level above the predicted human therapeutic dose is safe, the QD schedule will be initiated. If this QD cohort is deemed safe, the next BID dose level will be initiated.

[0681] From this point onwards, all dose level cohorts will begin alternating between BID and QD schedules: first, BID dose cohorts will be filled and then dropped down to the equivalent QD cohorts.

[0682] Successive cohorts of patients will receive increasing doses of Compound (1) until the MTD is reached. After all patients in a cohort either experience a DLT or are observed for 21 days without a DLT, the BLRM will be updated with newly accumulated data from both schedules. Overdose risk will then be calculated for each dose, and dose escalation to all doses that meet the EWOC criteria will be permitted. For each dosing schedule, based on the model and additional information (PK, pharmacodynamics, patient profile, information from other dosing schedules), members of the DEC will make a collaborative decision on the next dose level to investigate and the next cohort size. The pre-specified dose levels are tentative, and intermediate levels may be considered if the DEC deems them necessary.

[0683] All cohorts will contain at least three patients. If only two patients are evaluable within a cohort (i.e., one patient is unevaluable) and neither experiences a DLT within the MTD evaluation period, dose escalation can be performed based on these two patients.

[0684] If a DLT is observed in the first two consecutive patients at a dose level not yet tested, subsequent enrollment into that cohort will be halted. The BLRM will be updated to confirm that the dose level still meets the EWOC principle. Based on this information, the DEC will evaluate whether to enroll the next patient at the same dose level or at a lower dose level.

[0685] Once the criteria for the MTD are met, no further dose escalation will be performed. Additional patients may be included to confirm this MTD estimate, i.e., to confirm that the EWOC criteria are still met. The DEC may declare any dose that meets the EWOC criteria as the RP2D, regardless of the MTD estimate. The RP2D shall not exceed the MTD. Any DLT that occurs after the MTD evaluation period will be considered in the evaluation of the RP2D for compound (1). If no DLTs are observed, the DEC may decide to declare the RP2D based on the PK / pharmacodynamic endpoints and the overall safety profile. The MTD and RP2D are defined separately for both schedules.

[0686] Once dose escalation is complete and the dose selected for dose expansion has been declared, and with agreement with the DEC, centers participating in dose escalation may continue dose escalation, including patients who are not eligible for dose escalation to the selected dose.

[0687] The RP2D for compound (1) administered as a single agent BID and QD will be defined based on the DLT / MTD (if achieved), all safety data, and PK and PK / PD data collected during the study, if available. If the DLT or MTD is not reached, the RP2D will be determined based on safety data (i.e., overall tolerability and incidence of serious toxicity) and PK and PK / PD data, if available. The RP2D does not need to be the same for the two schedules (BID, QD). BLRM will be performed based on expanded data including all DLT-like events during the entire treatment period, not just for each treatment schedule, to further guide the selection of the RP2D.

[0688] The RP2D is defined and the dose escalation portion can begin before the MTD is reached / dose escalation is complete.

[0689] Patients may continue to receive treatment with Compound (1) until progressive disease (PD) according to RECIST or another reason arises requiring discontinuation of treatment (see Section 3.3.4).

[0690] 8.1.4 Dosage The starting dose for the dose escalation portion of this trial was - BID schedule: 15 mg twice daily - QD schedule: 60 mg once daily (unless otherwise suggested by DEC) Let's say.

[0691] Dose escalation steps will be determined by the DEC.

[0692] The predicted human dose for compound (1) was derived from a quantitative pharmacokinetic / tumor growth inhibition (PK / TGI) model. This preclinical mathematical model was constructed using input data from internal in vitro and in vivo data from efficacy studies in PC-9 YVMA xenografts. Plasma exposure data and tumor growth inhibition data from mice were used to train the model. The predicted human PK parameters were used to predict the human plasma profile in the preclinical PK / TGI model. In this setting, the PK / TGI model was used to identify the required human dose required to achieve TGI >100%, which was predicted to be 40 mg BID.

[0693] 8.1.5 Patient In the dose-escalation portion, patients with advanced, unresectable, and / or metastatic solid tumors who are refractory to or for whom standard therapy is inadequate are eligible. Patients must also have exhausted treatment options known to prolong survival for their disease. These patients must also have a confirmed positive diagnosis of HER2 aberration (described as overexpression according to standard diagnostic criteria or as gene amplification or asynchronous somatic mutation or gene rearrangement involving HER2 or NRG1 according to standard diagnostic criteria).

[0694] Based on the provisional dose levels and titration scheme, the dose escalation portion of this study is planned to enroll approximately 66 patients (approximately 36 patients on the BID dosing schedule and approximately 30 patients on the QD dosing schedule). The total number of patients will depend on the number of dose escalations required.

[0695] All patients, including those eligible for local trial-based studies, must provide a tumor sample to confirm HER2 status.

[0696] Key Inclusion Criteria - Patients with a confirmed diagnosis of advanced, unresectable and / or metastatic non-hematologic malignancy with at least one measurable or evaluable lesion. Patients must demonstrate the presence of at least one measurable lesion per RECIST 1.1.

[0697] - Eastern Cooperative Oncology Group score of 0 or 1.

[0698] - Be able and willing to provide a sample of archival formalin-fixed, paraffin-embedded (FFPE) tumor tissue material to confirm the patient's HER2 status.

[0699] - Patients must be willing and able to comply with blood sampling and tumor biopsy requirements for PK, pharmacodynamic (PD), and biomarker analysis.

[0700] - Organ function sufficient to be measured routinely in the field.

[0701] - At the time of treatment initiation, any prior treatment-related toxicities have resolved to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or less (except for alopecia, stable sensory neuropathy, and hypothyroidism (in patients receiving thyroid replacement therapy), which must be CTCAE Grade 2 or less).

[0702] - Life expectancy at the start of treatment of at least 12 weeks in the opinion of the investigator.

[0703] - At least 18 years of age at the time of consent, or the legal age of consent in countries where the legal age of consent is 18 years or older.

[0704] - Signed and dated written informed consent in accordance with the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Good Clinical Practice (ICH-GCP) and local legislation prior to participation in the study.

[0705] - Male or female patient. Women of childbearing potential (WOCBP) and males of potential fathers must be ready and able to use highly effective contraceptive methods according to ICH M3(R2) that, when used consistently and correctly, result in a low failure rate of less than 1% per year.

[0706] - Patients with proven HER2 gene abnormalities: including HER2 overexpression by immunohistochemistry (IHC), increased gene copy number by in situ hybridization (ISH), nonsynonymous gene mutations, or gene fusions of the HER2 or NRG-1 genes.

[0707] - Patients who have failed conventional treatments or for whom no proven effective therapy exists or who are ineligible for established treatment options. Patients must have exhausted or be ineligible for available treatment options known to extend survival for their disease.

[0708] Generally, patients may discontinue study treatment or withdraw consent to participate in the study.

[0709] 8.1.6 Compounds Compound (1) is administered as a film-coated tablet. This formulation was developed in three dosage strengths: 5 mg (approximately 10 mm round), 20 mg (approximately 10 mm round), and 100 mg (oval, approximately 16 x 7 mm). In addition to the drug substance, the tablets contain standard pharmaceutical excipients in conventional amounts.

[0710] 8.1.7 Efficacy Assessment Tumor assessments should include computed tomography (CT) scans (or PET / CT) of the chest and abdomen / pelvis and MRI of the brain at screening. If clinically indicated, imaging of any other known or suspected disease sites (e.g., bone) should be performed using appropriate methods (CT scan, MRI, PET / CT, or bone scan). The same radiographic techniques should be used throughout the trial. Assessments should be performed by the investigator at screening (up to 28 days before treatment initiation), every two cycles (6 weeks ± 5 days), at the end-of-treatment (EOT) visit (if not performed within the previous 3 weeks), and at the investigator's discretion; copies may be collected by the sponsor or designee. Whenever possible, the assessment schedule should not be altered; however, if there is a treatment interruption or delay, tumor assessments may be rescheduled to coincide with clinical evaluations. Additional unscheduled tumor assessments may be performed at the investigator's discretion. If a patient discontinues study drug for reasons other than progression, tumor assessments according to RECIST v1.1 will continue until progression (or death, loss to follow-up, or end of study, whichever occurs first).

[0711] Patients' clinical status will be assessed locally by each investigator. Decline in clinical status must be attributable to progression of the underlying tumor and not to comorbidities or concomitant medications. In the event of tumor-related clinical deterioration, every effort should be made to confirm disease progression with imaging studies.

[0712] Tumor response will be assessed according to RECIST Version 1.1 (Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45:228-247). RECIST 1.1 will be used for a) systemic assessment (classic RECIST 1.1) and b) non-CNS tumor assessment. Assessment according to classic RECIST 1.1 by the investigator and / or local radiologist will be the basis for continuing or discontinuing the study in individual patients (in addition to safety). Systemic RECIST assessment will not be performed during the dose escalation portion.

[0713] Baseline imaging should include imaging of all known or suspected sites of disease using appropriate methods. The investigator (or named person) will record target and non-target lesions on the case report form (CRF or eCRF). Lesions in previously irradiated sites may not be considered measurable at baseline unless they developed after radiation. The same assessment method and the same imaging technique must be used at each subsequent time point to characterize each reported lesion throughout treatment and during follow-up.

[0714] 8.1.8 Safety Assessment Physical examinations, including measurements of height (at screening only) and weight, will be performed at screening, Day 1 of each treatment cycle, at the EOT visit, and at the 30-day safety follow-up visit, except that patients will undergo an abbreviated physical examination (focused on specific disease, at the investigator's discretion) on Cycle 1 Day 1 (if the previous physical examination was performed within 72 hours of starting treatment) and Cycle 1 Day 15.

[0715] A thorough physical examination will assess general health and aid in clinical evaluation of the tumor and may include, but is not limited to, cardiopulmonary function testing, regional lymph node examination, abdominal examination, and evaluation of mental and neurological status. Any additional symptoms not reported during previous examinations should be clarified. Whenever possible, this examination should be performed by the same investigator.

[0716] A limited physical examination should include cardiopulmonary function testing, clinical evaluation of the tumor, examination of regional lymph nodes, and abdominal examination.

[0717] 8.1.9 Evaluation of Adverse Events An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a medicinal product, and does not necessarily have a causal relationship to that treatment.

[0718] Thus, an AE can be any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product.

[0719] A serious adverse event (SAE) is defined as any adverse event that meets at least one of the following criteria:

[0720] - As a result, death occurs.

[0721] - Life-threatening. This refers to an event that was at risk of causing death to the patient at the time it occurred, but does not refer to an event that is hypothesized to have caused death if it had been more severe.

[0722] - You need to be hospitalized or have an existing hospitalization extended.

[0723] - result in a persistent or significant disability or incapacity.

[0724] - Congenital anomalies / birth defects.

[0725] - Any other reason is considered serious if, based on sound medical judgment, it is a significant medical event that may endanger the patient and require medical or surgical intervention to prevent one of the other outcomes listed in the definition above. Examples of such events are emergency department or intensive home treatment for allergic bronchospasm, blood abnormalities, or seizures that do not result in hospitalization or development of addiction or abuse.

[0726] Medical judgment should be used to determine whether there is a reasonable possibility of a causal relationship between the adverse event and the BI investigational compound, taking into account all relevant factors, including the pattern of response, temporal relationship, de-addition or re-addition, confounding factors such as concomitant medications, intercurrent illnesses, and relevant medical history.

[0727] Arguments that may suggest that there is a reasonable possibility of a causal relationship may be as follows:

[0728] - The event is consistent with the known pharmacological effects of the drug.

[0729] - The event is known to be caused by or attributed to that drug class.

[0730] - Time to event is reasonable relative to drug exposure.

[0731] - There is evidence that the event is reproducible when the drug is reintroduced.

[0732] - There are no medically plausible alternative etiologies (e.g., pre-existing or comorbid conditions or concomitant medications) that could explain this event.

[0733] - The event is typically drug-related and rare in the general population not exposed to the drug (e.g., Stevens-Johnson syndrome).

[0734] - Dose-responsive (i.e., increasing the dose increases the effect size, and decreasing the dose decreases the effect size).

[0735] Arguments that may suggest that there is no reasonable possibility of a causal relationship may be as follows:

[0736] - The reasonable time to event occurrence related to the time of drug exposure is unclear (e.g., cases of pretreatment, diagnosis of cancer or chronic disease within days / weeks of drug administration, allergic reaction weeks after discontinuation of the drug).

[0737] - The event continues despite discontinuation of the drug (e.g., after 5 half-lives), taking into account the pharmacological properties of the compound.

[0738] - It is worth noting that this criterion may not be applicable to events that have continued for a prolonged period of time despite the removal of the original trigger.

[0739] - Additional claims beyond those mentioned above exist, e.g., alternative explanations (e.g., situations in which another drug or underlying condition would provide a more likely explanation for the observed events than the drug in question).

[0740] - The event resolves despite continued or unchanged treatment with the investigational drug.

[0741] The investigator will maintain and keep a detailed record of all AEs in the patient file.

[0742] 8.1.10 Pharmacokinetic Evaluation The pharmacokinetic (PK) profile of Compound (1) will be investigated after initial and repeated dosing. Standard PK parameters will be calculated when data is available and scientifically justified.

[0743] Individual concentration data and their calculated PK parameters will be tabulated and displayed graphically. Statistical analysis will be performed. In the event of a protocol violation related to PK assessment (to be determined no later than the reporting plan meeting) or PK non-assessment (as revealed during data analysis, based on the criteria specified below), the patient's PK data will be flagged and excluded from statistical analysis. The reason for exclusion of patient data will be documented in the Clinical Trial Report (CTR).

[0744] If the data can be prepared, the pharmacokinetic parameters of compound (1), C max ( ,ss ), AUC 0-t2 ( ,ss ) are assessed in terms of dose proportionality to reach steady state. If deemed necessary, additional PK parameters can be used for these assessments.

[0745] Preliminary PK analyses can be performed as needed to determine DEC. A final preliminary analysis is performed at the end of the dose escalation portion before proceeding to the dose expansion portion. In contrast to the final PK analysis, preliminary analyses are performed based on planned sampling times rather than actual times. These analyses do not use supplemental patient information, e.g., on AEs or concomitant medications, to validate the output. Therefore, minor discrepancies may occur between preliminary and final results.

[0746] 8.1.11 Compliance Patients will be asked to bring all remaining study medication, including empty packaging materials, with them to their appointment.

[0747] Based on the number of tablets, treatment compliance will be calculated as shown in the following formula: Doses not administered according to the protocol (e.g., dose interruptions due to AEs) will not be included in the calculation. Compliance will be verified by a Clinical Research Associate (CRA) authorized by the sponsor or designee.

number

[0748] Treatment compliance of 80-120% is considered good.

[0749] 8.1.12 Statistical methods Dose escalation will be guided by BLRM with excess weighting constraints (EWOC) adapted to dichotomous toxicity outcomes (DLTs). Parameter estimates will be updated as data accumulate using BLRM. Once the dose escalation phase is complete, toxicity probabilities at each dose level will be calculated to determine an estimate of the MTD.

[0750] 8.1.13 Clinical Trial Protocol All patients must adhere to the visit schedule. If treatment administration is delayed for any reason, all subsequent visits / cycles will be recalculated based on the actual treatment dates. For logistical reasons, visits may occur over more than one day, as long as all assessments fall within the specified time frame.

[0751] Each visit and assessment should occur within the timeframe allowed. If agreed upon between the investigator and sponsor, more flexibility may be allowed (e.g., for public holidays and patient inconvenience).

[0752] If a patient misses an appointment, the appointment should be rescheduled as soon as possible and the missed appointment should be documented with the actual date and reason for the absence. Subsequent appointments should not be rescheduled, so if it is not possible to reschedule before the next scheduled appointment, the missed appointment should be omitted.

[0753] If a patient is admitted for administrative reasons to undergo treatment and PK sampling, this will not be considered an SAE unless the criteria for any other SAE are met.

[0754] In addition to scheduled assessments, unscheduled visits for safety reasons or unscheduled assessments may occur at any time according to clinical need.

[0755] In the event of force majeure or other disruptive circumstances (e.g., pandemic, war), sites should adhere to required protocol procedures to the extent possible. However, in situations where an individual patient is unable or unwilling to attend a clinic visit (due to force majeure or other disruptive circumstances, e.g., pandemic, war), the investigator must assess the risk-benefit for the individual patient and may decide to conduct the visit remotely if it is in the patient's best interest and agreed with the sponsor. Any deviations from the original visit schedule and procedures should be documented and considered in relation to the analysis of the study data.

[0756] After informed consent, patients undergo a screening assessment. This assessment must occur within the screening availability period, but does not have to occur on the same day. The screening assessment may be repeated within the screening availability period. If more than one screening assessment is available, the most recent assessment prior to treatment initiation should be used to assess eligibility.

[0757] If the patient meets the eligibility criteria during screening, the first treatment visit will be scheduled. Any baseline conditions present at the time of the screening visit must be reported on the eCRF.

[0758] Eligible subjects will receive Compound (1) daily until they meet mid-treatment criteria.

[0759] Patients may continue treatment indefinitely until they meet criteria for discontinuing treatment.

[0760] After a decision is made to permanently discontinue treatment during this study, no further administration of study medication should be administered and an EOT visit should occur within 7 days of the decision. If the decision to permanently discontinue study treatment is made during a scheduled visit, an EOT visit should occur in place of the scheduled visit.

[0761] In the dose escalation portion of this study, a follow-up visit (FU) will be conducted at least 30 days after permanent discontinuation of Compound 1 and will primarily be used to collect safety follow-up information. Individuals who complete the follow-up visit will be considered to have completed the study.

[0762] 8.2.Results The study design is shown in Figure 17. Overall data for this trial will be compiled and pooled across QD and BID schedules and doses selected in the dose expansion portion of this trial.

[0763] 8.2.1 Safety As of data lock (March 9, 2023), safety data are available for 43 patients (Table 28). Patients were treated with Compound (1) monotherapy on a twice-daily (BID, 17 patients) or once-daily (QD,...

Claims

1. The following: 【Transformation 8】 A compound (1) as defined in, or a pharmaceutically acceptable salt thereof, A solid dispersant comprising a pharmaceutically acceptable dispersion carrier, Compound (1) is amorphous, It is intended for use in methods for preventing and / or treating cancer. Compound (1) or a pharmaceutically acceptable salt thereof is administered at a daily dose of at least 30 mg. Solid dispersant.

2. The following: 【Chemistry 9】 A compound (1) as defined in, or a pharmaceutically acceptable salt thereof, A solid dispersant comprising a pharmaceutically acceptable dispersion carrier, Compound (1) is amorphous, It is intended for use in methods for preventing and / or treating cancer. Compound (1) or a pharmaceutically acceptable salt thereof is administered following the administration of a systemic anti-cancer agent. Solid dispersant.

3. The solid dispersant according to claim 1 or 2, wherein the pharmaceutically acceptable dispersion carrier is a polymer.

4. The solid dispersant according to claim 1 or 2, wherein the polymer is enteric-coated or non-enteric-coated.

5. The solid dispersant according to claim 1 or 2, wherein the pharmaceutically acceptable dispersion carrier is a polymer selected from the group consisting of hydroxypropyl methylcellulose and its esters, polyvinylpyrrolidone and its copolymers, and polymethacrylate and its copolymers.

6. The solid dispersant according to claim 5, wherein the hydroxypropyl methylcellulose and its ester are selected from the group consisting of hydroxypropyl methylcellulose acetate succinate and hot-melt extruded grade hydroxypropyl methylcellulose.

7. The solid dispersant according to claim 5, wherein the polyvinylpyrrolidone and its copolymer are polyvinylpyrrolidone-vinyl acetate copolymer.

8. The solid dispersant according to claim 5, wherein the polymethacrylate and its copolymer are methylacrylic acid-methyl methacrylate copolymer.

9. The solid dispersant according to claim 1 or 2, wherein the pharmaceutically acceptable dispersion carrier is a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone-vinyl acetate copolymer, methylacrylic acid-methyl methacrylate copolymer, and hot-melt extruded grade hydroxypropyl methylcellulose.

10. The solid dispersant according to claim 1 or 2, wherein the pharmaceutically acceptable dispersion carrier is hydroxypropyl methylcellulose acetate succinate.

11. The solid dispersant according to claim 1 or 2, wherein the pharmaceutically acceptable dispersion carrier is grade M hydroxypropyl methylcellulose acetate succinate.

12. Compound (1) is present in an amount ranging from 25 wt% to 75 wt% based on 100 wt% of the total weight of the solid dispersant, and / or The solid dispersant according to claim 1 or 2, wherein a pharmaceutically acceptable dispersion carrier is present in an amount ranging from 25 wt% to 75 wt% based on 100 wt% of the total weight of the solid dispersant.

13. The solid dispersant according to claim 1 or 2, wherein the weight ratio of compound (1) to pharmaceutically acceptable dispersion carrier in the solid dispersant is 1:1 to 1:

3.

14. The solid dispersant according to claim 1 or 2, wherein the weight ratio of compound (1) to pharmaceutically acceptable dispersion carrier in the solid dispersant is 1:

1.

15. The solid dispersant according to claim 1 or 2, characterized in that, when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C, it has a powder X-ray diffraction pattern that does not contain diffraction peaks below a 2θ angle of 40.0°.

16. A pharmaceutical composition comprising a solid dispersant according to claim 1 or 2 and one or more pharmaceutically acceptable excipients, It is intended for use in methods for preventing and / or treating cancer. Compound (1) or a pharmaceutically acceptable salt thereof is administered at a daily dose of at least 30 mg. Pharmaceutical composition.

17. One or more pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, flow promoters, lubricants and coatings, and / or The filler is selected from the group consisting of microcrystalline cellulose, mannitol and mixtures thereof, and / or The disintegrant is selected from the group consisting of croscarmellose sodium, sodium bicarbonate, crospovidone, sodium starch glycolate and mixtures thereof, and / or The flow accelerator is colloidal silicon dioxide, and / or The pharmaceutical composition according to claim 16, wherein the lubricant is selected from the group consisting of stearyl fumarate, magnesium stearate, and mixtures thereof.

18. The pharmaceutical composition according to claim 16, wherein one or more pharmaceutically acceptable excipients include mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

19. The pharmaceutical composition, based on 100 wt% of the total weight of the pharmaceutical composition, - A solid dispersant in an amount ranging from 25 wt% to 65 wt%, and / or - One or more fillers in an amount ranging from 25 wt% to 65 wt%, and / or - Disintegrant in the range of 4 wt% to 10 wt%, and / or - A flow accelerator in the range of 1 wt% to 2 wt%, and / or - A lubricant in the range of 1 wt% to 2 wt%, and / or - Selectively, the coating agent can be added in a range of 2 wt% to 5 wt%. A pharmaceutical composition according to claim 16, including the one described in claim 16.

20. The pharmaceutical composition according to claim 16, wherein the composition is in the form of a tablet, granules, or capsule.

21. (i) A tablet core comprising a solid dispersant, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate, (ii) Film coating and A pharmaceutical composition according to claim 16, comprising:

22. The pharmaceutical composition according to claim 16, characterized in that, when measured using Cu-Kα radiation having a wavelength of 1.54056 Å or 1.54184 Å at a temperature in the range of 20 to 30°C, it has a powder X-ray diffraction pattern that does not contain diffraction peaks at a 2θ angle of 6.5° or less.

23. The solid dispersant according to claim 1 or 2, wherein the cancer is selected from the group consisting of brain tumors, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, esophageal tumors, head and neck tumors, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumors, kidney cancer, liver cancer, lung cancer, and prostate cancer.

24. The cancer is HER2 overexpression, HER2 amplification and / or HER2 mutation, and / or The solid dispersant according to claim 1 or 2, wherein the cancer is progressive or metastatic cancer.

25. The solid dispersant according to claim 1 or 2, wherein the cancer is progressive, unresectable, or metastatic NSCLC having a HER2 mutation, and the HER2 mutation is located in the tyrosine kinase domain.

26. The solid dispersant according to claim 1 or 2, wherein compound (1) is administered in a daily dose of 30 mg to 600 mg.

27. The solid dispersant according to claim 1 or 2, wherein compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, or 360 mg.

28. The solid dispersant according to claim 1 or 2, wherein compound (1) is administered once or twice a day.

29. The solid dispersant according to claim 1 or 2, wherein compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

30. The solid dispersant according to claim 1 or 2, wherein compound (1) is administered once daily at a daily dose of 60 mg.

31. The solid dispersant according to claim 1 or 2, wherein compound (1) is administered once daily at a daily dose of 120 mg.

32. The solid dispersant according to claim 1 or 2, wherein compound (1) is administered once daily at a daily dose of 180 mg.

33. The solid dispersant according to claim 1 or 2, wherein compound (1) is administered once daily at a daily dose of 240 mg.

34. The solid dispersant according to claim 1 or 2, wherein compound (1) is administered once daily at a daily dose of 300 mg.

35. The solid dispersant according to claim 1 or 2, wherein compound (1) is administered once daily at a daily dose of 360 mg.

36. The solid dispersant according to claim 1 or 2, wherein compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

37. The solid dispersant according to claim 2, wherein the systemic anticancer therapy agent is selected from the group consisting of platinum-based chemotherapy, anti-HER2 antibody-drug conjugates, and combinations thereof.

38. The pharmaceutical composition according to claim 16, wherein the cancer is selected from the group consisting of brain tumor, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

39. The cancer is HER2 overexpression, HER2 amplification and / or HER2 mutation, and / or The pharmaceutical composition according to claim 16, wherein the cancer is progressive or metastatic cancer.

40. The pharmaceutical composition according to claim 16, wherein the cancer is progressive, unresectable, or metastatic NSCLC having a HER2 mutation, and the HER2 mutation is located in the tyrosine kinase domain.

41. The pharmaceutical composition according to claim 16, wherein compound (1) is administered in a daily dose of 30 mg to 600 mg.

42. The pharmaceutical composition according to claim 16, wherein compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, or 360 mg.

43. The pharmaceutical composition according to claim 16, wherein compound (1) is administered once or twice a day.

44. The pharmaceutical composition according to claim 16, wherein compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

45. The pharmaceutical composition according to claim 16, wherein compound (1) is administered once a day at a daily dose of 60 mg.

46. The pharmaceutical composition according to claim 16, wherein compound (1) is administered once a day at a daily dose of 120 mg.

47. The pharmaceutical composition according to claim 16, wherein compound (1) is administered once a day at a daily dose of 180 mg.

48. The pharmaceutical composition according to claim 16, wherein compound (1) is administered once daily at a daily dose of 240 mg.

49. The pharmaceutical composition according to claim 16, wherein compound (1) is administered once a day at a daily dose of 300 mg.

50. The pharmaceutical composition according to claim 16, wherein compound (1) is administered once a day at a daily dose of 360 mg.

51. The pharmaceutical composition according to claim 16, wherein compound (1) is administered twice a day in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

52. The following: 【Chemistry 10】 Compound (1) as defined in, A solid dispersant comprising hydroxypropyl methylcellulose acetate succinate in a 1:1 weight ratio, Compound (1) is amorphous, It is intended for use in methods for preventing and / or treating cancer. Compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, or 360 mg. Solid dispersant.

53. Based on 100 wt% of the total weight of the pharmaceutical composition, comprising 15 wt% compound (1), 15 wt% hypromellose acetate succinate, 20 wt% microcrystalline cellulose, 42 wt% mannitol, 5 wt% croscarmellose sodium, 1.5 wt% colloidal silicon dioxide, and 1.5 wt% sodium stearyl fumarate, which are essentially or consist of these. Compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg. The pharmaceutical composition according to claim 16.

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