Dosing schedule for solid dispersions of HER2 inhibitors

Abstract

The present invention relates to dosing schedules for solid dispersions of HER2 inhibitors and pharmaceutically acceptable dispersion carriers useful in the prevention and / or treatment of cancer, in particular to their doses and / or the administration of two or additional lines.

Description

Technical Field

[0001] The present invention relates to a dosing 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 that can be used to prevent and / or treat cancer. In particular, the dosing schedule can be defined by the dose of the HER2 inhibitor and / or the administration of a second or additional line of therapy. Background Art

[0002] 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}propane-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, with no inhibition of wild-type epidermal growth factor receptor (EGFR). Therefore, it can be used to treat and / or prevent diseases and / or conditions in which inhibition of wild-type and / or mutant HER2 has therapeutic benefits, in particular neoplastic diseases and / or hyperproliferative diseases such as cancer.

[0003] It was found that the solubility of compound (1) in aqueous media is limited and strongly pH-dependent, with solubility increasing under acidic conditions. Specifically, a solubility of approximately 10 5 fold decrease. Thus, the in vivo absorption of compound (1) is affected by gastric pH. In particular, low gastric pH is associated with increased absorption of compound (1), while increased gastric pH leads to lower serum levels of compound (1). This pH dependence is undesirable because it can reduce the bioavailability and / or bioaccessibility of compound (1). Due to the variability of gastric pH between patients, this reduction may occur to different degrees in different patients.

[0004] In addition, the gastric pH of cancer patients may be altered by the therapeutic agents in their treatment plan (such as protein pump inhibitors (PPIs), antacids or antihistamines, which are acid suppressants known to increase gastric pH). These therapeutic agents are often administered to cancer patients, for example, to mediate gastrointestinal side effects caused by the agents (particularly those that lower gastric pH), but also to control the effects on tumors in the gastric area. Therefore, co-administration of acid suppressants and compound (1) can reduce the absorption and systemic exposure of compound (1).

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

[0006] Furthermore, there is a need to find a method of administering compound (1) which is therapeutically effective both in itself and in the context of an already ongoing treatment, while also being safe and tolerable. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1 Shown are x-ray powder diffraction patterns (XRPDs) of spray-dried amorphous solid dispersions of Compound (1) obtained from Example 1 herein with 75 wt% HPMCAS-M (top curve) and 50 wt% HPMCAS-M (bottom curve) compared to that of crystalline Compound (1).

[0008] Figure 2 Shown are x-ray powder diffraction patterns (XRPDs) of spray-dried amorphous solid dispersions of compound (1) obtained from Example 1 herein with 75 wt% PVP-VA (top curve) and 50 wt% PVP-VA (bottom curve) compared to that of crystalline compound (1).

[0009] Figure 3 The X-ray powder diffraction pattern (XRPD) of the crystalline compound (1) is shown as follows: L100 (top curve) and 50wt% XRPD of a spray-dried amorphous solid dispersion of L100 (bottom curve).

[0010] Figure 4 Shown are x-ray powder diffraction patterns (XRPDs) of spray-dried amorphous solid dispersions of Compound (1) obtained from Example 1 herein with 75 wt% HPMC HME 15LV (top curve) and 50 wt% HPMC HME 15LV (bottom curve) compared to that of crystalline Compound (1).

[0011] Figure 5 Shown are x-ray powder diffraction patterns (XRPD) 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).

[0012] Figure 6Shown are x-ray powder diffraction patterns (XRPD) of a spray-dried amorphous solid dispersion 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).

[0013] Figure 7 Shown are x-ray powder diffraction patterns (XRPD) of amorphous solid dispersions 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 three weeks. From top to bottom curves: unstressed sample (top), sample stressed at 75°C / 79% relative humidity (middle), and sample stressed at 80°C / 76% relative humidity (bottom).

[0014] Figure 8 Shown is a comparison of the Log solubility values determined in aqueous media at different pH for an amorphous solid dispersion of Compound (1) and HPMCAS-M (50 wt%:50 wt%) (circles), crystalline Form III of Compound (1) (squares), and crystalline Form IV of Compound (1) (triangles).

[0015] Figure 9 The in vitro dissolution profiles of various amorphous solid dispersions (25 wt%:75 wt% compound (1):polymer) containing different polymers are compared with the dissolution profile of crystalline compound (1) in simulated intestinal fluid after transfer from simulated gastric fluid in the two-stage gastric transfer test of Example 5.2. From top curve to bottom curve (relative to the first measurement point): HPMC HME 15LV, PVP-VA, HPMCAS-M, L100 and crystalline compound (1).

[0016] Figure 10 The in vitro dissolution profiles of various amorphous solid dispersions (50 wt%:50 wt% compound (1):polymer) containing different polymers are compared with the dissolution profile of crystalline compound (1) in simulated intestinal fluid after transfer from simulated gastric fluid in the two-stage gastric transfer test of Example 5.2. From top curve to bottom curve (relative to the first measurement point): HPMCAS-M, HPMC HME 15LV, PVP-VA, L100 and crystalline compound (1).

[0017] Figure 11 Shown are the results of an in vitro dissolution comparison at pH 2.0 between tablets containing crystalline Compound (1) (squares) and a solid dispersion of Compound (1) (circles).

[0018] Figure 12 Shown are the results of an in vitro dissolution comparison at pH 6.8 between conventional tablets containing crystalline Compound (1) (round) and tablets containing a solid dispersion of Compound (1) (square Example 6.2-A, triangular Example 6.2-C).

[0019] Figure 13 A schematic representation of a dynamic in vitro gastrointestinal model used to simulate physiological processes occurring in the tiny-TIM model of the human stomach and small intestine is shown. A: Food inlet; B: Gastric body; C: Proximal antrum; D: Distal antrum; E: Pyloric valve; F: Peristaltic valve; G: Small intestinal compartment; H: Filtration system; I: Gastric secretions; J: Intestinal secretions; K: pH electrode; L: Liquid level sensor.

[0020] Figure 14 Results are shown of an in vitro assay of the bioaccessibility of a solid dispersion of compound (1) ("SDD") over time following administration of a proton pump inhibitor (PPI) under fasting conditions (typically low gastric pH) and simulated higher gastric pH conditions, compared to administration of a conventional tablet of crystalline compound (1) ("Conventional"), both at a 100 mg dose.

[0021] Figure 15 Shown is the x-ray powder diffraction pattern (XRPD) of the formulation disclosed under Example 6.1-C.

[0022] Figure 16 Shown is the x-ray powder diffraction pattern (XRPD) of the formulation disclosed under Example 6.2-C.

[0023] Figure 17 Shown is the design of the dose escalation portion of a clinical trial testing different 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, twice daily; QD = once daily, once daily; RP2D = recommended dose for dose expansion.

[0024] Figure 18 A swimmer plot showing response assessment and treatment duration by patient and dose in the BID schedule as of March 16, 2023, is shown. Bars represent duration of progression-free survival, not duration of treatment. BID = twice daily; QD = once daily; PR = partial response; SD = stable disease; PD = progressive disease.

[0025] Figure 19A swimmer's chart showing response assessment and treatment duration by patient and dose in the BID schedule as of March 16, 2023. The bars represent duration of progression-free survival, not duration of treatment. Figure 2 As defined in .

[0026] Figure 20 A swimmer's chart showing response assessment and treatment duration by patient and dose in the QD schedule as of March 16, 2023, is shown. The bars represent duration of progression-free survival, not duration of treatment. Figure 2 As defined in .

[0027] Figure 21 Shown is a waterfall plot showing the best change from baseline in target lesions (RECIST v1.1) expressed as a percentage for the BID versus QD schedule.

[0028] Figure 22 Shown is a waterfall plot of the BID dose levels showing the best change from baseline in target lesions (RECIST v1.1) expressed as a percentage.

[0029] Figure 23 Shown is a waterfall plot of the QD dose levels showing the best change from baseline in target lesions (RECIST v1.1) expressed as a percentage.

[0030] Figure 24 Shown are waterfall plots of the BID dose levels showing the best change from baseline in target lesions (RECIST v1.1), expressed as a percentage, in (a) patients with non-small cell lung cancer and (b) patients with other tumors.

[0031] Figure 25 Shown are waterfall plots of QD dose levels showing the best change from baseline in target lesions (RECIST v1.1), expressed as a percentage, in (a) patients with non-small cell lung cancer and (b) patients with other tumors. Summary of the Invention

[0032] According to a first aspect, there is provided a solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof as defined below:

[0033]

[0034] 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 at a daily dose of at least 30 mg. Also provided herein is a method for preventing and / or treating cancer, the method 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 at a daily dose of at least 30 mg.

[0035] According to another aspect, there is provided a solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof as defined below:

[0036]

[0037] 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 after administration of a systemic anticancer therapeutic agent. Also provided herein is a method for preventing and / or treating cancer, the method comprising administering a solid dispersion comprising compound (1) as defined herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier to a subject in need thereof, wherein compound (1) is administered after administration of a systemic anticancer therapeutic agent.

[0038] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer.

[0039] In embodiments, the polymer is enteric or non-enteric.

[0040] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer selected from the group consisting of hydroxypropyl methylcellulose and its esters, polyvinyl pyrrolidone and its copolymers, and polymethacrylates and its copolymers.

[0041] In an embodiment, the hydroxypropyl methylcellulose and its esters are selected from hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose, in particular hot melt extrusion grade hydroxypropyl methylcellulose.

[0042] In an embodiment, the polyvinyl pyrrolidone and copolymers thereof are polyvinyl pyrrolidone vinyl acetate copolymers.

[0043] In an embodiment, the polymethacrylate and copolymers thereof are methacrylate-methyl methacrylate copolymers.

[0044] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, polyvinyl pyrrolidone vinyl acetate copolymer, methacrylic acid methyl methacrylate copolymer, and hot melt extrusion grade hydroxypropyl methylcellulose.

[0045] In an embodiment, compound (1) is amorphous.

[0046] 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.

[0047] 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.

[0048] In an embodiment, the weight ratio of compound (1) : the pharmaceutically acceptable dispersion carrier in the solid dispersion is 1:1 to 1:3.

[0049] In an embodiment, the solid dispersion for use as described herein is characterized in that when heated at a temperature in the range of 20°C to 30°C and with a wavelength of or An X-ray powder diffraction pattern having no diffraction peak at a 2θ angle equal to or lower than 40.0° when measured using Cu-Kα radiation.

[0050] Also provided herein is a pharmaceutical composition comprising a solid dispersion as defined herein and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is for use in a method for preventing and / or treating cancer, wherein compound (1) is administered at a daily dose of at least 30 mg.

[0051] In an embodiment, the one or more pharmaceutically acceptable excipients are selected from fillers, disintegrants, glidants, lubricants, and coating agents.

[0052] In an embodiment, the filler is selected from the group consisting of microcrystalline cellulose, mannitol, and mixtures thereof.

[0053] In an embodiment, the disintegrant is selected from the group consisting of croscarmellose sodium, sodium bicarbonate, crospovidone, sodium starch glycolate, and mixtures thereof.

[0054] In an embodiment, the glidant is colloidal silicon dioxide.

[0055] In an embodiment, the lubricant is selected from the group consisting of stearyl fumarate, magnesium stearate, and mixtures thereof.

[0056] In an embodiment, the one or more pharmaceutically acceptable excipients include mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

[0057] In an embodiment, the pharmaceutical composition for use as described herein comprises, based on 100 wt% of the total weight of the pharmaceutical composition:

[0058] - in the range of 25 wt% to 65 wt% of a solid dispersion as defined herein; and / or

[0059] - in the range of 25 wt% to 65 wt% of one or more fillers; and / or

[0060] - in the range of 4 wt% to 10 wt% of a disintegrant; and / or

[0061] - in the range of 1 wt% to 2 wt% of a glidant; and / or

[0062] - in the range of 1 wt% to 2 wt% of a lubricant; and / or

[0063] - Optionally in the range of 2 wt% to 5 wt% of a coating agent.

[0064] In an embodiment, the pharmaceutical composition for the use as described herein is in the form of a tablet, granules or capsule.

[0065] In an embodiment, the pharmaceutical composition for use as described herein comprises:

[0066] (i) a tablet core comprising a solid dispersion as defined herein, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; and

[0067] (ii) Film coating.

[0068] In an embodiment, the pharmaceutical composition for use as described herein is characterized in that when heated at a temperature in the range of 20°C to 30°C and with a wavelength of or An X-ray powder diffraction pattern having no diffraction peak at a 2θ angle equal to or lower than 6.5° when measured using Cu-Kα radiation.

[0069] 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, 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.

[0070] In embodiments, the cancer is a HER2-overexpressing, HER2-amplified, and / or HER2-mutated cancer.

[0071] In embodiments, the cancer is an advanced cancer or a metastatic cancer.

[0072] In an embodiment, the solid dispersion or the pharmaceutical composition is administered to a fasting subject.

[0073] In an embodiment, the solid dispersion or the pharmaceutical composition is administered in combination with an agent that increases gastric pH.

[0074] In an embodiment, the agent that increases gastric pH is selected from the group consisting of a proton pump inhibitor, an antacid, and an antihistamine.

[0075] In an embodiment, compound (1) is administered at a daily dose of 30 mg to 600 mg.

[0076] In an embodiment, 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.

[0077] In an embodiment, compound (1) is administered once or twice daily.

[0078] In an embodiment, 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.

[0079] 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.

[0080] In an embodiment, the systemic anti-cancer therapeutic is selected from the group consisting of platinum-based chemotherapy, anti-HER2 antibody-drug conjugates, and combinations thereof.

[0081] Additional embodiments are represented by the following:

[0082] 1) Compound (1) as defined below

[0083]

[0084] For use in the treatment of cancer, wherein compound (1) is administered in a daily dose of at least 30 mg.

[0085] 2) A method for preventing and / or treating cancer, which comprises administering a compound (1) as defined herein to a subject in need thereof at a daily dose of at least 30 mg.

[0086] 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.

[0087] 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 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.

[0088] 5) The compound for use according to embodiment 1) or 3) to 4) or the method according to embodiment 2) or 3) to 4), wherein compound (1) is administered once or twice daily.

[0089] 6) The compound for use according to embodiment 1) or 3) to 5) or the method according to embodiment 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. 7) The compound for use according to embodiment 1) or 3) to 6) or the method according to embodiment 2) or 3) to 6) wherein compound (1) is administered orally. 8) The compound for use according to embodiment 1) or 3) to 7) or the method according to embodiment 2) or 3) to 7), wherein compound (1) is administered as a tablet.

[0090] 9) Compound (1) as defined below

[0091]

[0092] For use in treating cancer, wherein compound (1) is administered after administration of a systemic anticancer therapeutic agent. 10) A method for preventing and / or treating cancer, comprising administering compound (1) to a subject in need thereof after administration of a systemic anticancer therapeutic agent.

[0093] 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 of the embodiments herein, in particular with respect to embodiments 1) to 8).

[0094] 12) The compound for use according to embodiment 9) or 11) or the method according to embodiment 10), wherein the systemic anti-cancer therapeutic agent is selected from platinum-based chemotherapy, anti-HER2 antibody-drug conjugates and combinations thereof.

[0095] 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 brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.

[0096] 14) The compound for use according to embodiment 9) or 11) to 13) or the method according to any one of embodiments 10) to 13), wherein the cancer is HER2 overexpressing, HER2 amplified and / or HER2 mutated.

[0097] 15) The compound for use according to embodiment 9) or 11) to 14) or the method according to any one of embodiments 10) to 14), wherein the cancer is advanced or metastatic.

[0098] 16) A pharmaceutical composition comprising compound (1) as defined below

[0099]

[0100] and at least one pharmaceutically acceptable excipient, the pharmaceutical composition is for use in treating cancer, wherein compound (1) is administered in a daily dose of at least 30 mg.

[0101] 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, wherein compound (1) is administered at a daily dose of at least 30 mg.

[0102] 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).

[0103] All embodiments described herein with respect to compound (1) for use in treating cancer or methods of treating a patient suffering from cancer with compound (1) apply to pharmaceutical compositions for treating cancer or methods of treating a patient suffering from cancer with pharmaceutical compositions. DETAILED DESCRIPTION

[0104] The object of the present invention is to reduce the pH dependence of compound (1) to improve its bioavailability and / or bioaccessibility.

[0105] It has been unexpectedly discovered that a formulation of compound (1) as a solid dispersion has the potential to achieve consistent bioavailability and / or bioaccessibility and overcome inter-patient variability in gastric pH compared to administration of a formulation 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.

[0106] Specifically, administration of a solid dispersion of compound (1) provides high uptake not only when administered to subjects with a normally low gastric pH, but also when administered in combination with an agent that increases gastric pH, such as a proton pump inhibitor, an antacid, or an antihistamine. The unexpected results shown in the Examples described herein, particularly the superior in vitro and in vivo performance of the solid dispersions of the present invention as compared to formulations comprising crystalline compound (1) as demonstrated in Examples 5.1, 5.2, and 7.1 to 7.4 herein, indicate that formulations of compound (1) as a solid dispersion provide consistently high uptake that is unaffected by pH changes (e.g., caused by co-medications that increase gastric pH levels), and therefore, may include patient populations receiving co-medications (e.g., receiving proton pump inhibitors, antacids, or antihistamines) within the therapeutic range of compound (1).

[0107] It has also been unexpectedly discovered that compound (1) can remain in an amorphous state, such as in a solid dispersion, even when subjected to prolonged temperature and moisture stress as demonstrated in Example 4 herein.

[0108] Another object of the present invention is to provide a safe and effective dosage regimen of compound (1) for the treatment of cancer. Unexpectedly, it was found that the dosage regimen according to the present invention achieved clinical efficacy, as demonstrated by partial responses, with an overall response rate (ORR) of 45.8% and a good disease control rate (DCR) of 95.8% (excluding patients with a best overall response of "not evaluable" at data cutoff).

[0109] Meanwhile, the side effect brought by the dosage regimen according to the present invention is unexpectedly few and gentle, as only observed 3 kinds of dose-limiting toxicities (DLT) outside the maximum tolerated dose (MTD) observation period and not yet reached the fact of MTD. This shows good safety and tolerability according to the medical use and therapies of the present invention, and low discontinuation rate. In addition, the dosage regimen according to the present invention seems to be also applicable to various patients who have received other cancer-related treatments. As used herein, the terms "dosage regimen" and "dosage arrangement scheme" are intended to be synonyms as "administration regimen" and "administration arrangement scheme", are therefore not necessarily limited to any specific dose, and this is the same as the situation of some aspects and embodiments about second-line or other lines. Therefore, the terms "dosage regimen" and "dosage arrangement scheme" also include the administration regimen or the arrangement scheme defined by the administration line (but not necessarily defined by dosage).

[0110] The positive safety profile observed with the dosing schedule of the present invention allows for the simultaneous administration of relatively high amounts of compound (1). This in turn may have several advantageous effects, such as improved patient compliance.

[0111] The dose-efficacy and dose-safety relationships were unexpectedly found to be flat, which may be indicative of a wide therapeutic window of the present invention.

[0112] Compound (1)

[0113] As used herein, the term "Compound (1)" refers to a compound as defined below or a pharmaceutically acceptable salt thereof:

[0114]

[0115] 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 discrepancy between the IUPAC name and the depicted chemical formula, the chemical formula shall prevail. Compound (1) is also known as Zongatinib. Compound (1) is disclosed in WO 2021 / 213800 as an exemplary compound I-01. WO 2021 / 213800 describes [1,3]diazino[5,4-d]pyrimidines, such as compound (1), as HER2 inhibitors and provides a synthetic procedure for compound (1). The properties of compound (1) and evidence of inhibition of HER2 wild-type and YVMA kinase activity (without inhibition of EGFR) are also disclosed in WO 2021 / 213800, which is incorporated herein by reference.

[0116] The term "compound (1)" as used herein also encompasses any tautomers and pharmaceutically acceptable salts and all solid forms of the compound, as well as solvates (including hydrates) and solvates of the pharmaceutically acceptable salts of the compound.

[0117] In an embodiment, compound (1) is a free base. Thus, in any aspect or embodiment, the expression "compound (1) or a pharmaceutically acceptable salt thereof" may be replaced by "compound (1)" without mentioning a pharmaceutically acceptable salt thereof. In an embodiment, a pharmaceutically acceptable salt of compound (1) is used. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human tissues without excessive toxicity, irritation, allergic reaction, or other problems or complications within the scope of sound medical judgment and are commensurate with a reasonable benefit / risk ratio.

[0118] As used herein, a "pharmaceutically acceptable salt" of compound (1) refers to a compound (1) in which the compound is modified by making an acid salt or a base salt thereof. The term pharmaceutically acceptable salt as used herein generally includes both acid addition salts and base addition salts. Pharmaceutically acceptable acid addition salts refer to those 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 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 and fumarate.

[0119] Pharmaceutically acceptable salts can be synthesized from compound (1) by conventional chemical methods. Generally, these salts can be prepared by reacting the free base form of compound (1) with a sufficient amount of an appropriate acid or base in water or in an organic diluent or solvent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile or a mixture thereof.

[0120] 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 in which the solvent molecule is water.

[0121] Solid dispersion

[0122] In an embodiment, a solid dispersion as described herein consists essentially of compound (1) as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable dispersion carrier. As used herein, the expressions "consists essentially of" and "consisting essentially of" have the meanings ascribed to them in the art. In particular, they indicate that additional components may be present, especially those that do not substantially affect the characteristics of the corresponding dispersion, composition or formulation. Such additional components may be, for example, residual solvents.

[0123] In an embodiment, the solid dispersion as described herein consists of compound (1) as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable dispersion carrier.

[0124] As used herein, the term "solid dispersion" refers to a system in a solid state comprising at least two components, wherein one component (such as compound (1) or generally an active pharmaceutical ingredient (API), preferably in an amorphous state) is dispersed in another component (such as a pharmaceutically acceptable solid dispersion carrier, in particular a dispersion polymer).

[0125] As used herein, the term "dispersion carrier" refers to a carrier component that allows the API, such as Compound (1), to be sufficiently dispersed so that a solid dispersion can be formed. In an embodiment, Compound (1) is dispersed at the molecular level in a pharmaceutically acceptable dispersion carrier.

[0126] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer. Thus, the present invention provides a solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof (particularly for use as defined herein) and a polymer. A polymer dispersion carrier is also denoted as a "dispersion polymer". Thus, the present invention provides a solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof as defined herein and a polymer, wherein in any aspect or embodiment, the solid dispersion is for use as defined herein. Polymers are widely used in solid dispersion formulations. Different polymer carriers give solid dispersions different properties in terms of physical stability, phase behavior, and drug release rate and extent. Due to the complex nature, it is necessary to test the solid dispersion formulation carrier that is most suitable for a given API. The pharmaceutically acceptable dispersion polymer is preferably a neutral or acidic polymer. In other embodiments, the pharmaceutically acceptable dispersion carrier is an enteric or non-enteric polymer, preferably an enteric polymer. In other embodiments, the polymer is enteric or non-enteric, preferably enteric. 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 to less than pH 3), but becomes soluble at higher pH (e.g., above pH 5). In certain embodiments, the pH-dependent polymer may become soluble at a pH range of about pH 5 or above (e.g., about pH 6) to about pH 9, about pH 6 to about pH 8, about pH 5 to about pH 7, or about pH 5 to about pH 6 (which is generally less acidic than the gastric environment and roughly corresponds to the pH value 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 (HPMCAS), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer ( L100), shellac, cellulose acetate trimellitate, sodium alginate and zein. The term "non-enteric polymer" refers to a neutral polymer that does not show pH-dependent solubility characteristics. 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), copolyvidone (such as polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), poly(ethylene glycol) PEG), starch derivatives (like cyclodextrins), (It is an amphiphilic copolymer composed of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate).

[0127] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer, or more simply, the polymer is selected from hydroxypropyl methylcellulose and its esters, polyvinyl pyrrolidone and its copolymers, and polymethacrylate and its copolymers. The pharmaceutically acceptable dispersion carrier may contain a mixture of two or more polymers.

[0128] In an embodiment, 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, hydroxypropyl methylcellulose and its esters are selected from the group consisting of hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose, in particular hot melt extrusion grade hydroxypropyl methylcellulose.

[0129] In an embodiment, polyvinyl pyrrolidone and its copolymers are selected from polyvinyl pyrrolidone vinyl acetate copolymer (PVP-VA), polyvinyl alcohol, polyvinyl alcohol polyvinyl acetate copolymer and polyvinyl pyrrolidone (PVP). Polyvinyl pyrrolidone (PVP) is also commonly expressed as polyvidone (polyvidone or povidone). In an embodiment, polyvinyl pyrrolidone and its copolymers are polyvinyl pyrrolidone vinyl acetate copolymer (PVP-VA).

[0130] In an embodiment, polymethacrylate and its copolymers are selected from methacrylic acid-ethyl acrylate copolymers, methacrylic acid-methyl methacrylate copolymers, methyl methacrylate and methacrylic acid copolymers. Polymethacrylate and its copolymers are available, for example, under the trade name Methacrylic acid-methyl methacrylate copolymers are available, for example, under the trade name In certain embodiments, the polymethacrylate and its copolymers are methyl methacrylate copolymers.

[0131] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer, or more simply, the polymer is selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone vinyl acetate copolymer (PVP-VA), methacrylic acid methyl methacrylate copolymer (such as L100) and hot melt extrusion grade hydroxypropyl methylcellulose (HPMC HME).

[0132] In certain embodiments, the pharmaceutically acceptable dispersion carrier is hydroxypropylmethylcellulose acetate succinate (HPMCAS). HPMCAS is also known as hypromellose acetate succinate. Hydroxypropylmethylcellulose acetate succinate (HPMCAS) can be obtained by introducing acetyl and succinyl groups into the hydroxyl groups of the backbone of hydroxypropylmethylcellulose (HPMC) (also known as hypromellose). This procedure can be performed by known methods, for example, by treating HPMC with acetic anhydride and / or succinic anhydride. Acetic anhydride and succinic anhydride can react with hydroxypropylmethylcellulose (HPMC) under specific controlled conditions to produce HPMCAS with varying degrees of acetyl and succinyl substitution.

[0133] Based on the acetyl and succinyl content (wt%) in the HPMCAS molecule, HPMCAS is available in several grades (L, M, and H) that differ in the degree of acetyl and succinyl substitution. Any grade of HPMCAS can be used in the solid dispersions of the present invention. Preferably, HPMCAS of grade L, M, or H is used. In certain embodiments, the pharmaceutically acceptable dispersion carrier is HPMCAS grade L. In certain embodiments, the pharmaceutically acceptable dispersion carrier is HPMCAS grade M. HPMCAS grade M can have an acetyl content of 7 wt% to 11 wt%; a succinyl content of 10 wt% to 14 wt%; a methoxy content of 21 wt% to 25 wt%; and a hydroxypropoxy content of 5 wt% to 9 wt%. Preferably, HPMCAS grade M (HPMCAS-M) is soluble at pH ≥ 6. In certain embodiments, the pharmaceutically acceptable dispersion carrier is HPMCAS grade H. Preferably, granular HPMCAS (HPMCAS-G) is used. HPMCAS-G can be used with any class of HPMCAS, but in particular with the G class, which uses HPMCAS-MG.

[0134] In certain embodiments, the pharmaceutically acceptable dispersion carrier is polyvinylpyrrolidone vinyl acetate copolymer (PVP-VA). Polyvinylpyrrolidone vinyl acetate copolymer is a linear random copolymer that can be obtained by free radical polymerization of monomers with a ratio of vinyl acetate to vinyl pyrrolidone varying from 70 / 30 to 30 / 70.

[0135] In certain embodiments, the pharmaceutically acceptable dispersion carrier is a methyl methacrylate copolymer, such as L100. As used herein, "methacrylic acid methyl methacrylate copolymer" and "methacrylic acid methyl methacrylate copolymer" are used interchangeably.

[0136] In certain embodiments, 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 that can be used to prepare solid dispersions via hot melt extrusion. HPMC HME is a water-soluble amorphous polymer typically provided as a white to off-white powder in three grades with different molecular weights: HPMC HME 15LV, HPMC HME 100LV, and HPMC HME 4M. Preferably, a molecular weight (M) of 15LV is used. W ) HPMC HME 15LV with a molecular weight (M) lower than 100 kDa. W ) HPMC HME 100LV below 200 kDa.

[0137] By dispersing compound (1) (preferably at the molecular level) in a pharmaceutically acceptable dispersion carrier, such as a polymer, the amorphous state can be maintained even when exposed to elevated temperature and / or humidity conditions, and the solid dispersion can reliably provide compound (1) in an amorphous form. In an embodiment, compound (1) is amorphous. The preferred feature that compound (1) is amorphous can be applied to any embodiment disclosed herein to provide additional embodiments according to the present invention, in particular, it can be applied to any embodiment of the solid dispersion described herein (including embodiments regarding the identity of the pharmaceutically acceptable dispersion carrier, the amounts of the components of the solid dispersion, specific dosing regimens, etc.), pharmaceutical compositions, kits, uses and methods. As used herein, the term "amorphous" refers to a condensed phase in which molecules are randomly oriented and characterized by the lack of any microscopic order, with no diffraction peaks in its XRPD; an amorphous solid system can be composed of a single chemical entity, or can be a multicomponent system (without stoichiometric composition) containing, for example, an API, a polymer and other excipients. Amorphous solids generally have a short-range molecular arrangement similar to a crystal, but do not have the long-range order of molecular packing seen in crystalline solids. The solid state form of a solid can be determined, for example, by x-ray powder diffraction ("XRPD") or modulated differential scanning calorimetry ("mDSC").

[0138] In an embodiment, the solid dispersion comprises, consists essentially of, or consists of: an amorphous compound (1) and a pharmaceutically acceptable dispersion carrier, wherein the compound (1) is substantially in an 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 a total weight of 100 wt% 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 a total weight of 100 wt% 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 a total weight of 100 wt% of compound (1). In certain embodiments, the substantially amorphous solid state form refers to a solid dispersion comprising at least 95 wt% amorphous compound (1) based on a total weight of 100 wt% of compound (1). In certain embodiments, a substantially amorphous solid state form refers to a solid dispersion comprising at least 96 wt%, 97 wt%, 98 wt% or 99 wt% of amorphous compound (1), based on a total weight of 100 wt% of compound (1). Thus, the solid dispersion can provide compound (1) in an amorphous or substantially amorphous state. Thus, such a solid dispersion can be referred to as an amorphous solid dispersion. Thus, in embodiments, the solid dispersion is an amorphous solid dispersion.

[0139] In one embodiment, the solid dispersion comprises a predetermined amount of compound (1) or a pharmaceutically acceptable salt thereof. In this context, the predetermined amount refers to the initial amount of compound (1) or a pharmaceutically acceptable salt thereof used to prepare the solid dispersion.

[0140] In another embodiment, the solid dispersion comprises a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof.

[0141] 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.

[0142] 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.

[0143] The solid dispersion may comprise approximately equal weight amounts of compound (1) and a pharmaceutically acceptable dispersion carrier. In an embodiment, the solid dispersion comprises, consists of, or consists essentially of about 50 wt% of compound (1) and about 50 wt% of a pharmaceutically acceptable dispersion carrier, based on a total weight of 100 wt%.

[0144] In an embodiment, the solid dispersion comprises, consists of, or consists essentially of about 25 wt% or 50 wt% of compound (1) and about 75 wt% or 50 wt% of a pharmaceutically acceptable dispersion carrier, based on 100 wt% of the total weight. In an embodiment, the weight ratio of compound (1) : pharmaceutically acceptable dispersion carrier in the solid dispersion is about 1:4 to 4:1, preferably 1:3 to 3:1, such as 1:1 to 1:3. In an embodiment, the weight ratio of compound (1) : pharmaceutically acceptable dispersion carrier in the solid dispersion is 1:1 to 1:3, in an embodiment, the weight ratio of compound (1) : pharmaceutically acceptable dispersion carrier in the solid dispersion is about 1:1.

[0145] As used herein, the terms "about" and "approximately" mean within a statistically significant range of values. Such ranges can be within an order of magnitude of the indicated value or range, typically within 10%, more typically within 5%, even more typically within 1%, and most typically within 0.1%. Sometimes, such ranges can be within the typical experimental error of the standard method used to measure and / or determine a given value or range.

[0146] In embodiments, the solid dispersion comprises a weight ratio of compound (1): pharmaceutically acceptable dispersion carrier of about 1:4 to 4:1, preferably 1:3 to 3:1, such as 1:1 to 1:3. In embodiments, the solid dispersion comprises a weight ratio of compound (1): pharmaceutically acceptable dispersion carrier of 1:1 to 1:3, in embodiments, the solid dispersion comprises a weight ratio of compound (1): pharmaceutically acceptable dispersion carrier of about 1:1.

[0147] In an embodiment, the solid dispersion is characterized by being soluble in water when heated at a temperature in the range of 20°C to 30°C and with a wavelength of or When measured with Cu-Kα radiation, the x-ray powder diffraction pattern (XRPD) does not include a diffraction peak at a 2θ angle equal to or lower than 40.0°. As used in the present invention, "Cu-Kα radiation" includes Cu-Kα1 radiation and Cu-Kα1,2 radiation, wherein the wavelength of Cu-Kα1 radiation is And the average wavelength of Cu-Kα1,2 radiation is .

[0148] In another embodiment, the solid dispersion is characterized by being ionized at a temperature in the range of 20°C to 30°C and at a wavelength of or The present invention has an X-ray powder diffraction pattern (XRPD) that does not include a diffraction peak in the range of 2.0° to 40.0° when measured with Cu-Kα radiation.

[0149] In yet another embodiment, the solid dispersion is characterized by a dispersion which is soluble in water when heated at a temperature in the range of 20°C to 30°C and with a wavelength of or When measuring Cu-Kα radiation, the following Figure 5 or Figure 6 The same X-ray powder diffraction pattern (XRPD) is shown.

[0150] In yet another embodiment, the solid dispersion is characterized by a differential scanning calorimetry curve comprising a single glass transition temperature (Tg) signal when measured using modulated differential scanning calorimetry (mDSC) with a modulation amplitude 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°C to 190°C, preferably 110°C to 120°C.

[0151] In yet other embodiments, the solid dispersion comprises particles characterized by a particle size distribution as determined by laser diffraction:

[0152] (i) a D90 value of no greater than 100 μm, preferably no greater than 90 μm, most preferably no greater than 85 μm; and / or

[0153] (ii) a D50 value of no greater than 50 μm, preferably no greater than 45 μm, most preferably no greater than 40 μm; and / or

[0154] (iii) a D10 value of not more than 20 μm, preferably not more than 15 μm, most preferably not more than 13 μm.

[0155] In still other embodiments, the solid dispersion comprises particles characterized by a particle size distribution as determined by laser diffraction:

[0156] (i) a D90 value in the range of 50 to 100 μm, preferably 55 to 90 μm, most preferably 60 to 85 μm; and / or

[0157] (ii) a D50 value in the range of 25 to 50 μm, preferably 30 to 45 μm, most preferably 30 to 40 μm; and / or

[0158] (iii) a D10 value ranging from 1 to 20 μm, preferably from 5 to 15 μm, most preferably from 10 to 13 μm.

[0159] As used herein, the term "particle size distribution" refers to a list of values or a mathematical function that defines the relative amount of particles present in a sample (usually by mass or volume) according to size. The particle size distribution can be characterized by one or more values, such as D90, D50, or D10. The particle size distribution can be determined by methods well known to those skilled in the art, for example, by laser diffraction.

[0160] As used herein, "D90" describes the value of the particle size at which 90% of the total volume of the particles is made up of particles no larger than the indicated size.

[0161] As used herein, "D50" describes the value of the particle size at which 50% of the total volume of the particles is made up of particles no larger than the indicated size.

[0162] As used herein, "D10" describes the value of the particle size at which 10% of the total volume of the particles is made up of particles no larger than the indicated size.

[0163] A further aspect relates to the use of a solid dispersion as described herein for the preparation of a pharmaceutical composition, wherein the pharmaceutical composition is preferably as defined below.

[0164] Pharmaceutical composition

[0165] Another aspect provides a pharmaceutical composition comprising a solid dispersion as described herein and one or more pharmaceutically acceptable excipients. Another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a solid dispersion as described herein and one or more pharmaceutically acceptable excipients.

[0166] Another embodiment of the present invention is a pharmaceutical composition comprising a predetermined amount of a solid dispersion as 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 to prepare the pharmaceutical composition.

[0167] The term "pharmaceutically acceptable excipient" refers to a non-toxic component that does not destroy the pharmacological activity of the compound formulated with the pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients that can be used in the composition of the present invention include fillers, disintegrants, glidants, lubricants, and coating agents. The composition may further comprise a pharmaceutically acceptable excipient selected from the group consisting of buffers, binders, dispersants, surfactants, wetting agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives useful in the manufacture of pharmaceutical products.

[0168] The pharmaceutical composition may contain conventional non-toxic pharmaceutically acceptable excipients. In an embodiment, the one or more pharmaceutically acceptable excipients are selected from fillers, disintegrants, glidants, lubricants, and coating agents. In an embodiment, the pharmaceutical composition comprises a filler, a disintegrant, a glidant, and a lubricant. In an embodiment, the pharmaceutical composition comprises a filler, a disintegrant, a glidant, a lubricant, and a coating agent. It should be understood that the pharmaceutical composition may contain one or more excipients of 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.

[0169] In embodiments, the one or more fillers are selected from microcrystalline cellulose, mannitol, and mixtures thereof. In embodiments, the one or more disintegrants are selected from cross-linked sodium carboxymethylcellulose, also known as croscarmellose sodium, sodium bicarbonate, crospovidone, sodium starch glycolate, and mixtures thereof. In certain embodiments, the disintegrant is croscarmellose sodium. In embodiments, the glidant is colloidal silicon dioxide. In embodiments, the one or more lubricants are selected from stearyl fumarate, magnesium stearate, and mixtures thereof. In certain embodiments, the lubricant is sodium stearyl fumarate.

[0170] In an embodiment, the one or more pharmaceutically acceptable excipients include mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

[0171] In an embodiment, the pharmaceutical composition comprises, consists of, or consists essentially of a solid dispersion comprising compound (1) as defined herein, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

[0172] In certain embodiments, the pharmaceutical composition comprises a coating, such as when formulated as a film-coated tablet. In embodiments, the coating comprises a film former such as partially hydrolyzable polyvinyl alcohol, an anti-adherent such as talc, a pigment such as titanium dioxide, monocaprylocaprin and dicaprylocaprin (GMDCC), and an iron oxide such as yellow iron oxide, and a lubricant such as sodium lauryl sulfate. Coatings are commercially available, such as those sold under the trade name For example AMB II yellow is commercially available.In a preferred embodiment, the coating does not contain titanium dioxide, eg is free of titanium dioxide.

[0173] In an embodiment, the pharmaceutical composition comprises:

[0174] (i) a tablet core comprising a solid dispersion as described herein, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; and

[0175] (ii) Film coating.

[0176] In an embodiment, the pharmaceutical composition consists of or consists essentially of:

[0177] (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; and

[0178] (ii) Film coating.

[0179] In certain embodiments, the film coating is a non-functional film coating.In one embodiment, the film coating does not contain titanium dioxide.

[0180] In an embodiment, the pharmaceutical composition comprises a solid dispersion as described herein in the range of 25 wt% to 65 wt%, preferably 35 wt% to 60 wt% or 25 wt% to 35 wt% or 27 wt% to 31 wt%, still preferably about 30 wt%, based on a total weight of 100 wt% of the pharmaceutical composition.

[0181] In an embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition:

[0182] - in the range of 25 wt% to 65 wt% of a solid dispersion as described herein; and / or

[0183] - in the range of 25 wt% to 65 wt% of one or more fillers; and / or

[0184] - in the range of 4 wt% to 10 wt% of a disintegrant; and / or

[0185] - in the range of 1 wt% to 2 wt% of a glidant; and / or

[0186] - in the range of 1 wt% to 2 wt% of a lubricant; and / or

[0187] - Optionally in the range of 2 wt% to 5 wt% of a coating agent.

[0188] In the present invention and any following embodiments, reference to wt% of a component of a pharmaceutical composition is to be understood as meaning that the sum of all component ranges or amounts does not exceed 100 wt%.

[0189] In another embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition:

[0190] - in the range of 30 wt% to 60 wt%, preferably 35 wt% to 60 wt% of a solid dispersion as described herein; and / or

[0191] - one or more fillers in the range of 30 wt% to 60 wt%, preferably 35 wt% to 60 wt%; and / or

[0192] - in the range of 4 wt% to 7 wt% of a disintegrant; and / or

[0193] - in the range of 1 wt% to 1.5 wt% of a glidant; and / or

[0194] - in the range of 1 wt% to 1.5 wt% of a lubricant; and / or

[0195] - Optionally in the range of 3 wt% to 5 wt% of a coating agent.

[0196] In still other embodiments, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition:

[0197] - in the range of 25 wt% to 35 wt% of a solid dispersion as described herein; and / or

[0198] - in the range of 55 wt% to 65 wt% of one or more fillers; and / or

[0199] - in the range of 4 wt% to 7 wt% of a disintegrant; and / or

[0200] - in the range of 1 wt% to 2 wt% of a glidant; and / or

[0201] - in the range of 1 wt% to 2 wt% of a lubricant; and / or

[0202] - Optionally in the range of 3 wt% to 5 wt% of a coating agent.

[0203] In an embodiment, the pharmaceutical composition comprises, based on 100 wt% of the total weight of the pharmaceutical composition:

[0204] - in the range of 28 wt% to 30 wt% of a solid dispersion as described herein; and / or

[0205] - in the range of 57 wt% to 62 wt% of one or more fillers; and / or

[0206] - in the range of 4 wt% to 5 wt% of a disintegrant; and / or

[0207] - in the range of 1.4 wt% to 1.5 wt% of a glidant; and / or

[0208] - in the range of 1.4 wt% to 1.5 wt% of a lubricant; and / or

[0209] - Optionally about 4 wt% of a coating agent.

[0210] In this embodiment, preferably, the lower limits of the ranges of solid dispersion, filler, disintegrant, glidant and lubricant refer to the pharmaceutical composition with a coating agent, while the upper limits of the same ranges refer to the pharmaceutical composition without a coating agent.

[0211] In an embodiment, the pharmaceutical composition consists essentially of or consists of, based on 100 wt% of the total weight of the pharmaceutical composition

[0212] - in the range of 25 wt% to 65 wt% of a solid dispersion as described herein;

[0213] - one or more fillers in the range of 25 wt% to 65 wt%;

[0214] - a disintegrant in the range of 4 wt% to 10 wt%;

[0215] - a glidant in the range of 1 wt% to 2 wt%; and

[0216] - Lubricant in the range of 1 wt% to 2 wt%, wherein the sum of the ranges of all components does not exceed 100 wt%.

[0217] In further embodiments, the pharmaceutical composition consists essentially of or consists of, based on 100 wt% of the total weight of the pharmaceutical composition:

[0218] - ranges from 30 wt% to 60 wt%, preferably 35 wt% to 60 wt% as herein described

[0219] The solid dispersion;

[0220] - one or more in the range of 30 wt% to 60 wt%, preferably 35 wt% to 60 wt%

[0221] fillers;

[0222] - a disintegrant ranging from 4 wt% to 7 wt%;

[0223] - a glidant in the range of 1 wt% to 1.5 wt%; and

[0224] - Lubricant in the range of 1 wt% to 1.5 wt%, wherein the sum of the ranges of all components does not exceed 100 wt%.

[0225] In still further embodiments, the pharmaceutical composition consists essentially of or consists of, based on 100 wt% of the total weight of the pharmaceutical composition:

[0226] - in the range of 25 wt% to 35 wt% of a solid dispersion as described herein;

[0227] - one or more fillers in the range of 55 wt% to 65 wt%;

[0228] - a disintegrant ranging from 4 wt% to 7 wt%;

[0229] - a glidant in the range of 1 wt% to 2 wt%; and

[0230] - Lubricant in the range of 1 wt% to 2 wt%, wherein the sum of the ranges of all components does not exceed 100 wt%.

[0231] In an embodiment, the pharmaceutical composition comprises compound (1) in an amount ranging from 10 wt% to 20 wt% based on 100 wt% of the total weight of the pharmaceutical composition. In an embodiment, the pharmaceutical composition comprises compound (1) in an amount of about 15 wt% based on 100 wt% of the total weight of the pharmaceutical composition.

[0232] In a specific embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of, based on 100 wt% of the total weight of the pharmaceutical composition: 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.

[0233] In a specific embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of, based on 100 wt% of the total weight of the pharmaceutical composition: 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.

[0234] In a specific embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of, based on 100 wt % of the total weight of the pharmaceutical composition: 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.

[0235] In a specific embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of, based on 100 wt% of the total weight of the pharmaceutical composition: 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.

[0236] In a specific embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of, based on 100 wt% of the total weight of the pharmaceutical composition: 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.

[0237] In one embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of about 15 mg of compound (1), about 15 mg of hypromellose acetate succinate, about 36 mg of microcrystalline cellulose, about 24 mg of mannitol, about 7 mg of croscarmellose sodium, about 1.5 mg of colloidal silicon dioxide, and about 1.5 mg of sodium stearyl fumarate.

[0238] In one embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of about 15 mg of compound (1), about 15 mg of hypromellose acetate succinate, about 20 mg of microcrystalline cellulose, about 42 mg of mannitol, about 5 mg of croscarmellose sodium, about 1.5 mg of colloidal silicon dioxide, and about 1.5 mg of sodium stearyl fumarate.

[0239] In one embodiment, the pharmaceutical composition comprises, consists essentially of, or consists of about 60 mg of compound (1), about 60 mg of hypromellose acetate succinate, about 80 mg of microcrystalline cellulose, about 168 mg of mannitol, about 20 mg of croscarmellose sodium, about 6 mg of colloidal silicon dioxide, and about 6 mg of sodium stearyl fumarate.

[0240] In an embodiment, the pharmaceutical composition is characterized in that when heated at a temperature in the range of 20°C to 30°C and with a wavelength of or The present invention has an X-ray powder diffraction pattern (XRPD) that does not include a diffraction peak at a 2θ angle equal to or lower than 10.0° when measured with Cu-Kα radiation.

[0241] In another embodiment, the pharmaceutical composition is characterized in that when heated at a temperature in the range of 20°C to 30°C and with a wavelength of or The present invention has an X-ray powder diffraction pattern (XRPD) that does not include a diffraction peak at a 2θ angle equal to or lower than 9.0° when measured with Cu-Kα radiation.

[0242] In yet another embodiment, the pharmaceutical composition is characterized in that when heated at a temperature in the range of 20°C to 30°C and with a wavelength of or The present invention has an X-ray powder diffraction pattern (XRPD) that does not include a diffraction peak at a 2θ angle equal to or lower than 6.5° when measured with Cu-Kα radiation.

[0243] In another embodiment, the pharmaceutical composition is characterized in that when heated at a temperature in the range of 20°C to 30°C and with a wavelength of or The present invention has an X-ray powder diffraction pattern (XRPD) that does not include a diffraction peak in the range of 2.0° to 10.0° when measured with Cu-Kα radiation.

[0244] In yet another embodiment, the pharmaceutical composition is characterized in that when heated at a temperature in the range of 20°C to 30°C and with a wavelength of or The present invention has an X-ray powder diffraction pattern (XRPD) that does not include a diffraction peak in the range of 2.0° to 9.0° when measured with Cu-Kα radiation.

[0245] In one embodiment, the pharmaceutical composition is characterized in that when heated at a temperature in the range of 20°C to 30°C and with a wavelength of or The invention further comprises an X-ray powder diffraction pattern (XRPD) having no diffraction peak in the range of 2.0° to 6.5° when measured with Cu-Kα radiation.

[0246] In another embodiment, the pharmaceutical composition is characterized in that when heated at a temperature in the range of 20°C to 30°C and with a wavelength of or The present invention has an X-ray powder diffraction pattern (XRPD) that does not include a diffraction peak in the range of 2.0° to 10.0° when measured with Cu-Kα radiation.

[0247] In yet another embodiment, the pharmaceutical composition is characterized in that when heated at a temperature in the range of 20°C to 30°C and with a wavelength of or The present invention has an X-ray powder diffraction pattern (XRPD) which does not include a diffraction peak at a 2θ angle of (5.9±0.2)° when measured with Cu-Kα radiation.

[0248] In another embodiment, the pharmaceutical composition is characterized in that when heated at a temperature in the range of 20°C to 30°C and with a wavelength of or The present invention has an X-ray powder diffraction pattern (XRPD) which does not include a diffraction peak at a 2θ angle of (6.2±0.2)° when measured with Cu-Kα radiation.

[0249] In another embodiment, the pharmaceutical composition is characterized in that when heated at a temperature in the range of 20°C to 30°C and with a wavelength of or When measuring Cu-Kα radiation, the following Figure 15 or Figure 16 The same X-ray powder diffraction pattern (XRPD) is shown.

[0250] In order to be used for the treatment of, solid dispersion or pharmaceutical composition can comprise or be formulated into suitable dosage unit to promote administration.Therefore, solid dispersion or pharmaceutical composition can be formulated into suitable dosage unit formulations applicable to every kind of administration route.Typical pharmaceutical unit formulations include, for example, tablets, pills, capsules, suppositories, lozenges, dragees, solutions (particularly solutions for infusion), elixirs, syrups, sachets, emulsions or dispersible powders.The dosage form and formulation of active ingredient are known in the art, and dosage unit can be prepared in any conventional manner usually.

[0251] The solid dispersion or pharmaceutical composition can preferably be administered by oral administration and can be formulated into suitable dosage unit formulations. The pharmaceutical composition can be administered as tablets, hard or soft gelatin capsules, pills, granules or suspensions. In an embodiment, the pharmaceutical composition is in the form of tablets, granules or capsules. In a preferred embodiment, the pharmaceutical composition is in the form of film-coated tablets. 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 tableted from a mixture of a solid dispersion or a solid dispersion and an excipient or from its pellets. In other embodiments, the solid dispersion, the mixture of a solid dispersion and an excipient or its pellets can be encapsulated.

[0252] Although oral administration may be preferred in view of compliance, the route of administration is not limited to oral administration, and the solid dispersion or pharmaceutical composition can be administered parenterally, for example, by intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection, or by implantation, or enterally, nasally, vaginally, rectally or topically.

[0253] The solid dispersion or pharmaceutical composition can be administered or contained in a dosage form in a therapeutically effective amount. A therapeutically effective amount is an amount that is effective at the dosage and for the time period necessary to achieve the desired therapeutic result and is the minimum amount necessary to prevent, ameliorate or treat a disease or disorder, or the minimum amount in which the therapeutically beneficial effects outweigh any toxic or deleterious effects of the compound. As used herein, the terms "active ingredient," "active pharmaceutical ingredient," "active substance," and "API" refer to a component, such as compound (1), that is intended to provide pharmacological activity or other direct action.

[0254] The pharmaceutical composition preferably contains a therapeutically effective amount of compound (1). In an embodiment, a therapeutically effective amount of compound (1) can be divided into one or more individual dosage unit formulations, and thus several individual dosage unit formulations can contain a portion of a therapeutically effective amount of compound (1). In an embodiment, a tablet, a portion of a granule, or a capsule can contain between 5 mg and 100 mg of compound (1). In an embodiment, a tablet, a portion of a granule, or a capsule can contain between 15 mg and 80 mg of compound (1). In an embodiment, a tablet, a portion of a granule, or a capsule can contain between 15 mg and 30 mg of compound (1). In an embodiment, a tablet, a portion of a granule, or a capsule can contain approximately 15, 30, or 60 mg of compound (1).

[0255] For storage, the solid dispersion or pharmaceutical composition can be packaged in a suitable container (i.e., a device containing the solid dispersion or pharmaceutical composition). Such containers can be selected from bags, blisters, bottles, ampoules and vials. The container can be made of a suitable packaging material.

[0256] 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 a specific embodiment, the solid dispersion is packaged in a double-layer low density polyethylene (LDPE) bag. In still 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.

[0257] Another embodiment of the present invention relates to a kit comprising:

[0258] - a solid dispersion or pharmaceutical composition as described herein; and

[0259] - A device containing the solid dispersion or pharmaceutical composition, preferably a high-density polyethylene

[0260] bottle; and

[0261] -Optionally a desiccant, preferably silica gel.

[0262] Use for the treatment and / or prevention of tumor diseases and / or hyperproliferative diseases

[0263] In an embodiment, compound (1) is provided for use in the treatment and / or prevention of cancer at a dosage regimen as described herein. Additionally, further aspects relate to compound (1) and dosage regimens as described herein for use in the treatment and / or prevention of cancer, wherein the patient has previously received one or more anti-cancer treatments or therapies.

[0264] Another 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 additional line of treatment. The different treatment comprises administering an anticancer therapy, drug or medicament that is different from and does not include compound (1). The previously performed first-line, second-line or additional line of treatment is unrelated to the administration of compound (1), and the previously performed first-line, second-line or additional line of treatment is completed or has ended before the treatment comprising administration of compound (1) is performed.

[0265] Another aspect relates to a method for treating and / or preventing cancer, wherein the method comprises the step of administering compound (1) to a patient at a dosage regimen as described herein. In an embodiment, the method comprises administering a disclosed therapeutically effective amount of compound (1) to a person in need of such treatment. Another aspect relates to a method for treating and / or preventing cancer, wherein the method comprises the step of administering compound (1) to a patient at a dosage regimen as described herein, wherein the patient has received a different first-line, second-line, or additional line of treatment. In an embodiment, the method comprises administering a therapeutically effective amount of compound (1) as described herein to a person in need of such treatment, wherein the patient has received a different first-line, second-line, or additional line of treatment.

[0266] An embodiment relates to the use of compound (1) in the dosage regimen described herein in the manufacture of a medicament for the treatment and / or prevention of cancer.

[0267] The solid dispersions and pharmaceutical compositions as described herein can be used as medicaments with dosage regimens as described herein. In particular, the solid dispersions and pharmaceutical compositions as described herein can be used to treat and / or prevent tumor disorders and / or hyperproliferative disorders, particularly in anticancer therapy, with dosage regimens as described herein.

[0268] According to one aspect, there is provided a solid dispersion as described herein for use as a medicament in a dosage regimen as described herein. According to another aspect, there is provided a pharmaceutical composition as described herein for use as a medicament in a dosage regimen as described herein. Another embodiment of the present invention is a solid dispersion or pharmaceutical composition for use in a dosage regimen as described herein for treating or preventing a disease.

[0269] According to one aspect there is provided a solid dispersion as described herein for use as an anticancer agent in a dosage regimen as described herein. According to another aspect there is provided a pharmaceutical composition as described herein for use as an anticancer agent in a dosage regimen as described herein.

[0270] In embodiments, solid dispersion as described herein is provided, it is used for treating and / or preventing a disease or obstacle regulated by HER2 with a dosage regimen as described herein, particularly tumor disease and / or hyperproliferative disease. Other embodiments provide a pharmaceutical composition as described herein, it is used for treating and / or preventing a disease or obstacle regulated by HER2 with a dosage regimen as described herein, particularly tumor disease and / or hyperproliferative disease. On the other hand, it relates to solid dispersion as described herein or pharmaceutical composition as described herein, it is used for using in a method for treating and / or preventing a disease or obstacle regulated by HER2 with a dosage regimen as described herein, particularly tumor disease or hyperproliferative disease.

[0271] Additional aspects relate to a method of treating and / or preventing a disease or disorder regulated by HER2, particularly a neoplastic disease and / or a hyperproliferative disease, wherein the method comprises administering to a patient a solid dispersion as described herein or a pharmaceutical composition as described herein in a dosage regimen as described herein. In embodiments, the method comprises administering to a human in need of such treatment a therapeutically effective amount of a solid dispersion or pharmaceutical composition as described herein.

[0272] Related aspects relate to the use of a solid dispersion as described herein or a pharmaceutical composition as described herein, in a dosage regimen as described herein, in the manufacture of a medicament. Embodiments relate to the use of a solid dispersion as described herein or a pharmaceutical composition as described herein, in a dosage regimen as described herein, in the manufacture of a medicament for treating and / or preventing a disease or disorder modulated by HER2, particularly a neoplastic disease and / or a hyperproliferative disease.

[0273] In one aspect, a solid dispersion or pharmaceutical composition as described herein is provided for use in treating and / or preventing a disease and / or condition with a dosage regimen as described herein, wherein inhibition of wild-type and / or mutant HER2 has a therapeutic benefit, particularly when treating and / or preventing a disease and / or condition with a dosage regimen as described herein, wherein inhibition of HER2 exon 20 mutant protein has a therapeutic benefit. Examples of such diseases and / or conditions include, but are not limited to, neoplastic diseases and / or hyperproliferative diseases, such as cancer.

[0274] One aspect relates to a solid dispersion as described herein for use in treating and / or preventing tumor diseases and / or hyperproliferative diseases with a dosage regimen as described herein. Another aspect relates to a pharmaceutical composition as described herein for use in treating and / or preventing tumor diseases and / or hyperproliferative diseases with a dosage regimen as described herein.

[0275] As used herein, the term "hyperproliferative disease" refers to a condition in which cell growth increases beyond normal levels. Hyperproliferative diseases include malignant diseases, such as cancer, and non-malignant diseases. In preferred embodiments, the hyperproliferative disorder is cancer. As used herein, the term "neoplastic disease" refers to a disease or medical condition associated with cancer or a cancer indication. Cancer can be classified according to the tissue type from which the cancer originates (histological type) and according to the primary site, or location in the body where the cancer first develops.

[0276] In an embodiment, the neoplastic disease and / or hyperproliferative disease is cancer.

[0277] In an embodiment, a solid dispersion as described herein is provided for use in treating and / or preventing cancer at a dosage regimen as described herein. Another embodiment provides a pharmaceutical composition as described herein for use in treating and / or preventing cancer at a dosage regimen as described herein. Another aspect relates 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 at a dosage regimen as described herein.

[0278] In addition, further aspects relate to a solid dispersion or pharmaceutical composition as described herein for use in the treatment and / or prevention of cancer at a dosage regimen as described herein, wherein the patient has previously received one or more anti-cancer treatments or therapies. Further embodiments provide a solid dispersion or pharmaceutical composition as described herein for use in the treatment and / or prevention of cancer at a dosage regimen as described herein, wherein the patient has previously received a different first-line, second-line, or additional line of treatment.

[0279] Another aspect relates to a method for treating and / or preventing cancer, wherein the method comprises the step of administering to a patient a solid dispersion as described herein or a pharmaceutical composition as described herein at a dosage regimen as described herein. In an embodiment, the method comprises administering to a human in need of such treatment a therapeutically effective amount of a disclosed compound (1).

[0280] Another aspect relates to a method of treating and / or preventing cancer, wherein the method comprises administering a solid dispersion as described herein or a pharmaceutical composition as described herein to a patient at a dosage regimen as described herein, wherein the patient has received a different first-line, second-line, or additional line of treatment. In an embodiment, the method comprises administering a therapeutically effective amount of a compound as described herein (1) to a human in need of such treatment, wherein the patient has received a different first-line, second-line, or additional line of treatment.

[0281] Embodiments relate to the use of a solid dispersion as described herein or a pharmaceutical composition as described herein, in a dosage regimen as described herein, in the manufacture of a medicament for the treatment and / or prevention of cancer.

[0282] In embodiments, the cancer is HER2 overexpressing, HER2 amplified, and / or HER2 mutant. In embodiments, the cancer is HER2 exon 20 mutant cancer. In embodiments, the neoplastic disease and / or hyperproliferative disease is HER2 overexpressing, HER2 amplified, and / or HER2 mutant cancer.

[0283] As used herein, "HER2 overexpressing" refers to a cancer in which cells of the cancer or tumor express HER2 at levels detectable by immunohistochemistry (eg, IHC 2+ and IHC 3+) and / or measuring ERBB2 messenger RNA.

[0284] As used herein, "HER2-amplified" refers to a cancer in which the cancer or tumor cells exhibit more than 2, particularly more than 3, 4, 5, 6, 7, 8, 9 or 10, preferably more than 6 copies of the HER2 gene ERBB2.

[0285] HER2 expression, gene copy number and amplification can be measured, for example, by determining nucleic acid sequencing (such as genomic DNA or cDNA sequencing), measuring mRNA expression, measuring protein abundance or its combination. HER2 testing methods include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), ELISA, and the RNA quantification using technologies such as RT-PCR, microarray analysis and next generation sequencing (NGS). HER2 expression in or on cancer sample cells can be compared with reference cells. Reference cells can be non-cancerous cells obtained from the subject identical with the sample cell. Reference cells can be non-cancerous cells obtained from different subjects or subject colonies.

[0286] A cancer may be referred to as "HER2-positive" when it overexpresses HER2 and / or amplifies HER2 in or on its cells.

[0287] As used herein, "HER2 mutant" refers to a cancer that carries 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), including but not limited to those listed below. Mutations can be found using any method known to technicians (such as molecular diagnostic methods, including but not limited to polymerase chain reaction (PCR), single-stranded conformational polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE), heteroduplex analysis, restriction fragment length polymorphism (RFLP), next generation sequencing (NGS) and whole exome sequencing).

[0288] As used herein, "cancer with a HER2 exon 20 mutation" or "HER2 exon 20 mutant cancer" refers to a cancer in which cancer cells or tumor cells have at least one HER2 exon 20 mutation, including but not limited to the mutations listed below.

[0289] ERBB2 (HER2) exon 20 encodes part of the kinase domain and ranges from amino acids 769 to 835. Each 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_G776insYVMS; p.A775_G776insC; p.A776_delinsVC; p.A776_delinsLC; p.A776_delinsVV; p.A776_delinsAVGC; p.A776_delinsI C; p.A776_V777delinsCVC; p.V777_insE; p.G778_P780dup(GSP); p.G776_delinsVC ("p." refers to HER2 protein).

[0290] In addition, oncogenic HER2 mutations are present outside of exon 20 including 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 HER2 protein).

[0291] In embodiments, the neoplastic disease and / or hyperproliferative disease or cancer is one of the following cancers, tumors or other proliferative diseases, but is not limited thereto:

[0292] Cancers / tumors / cancers of the head and neck: for example, tumors / cancers / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lips, gums, alveolar ridges, retromolar trigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including tongue base, tonsils, tonsillar pillars, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including upper larynx, glottis, subglottis, vocal cords), hypopharynx, and salivary glands (including minor salivary glands);

[0293] Cancer / tumors / carcinomas of the lung: e.g., non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioloalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, mixed oat cell carcinoma); neoplasms of the mediastinum: e.g., neurogenic tumors (including neurofibromas, schwannomas, malignant schwannomas, neurosarcomas, ganglioneuromas, ganglioneuromas, neuroblastomas, chromaffin cells, sarcoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymal tumor, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma);

[0294] Cancers / tumors / cancers of the gastrointestinal (GI) tract: for example, tumors / cancers / cancers of the esophagus, stomach (gastric cancer), pancreas, liver, and biliary tract (including hepatocellular carcinoma (HCC), such as childhood HCC, fibrolamellar HCC, mixed HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; bile duct carcinoma; cholangiocarcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant neurilemoma, fibrosarcoma, Klatskin tumor), gallbladder, extrahepatic bile duct, small intestine (including duodenal carcinoma), Tumors / carcinomas / cancers of the urethra (including the umbilicus, jejunum, and ileum), large intestine (including cecum, colon, rectum, and anus; colorectal cancer, gastrointestinal stromal tumors (GIST)), genitourinary system (including kidney, such as renal pelvis, renal cell carcinoma (RCC), Wilms tumor, adrenal tumor, and Grawitz tumor; ureter; bladder, such as urachal carcinoma and urothelial carcinoma; urethra, such as distal, membranous, and prostate; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, and hormone-resistant), and penis); and appendix cancer.

[0295] Testicular cancer / tumor / carcinoma: e.g., seminoma, nonseminoma;

[0296] Gynecological cancers / tumors / cancers: for example, tumors / cancers / cancers of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine corpus (including endometrium and fundus);

[0297] Cancer / tumor / carcinoma of the breast: e.g., breast cancer (invasive ductal, colloid, lobular invasive, tubular, 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;

[0298] Cancer / tumor / carcinoma of the endocrine system: for example, tumors / carcinomas / cancers of the following: endocrine glands, thyroid (thyroid cancer / tumors; papillary, follicular, anaplastic, medullary), parathyroid (parathyroid cancer / tumors), adrenal cortex (adrenocortical cancer / tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, carotid body, islet cell tumor, paraganglioma, pancreatic endocrine tumor (PET; non-functional PET, pancreatic polypeptide tumor (PPoma), gastrinoma, insulinoma, vasoactive intestinal polypeptide tumor (VIPoma), glucagonoma, somatostatinoma, growth hormone-releasing factor tumor (GRFoma), adrenocorticotropin tumor (ACTHoma)), carcinoid tumor;

[0299] Soft tissue sarcomas: e.g., fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi 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 sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymal tumor, alveolar soft tissue sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor;

[0300] Osteosarcoma: e.g., myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, and mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, high-grade surface, small cell, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma;

[0301] Mesothelioma: for example, pleural mesothelioma, peritoneal mesothelioma;

[0302] Skin cancer: for example, 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;

[0303] Neoplasms of the central nervous system and brain: for example, astrocytomas (cerebral, cerebellar, diffuse, fibrous, anaplastic, hair cell, protoplasmic, fat cell), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, ganglioneuroma, neuroblastoma, retinoblastoma, schwannoma (e.g., auditory), spinal cord axis tumors;

[0304] Peripheral nervous system cancer;

[0305] Lymphomas and leukemias: e.g., B-cell non-Hodgkin lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt lymphoma (BL)), T-cell non-Hodgkin lymphoma (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphocytic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunoglobulin, chronic B-cell lymphocytic leukemia (CLL), chronic T-cell lymphocytic leukemia (CLL), B-cell small lymphocytic lymphoma (B-SLL), cutaneous T-cell lymphoma (CTL), leukemia (MLL), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte-predominant HD (NLPHD), tuberous sclerosis HD (NSHD), mixed cellularity HD (MCHD), classical lymphocyte-rich HD, and lymphocyte-depleted HD (LDHD)), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), acute myeloid / myeloid leukemia (AML), acute lymphoblastic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myeloid / myeloid leukemia (CML), myeloma, plasma cell neoplasm, multiple myeloma (MM), plasma cell neoplasm, myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML);

[0306] Cancer of unknown primary site (CUP).

[0307] All cancers / tumors / cancers mentioned above that are characterized by their specific location / origin in the body are intended to include primary tumors and metastatic tumors derived therefrom. Preferably, the cancer as defined herein (including in any embodiment involving, for example, a cancer type) is metastatic, advanced and / or unresectable.

[0308] All of the above cancers / tumors / carcinomas can be further differentiated by their histopathological classification:

[0309] Epithelial cancers, e.g., squamous cell carcinoma (SCC) (carcinoma in situ, superficial invasive, verrucous carcinoma, pseudosarcoma, anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet ring cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); oncocytic carcinoma;

[0310] Non-epithelial cancers, for example, sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrohistiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological tumors, mixed and undifferentiated carcinomas.

[0311] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer manifests as at least one solid tumor.

[0312] In some embodiments, the cancer is selected from brain cancer, breast cancer, endocrine cancer, gastrointestinal cancer, gynecological cancer, head and neck tumors, lung cancer, nervous system cancer, and skin cancer.

[0313] Preferably, the brain cancer is glioblastoma or glioma.

[0314] Preferably, the breast cancer is lobular breast cancer. Additionally or alternatively, the breast cancer is preferably metastatic.

[0315] Preferably, the endocrine cancer is schwannoma, more preferably HER2 mutant schwannoma.

[0316] Preferably, the gastrointestinal cancer is selected from anal cancer, appendiceal cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, gastric 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. Still preferably, the gastrointestinal cancer is selected from gastric adenocarcinoma, gastroesophageal junction adenocarcinoma and esophageal adenocarcinoma, in particular metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma and metastatic esophageal adenocarcinoma.

[0317] Preferably, the gynecological cancer is selected from cervical cancer, uterine cancer, endometrial cancer and ovarian cancer.

[0318] Preferably, the head and neck tumor is a salivary gland cancer or tumor.

[0319] Preferably, the lung cancer is non-small cell lung cancer (NSCLC).

[0320] Preferably, the nervous system cancer is peripheral nervous system cancer, more preferably HER2-amplified peripheral nervous system cancer.

[0321] Preferably, the skin cancer is not melanoma, ie a non-melanoma skin cancer.

[0322] In some embodiments, the cancer is selected from glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, schwannoma, anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, gastric 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.

[0323] In some embodiments, the cancer is a HER2-overexpressing, HER2-amplified and / or HER2-mutant (particularly HER2 exon 20 mutant) cancer selected from the group consisting of glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, schwannoma, anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, gastric 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.

[0324] 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, 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.

[0325] In some embodiments, the cancer is a HER2 overexpressing, HER2 amplified and / or HER2 mutant (particularly HER2 exon 20 mutant) cancer selected from the group consisting of brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric cancer, esophageal cancer, head and neck cancer, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder cancer, kidney cancer, liver cancer, lung cancer and prostate cancer.

[0326] 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, colorectal 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.

[0327] In an embodiment, the cancer is a HER2 overexpressing, HER2 amplified and / or HER2 mutant (particularly HER2 exon 20 mutant) cancer selected from the group consisting of brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.

[0328] In other embodiments, the cancer is selected from breast cancer, bladder cancer, colorectal cancer, gastrointestinal cancer, esophageal cancer or lung cancer. In other embodiments, the cancer is selected from cancer / tumor / cancer of the lung: for example, non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, mixed oat cell carcinoma). In still other embodiments, the cancer is NSCLC. In still other embodiments, the cancer is HER2 exon 20 mutant NSCLC. In other embodiments, the cancer is unresectable. In still other embodiments, the cancer is unresectable HER2 exon 20 mutant NSCLC.

[0329] In a preferred embodiment, the cancer is advanced or metastatic. In a further preferred embodiment, the cancer is advanced and metastatic. In a further preferred embodiment, when the cancer is metastatic, the metastases are located in the lungs, lymph nodes, or bones. In a further preferred embodiment, the cancer is an advanced cancer comprising metastases, and the metastases are located in the lungs, lymph nodes, or bones.

[0330] Additionally or alternatively, the cancer may be unresectable.

[0331] In preferred embodiments, the cancer is an unresectable advanced cancer, including solid tumors and solid metastases, and the metastases are located in the lung or lymph node tissue or bone.

[0332] In preferred embodiments, the cancer is advanced NSCLC, including solid unresectable tumors and metastases, and the metastases are located in the lung or lymph node tissue or bone.

[0333] In a preferred embodiment, the cancer is HER2 exon 20 mutant advanced NSCLC, which includes solid unresectable tumors and metastases, and the metastases are located in the lung or lymph node tissue or bone.

[0334] In an embodiment, the cancer is advanced, unresectable or metastatic NSCLC carrying a HER2 mutation, wherein the HER2 mutation is in the tyrosine kinase domain. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a first-line therapy. Still preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a second-line therapy or an additional line of therapy.

[0335] In an embodiment, the cancer is HER2-positive metastatic breast cancer. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a first-line therapy. Still preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a second-line therapy or an additional line of therapy.

[0336] 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 as described herein is administered as a first-line therapy. Still preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a second-line therapy or an additional line of therapy.

[0337] A further aspect relates to compound (1), a solid dispersion or a pharmaceutical composition for use as a medicament in a dosage regimen as described herein, in particular for the treatment and / or prevention of oncological disorders and / or hyperproliferative disorders, such as cancer, wherein compound (1), a solid dispersion or a pharmaceutical composition:

[0338] -Administered to fasting subjects, and / or

[0339] - administered in combination with an agent that increases gastric pH, preferably a proton pump inhibitor (PPI), an antacid or an antihistamine, and / or

[0340] -Administered to a subject having a gastric pH in the range of about 1 to 7, preferably administered to a subject having a gastric pH in the range of about 1 to 5.

[0341] In an embodiment, a solid dispersion as described herein or a pharmaceutical composition as described herein is administered in a dosage regimen as described herein:

[0342] -Administered to fasting subjects, and / or

[0343] - Administration in combination with an agent that increases gastric pH, preferably a proton pump inhibitor (PPI), an antacid or an antihistamine.

[0344] Another aspect relates to compound (1) as defined above for use in the treatment and / or prevention of neoplastic diseases and / or hyperproliferative diseases, wherein compound (1) is administered in a dosage regimen as described herein:

[0345] -Administered to fasting subjects, and / or

[0346] -Administered in combination with agents that increase gastric pH.

[0347] In an embodiment, compound (1), solid dispersion or pharmaceutical composition is administered to a fasting subject at a dosage regimen as described herein.

[0348] As used herein, the term "subject" refers to a human, eg, a human having cancer, at risk for developing cancer, or potentially capable of developing cancer.

[0349] In an embodiment, compound (1), solid dispersion or pharmaceutical composition is administered in combination with an agent that increases gastric pH, preferably a proton pump inhibitor (PPI), antacid or antihistamine, at a dosage regimen as described herein.

[0350] In an embodiment, compound (1), solid dispersion or pharmaceutical composition is administered to a fasting subject at a dosage regimen as described herein and in combination with an agent that increases gastric pH, preferably a proton pump inhibitor (PPI), antacid or antihistamine.

[0351] In an embodiment, compound (1), solid dispersion or pharmaceutical composition is administered to a subject having a gastric pH ranging from about 1 to 7 at a dosage regimen as described herein.

[0352] In an embodiment, compound (1), solid dispersion or pharmaceutical composition is administered to a subject having a gastric pH ranging from about 1 to 5 at a dosage regimen as described herein.

[0353] As used herein, "fasting subjects" refers to subjects who have not eaten for at least eight hours, preferably at least ten hours, and usually overnight, before administration of the solid dispersion or pharmaceutical composition or dosage form thereof. Fasting subjects can conveniently receive compound (1), solid dispersion, pharmaceutical composition or dosage form thereof with water after fasting for at least eight or ten hours. Thereafter, they may not eat for a period of, for example, four hours, but may drink a small amount of water, for example, two hours after receiving the dose.

[0354] In embodiments, a fasting subject is a subject that has not consumed food for at least two hours prior to administration of a solid dispersion or pharmaceutical composition described herein and / or has not consumed food for at least one hour after administration of a solid dispersion or pharmaceutical composition described herein.

[0355] In embodiments, a fasting subject is one that has not eaten for about two hours prior to administration of a solid dispersion or pharmaceutical composition described herein and has not eaten for about one hour after administration of a solid dispersion or pharmaceutical composition described herein. In these embodiments, a fasting subject may be referred to as a "modified fasting subject."

[0356] "Agents that increase gastric pH" refers to a class of agents that neutralize gastric acidity. Agents that neutralize gastric acid can reduce pepsin activity. In an embodiment, the agent that increases gastric pH is a proton pump inhibitor. The term "proton pump inhibitor" (PPI) refers to a class of drugs that cause a significant and sustained reduction in gastric acid production. In an embodiment, they are gastric acid secretion inhibitors. In an embodiment, PPIs that can be administered in combination with compound (1), a solid dispersion or a 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 where an increase in gastric pH is beneficial, such as reflux esophagitis.

[0357] In an embodiment, the agent that increases gastric pH is an antacid. The term "antacid" refers to a class of drugs that neutralize gastric acidity. In an embodiment, antacids that can be administered in combination with compound (1), a solid dispersion, or a pharmaceutical composition include, but are not limited to, salts of aluminum, calcium, magnesium, or sodium, such as aluminum hydroxide, magnesium hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate, and sodium bicarbonate.

[0358] In an embodiment, the agent that increases gastric pH is an antihistamine, particularly an H2 receptor antagonist. The term "H2 receptor antagonist" refers to a class of drugs that block the effects of histamine in the stomach. In an embodiment, antihistamines that can be administered in combination with compound (1), a solid dispersion, or a pharmaceutical composition include, but are not limited to, cimetidine, ranitidine, famotidine, nizatidine, roxatidine, lafutidine, lavoltidine, and niperotidine.

[0359] Compound (1), solid dispersion, pharmaceutical composition or its dosage form and the agent that increases gastric pH can be administered simultaneously, concurrently, sequentially or successively. The term "concurrently" refers to administering both compounds / compositions substantially simultaneously. The term "concurrently" refers to administering the active ingredients in the same general time period (e.g., on the same day or days, but not necessarily at the same time). The term "sequentially" administering includes administering one active ingredient using one or more doses over a first time period (e.g., over the course of a few hours, a few days, or a week), followed by administering another active ingredient using one or more doses over a second time period (e.g., over the course of a few hours, a few days, or a week). Overlapping arrangements can also be employed, which include administering the active ingredients on different days within the treatment time period, not necessarily in a regular order. Alternatively, the term "sequentially" administering refers to administering the second administration step immediately after completing the administration of the first compound. Variants of these general administration forms can also be employed.

[0360] In an embodiment, compound (1), solid dispersion, pharmaceutical composition or dosage form thereof is administered in a dosage regimen as described herein after an agent that increases gastric pH, preferably a proton pump inhibitor (PPI), antacid or antihistamine.

[0361] In another aspect, the present invention relates to a solid dispersion or a pharmaceutical composition as described herein for use in the treatment and / or prevention of tumor diseases and / or hyperproliferative diseases as defined herein, wherein the solid dispersion or the pharmaceutical composition is administered in combination with a cytostatically active substance and / or a cytotoxically active substance and / or in combination with radiotherapy and / or immunotherapy in a dosage regimen as described herein.

[0362] In another aspect, the present invention relates to a solid dispersion or a pharmaceutical composition as described herein in combination with a cytostatic and / or cytotoxic active substance and / or in combination with radiotherapy and / or immunotherapy in a dosage regimen as described herein for use in the treatment and / or prevention of cancer.

[0363] The solid dispersion or pharmaceutical composition as described herein can be used alone or in combination with one or more other pharmacologically active substances, such as prior art or standard of care compounds, for example, cell proliferation inhibitors, anti-angiogenic substances, steroids, or immunomodulators / checkpoint inhibitors, etc.

[0364] Pharmacologically active substances that can be administered in combination with the solid dispersions or pharmaceutical compositions as described herein include, but are not limited to, 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, lirazole, fluclozole, exemestane, atamestane), LHRH agonists and antagonists (e.g., goserelin acetate, luprolide), inhibitors of growth factors and / or their corresponding receptors (growth factors such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and / or cytokine receptor agonists. , epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, such as HER2, HER3, HER4) and hepatocyte growth factor (HGF) and / or their corresponding receptors), inhibitors are, for example, (anti) growth factor antibodies, (anti) growth factor receptor antibodies and tyrosine kinase inhibitors, for example, cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab, pertuzumab and trastuzumab); antimetabolites (for example, antifolates such as methotrexate, raltitrexed, pyrimidine analogs such as 5-fluorouracil (5fluorineU), ribonucleoside and deoxyribonucleoside analogs, capecitabine and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (arabinoside); C), fludarabine); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride, myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin C, bleomycin, dactinomycin, plicamycin, streptozotocin); 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); antimitotic agents (e.g., vinca alkaloids such as vinblastine, vindesine, vinorelbine and vincristine; and taxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g., taquimod), microtubule inhibitors;DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (e.g., PDK 1 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, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDK, 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., KRAS G12C inhibitors), signaling pathway inhibitors (e.g., SOS1 inhibitors), FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-2 inhibitors, Bcl-xL inhibitors, Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs (e.g., everolimus, temsirolimus, dafolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, H DAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors, immunotherapeutics such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3 and TIM3 binding molecules / immunoglobulins such as ipilimumab, nivolumab, pembrolizumab), 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); For example, CD3 x BCMA, CD3 x CD33, CD3 x CD19), PSMA x CD3), tumor vaccines and various chemotherapeutic agents such as amifostin, anagrelide, clodronate, filgrastim, interferon, interferon alpha, folinic acid, procarbazine, levamisole, mesna, mitotane, pamidronate disodium and porfibril sodium.

[0365] Dosage and Dosage Regimen of Compound (1)

[0366] The object of the present invention is to provide a safe and effective dosage regimen for administering compound (1) or a pharmaceutical composition comprising compound (1) at said dosage regimen. This dosage regimen is particularly useful for treating cancer. In addition, this dosage regimen of compound (1) or a pharmaceutical composition comprising compound (1) is particularly useful in methods of treating patients suffering from cancer. In addition, the dosage regimen also appears to be suitable as a second or additional line of treatment where the patient has previously received one or more types of cancer treatment.

[0367] As used herein, "daily dose" or "total daily dose" refers to the amount of active substance, ie compound (1), administered to a patient within a 24-hour time frame. The 24-hour time frame does not necessarily start at noon or midnight.

[0368] It has unexpectedly been found that, as described above and in the examples below, compound (1) is safe and effective for treating cancer at a daily dose of at least 30 mg.

[0369] In a preferred embodiment, compound (1) is administered at a daily dose of at least 60 mg. Alternatively, the above method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of at least 60 mg.

[0370] 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.

[0371] In a preferred embodiment, compound (1) is administered at a daily dose of at least 120 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of at least 120 mg.

[0372] In a preferred embodiment, compound (1) is administered at a daily dose of at least 180 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of at least 180 mg.

[0373] In a preferred embodiment, compound (1) is administered at a daily dose of at least 200 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of at least 200 mg.

[0374] In a preferred embodiment, compound (1) is administered at a daily dose of at least 240 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of at least 240 mg.

[0375] In a preferred embodiment, compound (1) is administered at a daily dose of at least 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of at least 300 mg.

[0376] In a preferred embodiment, compound (1) is administered at a daily dose of 30 mg to 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 30 mg to 600 mg.

[0377] In a preferred embodiment, compound (1) is administered at a daily dose of 60 mg to 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 60 mg to 600 mg.

[0378] In a preferred embodiment, compound (1) is administered at a daily dose of 80 mg to 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 80 mg to 600 mg.

[0379] In a preferred embodiment, compound (1) is administered at a daily dose of 120 mg to 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 120 mg to 600 mg.

[0380] In a further preferred embodiment, compound (1) is administered at a daily dose of 30 mg to 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 30 mg to 300 mg.

[0381] In a further preferred embodiment, compound (1) is administered at a daily dose of 60 mg to 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 60 mg to 300 mg.

[0382] In a further preferred embodiment, compound (1) is administered at a daily dose of 80 mg to 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 80 mg to 300 mg.

[0383] In a further preferred embodiment, compound (1) is administered at a daily dose of 120 mg to 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 120 mg to 300 mg.

[0384] In a preferred embodiment, 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. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) 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.

[0385] In a preferred embodiment, 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. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) 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.

[0386] In a preferred embodiment, compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg or 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg or 300 mg.

[0387] In a preferred embodiment, compound (1) is administered at a daily dose of 30 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 30 mg.

[0388] In a preferred embodiment, compound (1) is administered at a daily dose of 60 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 60 mg.

[0389] In a preferred embodiment, compound (1) is administered at a daily dose of 120 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 120 mg.

[0390] In a preferred embodiment, compound (1) is administered at a daily dose of 180 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 180 mg.

[0391] In a preferred embodiment, compound (1) is administered at a daily dose of 200 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 200 mg.

[0392] In a preferred embodiment, compound (1) is administered at a daily dose of 240 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 240 mg.

[0393] In a preferred embodiment, compound (1) is administered at a daily dose of 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 300 mg.

[0394] In a preferred embodiment, compound (1) is administered at a daily dose of 360 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 360 mg.

[0395] In a preferred embodiment, compound (1) is administered at a daily dose of 400 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 400 mg.

[0396] In a preferred embodiment, compound (1) is administered at a daily dose of 420 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 420 mg.

[0397] In a preferred embodiment, compound (1) is administered at a daily dose of 480 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 480 mg.

[0398] In a preferred embodiment, compound (1) is administered at a daily dose of 500 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 500 mg.

[0399] In a preferred embodiment, compound (1) is administered at a daily dose of 540 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 540 mg.

[0400] In a preferred embodiment, compound (1) is administered at a daily dose of 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) at a daily dose of 600 mg.

[0401] In a preferred embodiment, compound (1) is administered once or twice daily. This means that the daily dose is administered as a single dose or divided into two separate doses, each administered at a different time point during the day (ie within 24 hours).

[0402] In a preferred embodiment, compound (1) is administered once daily. In a preferred embodiment, compound (1) is administered as a single dose within 24 hours.

[0403] In a preferred embodiment, compound (1) is administered twice daily. In a preferred embodiment, compound (1) is administered twice within 24 hours.

[0404] In a preferred embodiment, each of the two daily administrations of compound (1) corresponds to half the daily dose. By administering the required daily dose of compound (1) in two doses comprising the same amount, a simple and error-proof application regimen can be provided.

[0405] 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 21 days multiplied by X, where X is a natural number equal to or greater than 1. It is also possible to include a dose-free interval in the overall cancer treatment between treatment times including the administration of compound (1).

[0406] 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, 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 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.

[0407] 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, 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 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.

[0408] 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, or compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 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, or 300 mg, or administering compound (1) twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg.

[0409] 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, 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.

[0410] 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, 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.

[0411] 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, 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, or 300 mg.

[0412] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 60 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) once daily at a daily dose of 60 mg.

[0413] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 120 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) once daily at a daily dose of 120 mg.

[0414] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 180 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) once daily at a daily dose of 180 mg.

[0415] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 240 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) once daily at a daily dose of 240 mg.

[0416] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) once daily at a daily dose of 300 mg.

[0417] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 360 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) once daily at a daily dose of 360 mg.

[0418] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 400 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) once daily at a daily dose of 400 mg.

[0419] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 420 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) once daily at a daily dose of 420 mg.

[0420] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 480 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) once daily at a daily dose of 480 mg.

[0421] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 500 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) once daily at a daily dose of 500 mg.

[0422] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 540 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) once daily at a daily dose of 540 mg.

[0423] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) once daily at a daily dose of 600 mg.

[0424] 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, the 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.

[0425] 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, the 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.

[0426] 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, the 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.

[0427] 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 two daily administrations is 15 mg.

[0428] 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 two daily administrations is 30 mg.

[0429] 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 two daily administrations is 60 mg.

[0430] 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 two daily administrations is 100 mg.

[0431] 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 two daily administrations is 150 mg.

[0432] 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 two daily administrations is 180 mg.

[0433] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 400 mg. Alternatively, the 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 two daily administrations is 200 mg.

[0434] 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 two daily administrations is 210 mg.

[0435] 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 two daily administrations is 240 mg.

[0436] 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 two daily administrations is 250 mg.

[0437] 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 two daily administrations is 270 mg.

[0438] 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 two daily administrations is 300 mg.

[0439] In some embodiments, compound (1) is administered orally 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, preferably as a tablet. 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, preferably as a tablet.

[0440] In some embodiments, compound (1) is administered orally 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, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally 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, preferably as a tablet.

[0441] In some embodiments, compound (1) is administered orally once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg, preferably as a tablet.

[0442] In some embodiments, compound (1) is administered orally once daily at a daily dose of 60 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally once daily at a daily dose of 60 mg, preferably as a tablet.

[0443] In some embodiments, compound (1) is administered orally once daily at a daily dose of 120 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally once daily at a daily dose of 120 mg, preferably as a tablet.

[0444] In some embodiments, compound (1) is administered orally once daily at a daily dose of 180 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally once daily at a daily dose of 180 mg, preferably as a tablet.

[0445] In some embodiments, compound (1) is administered orally once daily at a daily dose of 240 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally once daily at a daily dose of 240 mg, preferably as a tablet.

[0446] In some embodiments, compound (1) is administered orally once daily at a daily dose of 300 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally once daily at a daily dose of 300 mg, preferably as a tablet.

[0447] In some embodiments, compound (1) is administered orally once daily at a daily dose of 360 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally once daily at a daily dose of 360 mg, preferably as a tablet.

[0448] In some embodiments, compound (1) is administered orally once daily at a daily dose of 400 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally once daily at a daily dose of 400 mg, preferably as a tablet.

[0449] In some embodiments, compound (1) is administered orally once daily at a daily dose of 420 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally once daily at a daily dose of 420 mg, preferably as a tablet.

[0450] In some embodiments, compound (1) is administered orally once daily at a daily dose of 480 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally once daily at a daily dose of 480 mg, preferably as a tablet.

[0451] In some embodiments, compound (1) is administered orally once daily at a daily dose of 500 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally once daily at a daily dose of 500 mg, preferably as a tablet.

[0452] In some embodiments, compound (1) is administered orally once daily at a daily dose of 540 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally once daily at a daily dose of 540 mg, preferably as a tablet.

[0453] In some embodiments, compound (1) is administered orally once daily at a daily dose of 600 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally once daily at a daily dose of 600 mg, preferably as a tablet.

[0454] In some embodiments, compound (1) is administered orally 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, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally 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, preferably as a tablet.

[0455] In some embodiments, compound (1) is administered orally 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, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally 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, preferably as a tablet.

[0456] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg, preferably as a tablet.

[0457] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 30 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally twice daily at a daily dose of 30 mg, preferably as a tablet. Preferably, in these embodiments, each of the two daily administrations is 15 mg.

[0458] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 60 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally twice daily at a daily dose of 60 mg, preferably as a tablet. Preferably, in these embodiments, each of the two daily administrations is 30 mg.

[0459] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 120 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally twice daily at a daily dose of 120 mg, preferably as a tablet. Preferably, in these embodiments, each of the two daily administrations is 60 mg.

[0460] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 200 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally twice daily at a daily dose of 200 mg, preferably as a tablet. Preferably, in these embodiments, each of the two daily administrations is 100 mg.

[0461] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 300 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally twice daily at a daily dose of 300 mg, preferably as a tablet. Preferably, in these embodiments, each of the two daily administrations is 150 mg.

[0462] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 360 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally twice daily at a daily dose of 360 mg, preferably as a tablet. Preferably, in these embodiments, each of the two daily administrations is 180 mg.

[0463] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 400 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally twice daily at a daily dose of 400 mg, preferably as a tablet. Preferably, in these embodiments, each of the two daily administrations is 200 mg.

[0464] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 420 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally twice daily at a daily dose of 420 mg, preferably as a tablet. Preferably, in these embodiments, each of the two daily administrations is 210 mg.

[0465] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 480 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally twice daily at a daily dose of 480 mg, preferably as a tablet. Preferably, in these embodiments, each of the two daily administrations is 240 mg.

[0466] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 500 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally twice daily at a daily dose of 500 mg, preferably as a tablet. Preferably, in these embodiments, each of the two daily administrations is 250 mg.

[0467] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 540 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally twice daily at a daily dose of 540 mg, preferably as a tablet. Preferably, in these embodiments, each of the two daily administrations is 270 mg.

[0468] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 600 mg, preferably as a tablet. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally twice daily at a daily dose of 600 mg, preferably as a tablet. Preferably, in these embodiments, each of the two daily administrations is 300 mg.

[0469] In a preferred embodiment, the above-defined dosage regimens of compound (1) can also be combined and the daily dose can be varied during the course of treatment. Thus, for example, treatment can be started by administering a daily dose of 30 mg (once or twice a day) and the dose can be switched to a higher or lower daily dose (once or twice a day).

[0470] The dosage regimens described in this paragraph are also applicable in situations where the patient has already received one or more systemic anti-cancer treatments or therapies.

[0471] Dosages and dosage regimens of solid dispersions and pharmaceutical compositions

[0472] The present invention aims to provide a safe and effective dosage regimen for administering a solid dispersion comprising compound (1) in said dosage regimen. This dosage regimen is particularly useful for treating cancer. In addition, this dosage regimen of a solid dispersion comprising compound (1) is particularly useful in methods of treating patients suffering from cancer. In addition, the dosage regimen also appears to be suitable as a second or additional line of treatment where the patient has previously received one or more types of cancer treatment.

[0473] It has unexpectedly been discovered that, as described above and in the Examples below, the use of a solid dispersion comprising Compound (1) as described herein at a daily dose of at least 30 mg of Compound (1) is safe and effective for treating cancer.

[0474] In a preferred embodiment, the solid dispersion is administered at a daily dose of at least 60 mg of compound (1). Alternatively, the above method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein compound (1) is administered at a daily dose of at least 60 mg.

[0475] In a preferred embodiment, the solid dispersion is administered at a daily dose of at least 80 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein compound (1) is administered at a daily dose of at least 80 mg.

[0476] In a preferred embodiment, the solid dispersion is administered at a daily dose of at least 120 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein compound (1) is administered at a daily dose of at least 120 mg.

[0477] In a preferred embodiment, the solid dispersion is administered at a daily dose of at least 180 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein compound (1) is administered at a daily dose of at least 180 mg.

[0478] In a preferred embodiment, the solid dispersion is administered at a daily dose of at least 200 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein compound (1) is administered at a daily dose of at least 200 mg.

[0479] In a preferred embodiment, the solid dispersion is administered at a daily dose of at least 240 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein compound (1) is administered at a daily dose of at least 240 mg.

[0480] In a preferred embodiment, the solid dispersion is administered at a daily dose of at least 300 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion, wherein compound (1) is administered at a daily dose of at least 300 mg.

[0481] In a preferred embodiment, the solid dispersion is administered at a daily dose of 30 mg to 600 mg of compound (1). Alternatively, the 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 600 mg.

[0482] In a preferred embodiment, the solid dispersion is administered at a daily dose of 60 mg to 600 mg of compound (1). Alternatively, the 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.

[0483] In a preferred embodiment, the solid dispersion is administered at a daily dose of 80 mg to 600 mg of compound (1). Alternatively, the 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.

[0484] In a preferred embodiment, the solid dispersion is administered at a daily dose of 120 mg to 600 mg of compound (1). Alternatively, the 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.

[0485] In a further preferred embodiment, the solid dispersion is administered at a daily dose of 30 mg to 300 mg of compound (1). Alternatively, the 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.

[0486] In a further preferred embodiment, the solid dispersion is administered at a daily dose of 60 mg to 300 mg of compound (1). Alternatively, the 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.

[0487] In a further preferred embodiment, the solid dispersion is administered at a daily dose of 80 mg to 300 mg of compound (1). Alternatively, the 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.

[0488] In a further preferred embodiment, the solid dispersion is administered at a daily dose of 120 mg to 300 mg of compound (1). Alternatively, the 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.

[0489] 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, the method of treating a patient suffering from cancer comprises administering a 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.

[0490] 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, the method of treating a patient suffering from cancer comprises administering a 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.

[0491] 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, the 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.

[0492] In a preferred embodiment, the solid dispersion is administered at a daily dose of 30 mg of compound (1). Alternatively, the 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.

[0493] In a preferred embodiment, the solid dispersion is administered at a daily dose of 60 mg of compound (1). Alternatively, the 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.

[0494] In a preferred embodiment, the solid dispersion is administered at a daily dose of 120 mg of compound (1). Alternatively, the 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.

[0495] In a preferred embodiment, the solid dispersion is administered at a daily dose of 180 mg of compound (1). Alternatively, the 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.

[0496] In a preferred embodiment, the solid dispersion is administered at a daily dose of 200 mg of compound (1). Alternatively, the 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.

[0497] In a preferred embodiment, the solid dispersion is administered at a daily dose of 240 mg of compound (1). Alternatively, the 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.

[0498] In a preferred embodiment, the solid dispersion is administered at a daily dose of 300 mg of compound (1). Alternatively, the 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.

[0499] In a preferred embodiment, the solid dispersion is administered at a daily dose of 360 mg of compound (1). Alternatively, the 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.

[0500] In a preferred embodiment, the solid dispersion is administered at a daily dose of 400 mg of compound (1). Alternatively, the 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.

[0501] In a preferred embodiment, the solid dispersion is administered at a daily dose of 420 mg of compound (1). Alternatively, the 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.

[0502] In a preferred embodiment, the solid dispersion is administered at a daily dose of 480 mg of compound (1). Alternatively, the 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.

[0503] In a preferred embodiment, the solid dispersion is administered at a daily dose of 500 mg of compound (1). Alternatively, the 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.

[0504] In a preferred embodiment, the solid dispersion is administered at a daily dose of 540 mg of compound (1). Alternatively, the 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.

[0505] In a preferred embodiment, the solid dispersion is administered at a daily dose of 600 mg of compound (1). Alternatively, the 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.

[0506] In a preferred embodiment, the solid dispersion is administered once or twice daily.

[0507] In a preferred embodiment, the solid dispersion is administered once daily.In a preferred embodiment, the solid dispersion is administered as a single dose within 24 hours.

[0508] In a preferred embodiment, the solid dispersion is administered twice daily.In a preferred embodiment, the solid dispersion is administered twice within 24 hours.

[0509] In a preferred embodiment, each of the two daily administrations of the solid dispersion corresponds to half the daily dose of compound (1). By administering the required daily dose of compound (1) in two doses comprising the same amount, a simple and error-proof application regimen can be provided.

[0510] 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 21 days multiplied by X, where X is a natural number equal to or greater than 1. It is also possible to include no-dose intervals in the overall cancer treatment between treatment times that include administration of the solid dispersion.

[0511] In some embodiments, the solid dispersion 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 of compound (1), or 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 of compound (1). Alternatively, the 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, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg, or 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.

[0512] In some embodiments, the solid dispersion 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 of compound (1), or 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 of compound (1). Alternatively, the 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, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg, or 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.

[0513] In some 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, the 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, or twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg of compound (1).

[0514] In some embodiments, the solid dispersion 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 of compound (1). Alternatively, the 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, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0515] In some embodiments, the solid dispersion 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 of compound (1). Alternatively, the 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, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0516] In some 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). Alternatively, the 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.

[0517] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 60 mg of compound (1). Alternatively, the 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.

[0518] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 120 mg of compound (1). Alternatively, the 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.

[0519] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 180 mg of compound (1). Alternatively, the 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.

[0520] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 240 mg of compound (1). Alternatively, the 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.

[0521] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 300 mg of compound (1). Alternatively, the 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.

[0522] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 360 mg of compound (1). Alternatively, the 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.

[0523] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 400 mg of compound (1). Alternatively, the 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.

[0524] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 420 mg of compound (1). Alternatively, the 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.

[0525] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 480 mg of compound (1). Alternatively, the 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.

[0526] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 500 mg of compound (1). Alternatively, the 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.

[0527] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 540 mg of compound (1). Alternatively, the 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.

[0528] In a preferred embodiment, the solid dispersion is administered once daily at a daily dose of 600 mg of compound (1). Alternatively, the 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.

[0529] In some embodiments, the solid dispersion 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 of compound (1). Alternatively, the 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.

[0530] In some embodiments, the solid dispersion 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 of compound (1). Alternatively, the 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.

[0531] In some embodiments, the solid dispersion is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg of compound (1). Alternatively, the 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.

[0532] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 30 mg of compound (1). Alternatively, the 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 two daily administrations is 15 mg.

[0533] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 60 mg of compound (1). Alternatively, the 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 two daily administrations is 30 mg.

[0534] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 120 mg of compound (1). Alternatively, the 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 two daily administrations is 60 mg.

[0535] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 200 mg of compound (1). Alternatively, the 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 two daily administrations is 100 mg.

[0536] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 300 mg of compound (1). Alternatively, the 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 two daily administrations is 150 mg.

[0537] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 360 mg of compound (1). Alternatively, the 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 two daily administrations is 180 mg.

[0538] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 400 mg of compound (1). Alternatively, the 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 two daily administrations is 200 mg.

[0539] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 420 mg of compound (1). Alternatively, the 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 two daily administrations is 210 mg.

[0540] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 480 mg of compound (1). Alternatively, the 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 two daily administrations is 240 mg.

[0541] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 500 mg of compound (1). Alternatively, the 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 two daily administrations is 250 mg.

[0542] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 540 mg of compound (1). Alternatively, the 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 two daily administrations is 270 mg.

[0543] In a preferred embodiment, the solid dispersion is administered twice daily at a daily dose of 600 mg of compound (1). Alternatively, the 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 two daily administrations is 300 mg.

[0544] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, 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 of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered 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.

[0545] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, 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 of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered 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.

[0546] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg.

[0547] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, at a daily dose of 60 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 60 mg.

[0548] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, at a daily dose of 120 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 120 mg.

[0549] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, at a daily dose of 180 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 180 mg.

[0550] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, at a daily dose of 240 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 240 mg.

[0551] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, at a daily dose of 300 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 300 mg.

[0552] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, at a daily dose of 360 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 360 mg.

[0553] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, at a daily dose of 400 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 400 mg.

[0554] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, at a daily dose of 420 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 420 mg.

[0555] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, at a daily dose of 480 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 480 mg.

[0556] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, at a daily dose of 500 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 500 mg.

[0557] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, at a daily dose of 540 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 540 mg.

[0558] In some embodiments, the solid dispersion is administered orally once daily, preferably as a tablet, at a daily dose of 600 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally once daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 600 mg.

[0559] In some embodiments, the solid dispersion is administered orally twice daily, preferably as a tablet, 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 of compound (1). Alternatively, the method comprises administering the solid dispersion orally twice daily, preferably as a tablet, 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.

[0560] In some embodiments, the solid dispersion is orally administered twice daily, preferably as a tablet, 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 of compound (1). Alternatively, the method comprises orally administering the solid dispersion twice daily, preferably as a tablet, 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.

[0561] In some embodiments, the solid dispersion is administered orally twice daily, preferably as a tablet, at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally twice daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg.

[0562] In some embodiments, the solid dispersion is administered orally twice daily, preferably as a tablet, at a daily dose of 30 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally twice daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 30 mg. Preferably, in these embodiments, each of the two daily administrations is 15 mg.

[0563] In some embodiments, the solid dispersion is administered orally twice daily, preferably as a tablet, at a daily dose of 60 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally twice daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 60 mg. Preferably, in these embodiments, each of the two daily administrations is 30 mg.

[0564] In some embodiments, the solid dispersion is administered orally twice daily, preferably as a tablet, at a daily dose of 120 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally twice daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 120 mg. Preferably, in these embodiments, each of the two daily administrations is 60 mg.

[0565] In some embodiments, the solid dispersion is administered orally twice daily, preferably as a tablet, at a daily dose of 200 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally twice daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 200 mg. Preferably, in these embodiments, each of the two daily administrations is 100 mg.

[0566] In some embodiments, the solid dispersion is administered orally twice daily, preferably as a tablet, at a daily dose of 300 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally twice daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 300 mg. Preferably, in these embodiments, each of the two daily administrations is 150 mg.

[0567] In some embodiments, the solid dispersion is administered orally twice daily, preferably as a tablet, at a daily dose of 360 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally twice daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 360 mg. Preferably, in these embodiments, each of the two daily administrations is 180 mg.

[0568] In some embodiments, the solid dispersion is administered orally twice daily, preferably as a tablet, at a daily dose of 400 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally twice daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 400 mg. Preferably, in these embodiments, each of the two daily administrations is 200 mg.

[0569] In some embodiments, the solid dispersion is administered orally twice daily, preferably as a tablet, at a daily dose of 420 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally twice daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 420 mg. Preferably, in these embodiments, each of the two daily administrations is 210 mg.

[0570] In some embodiments, the solid dispersion is administered orally twice daily, preferably as a tablet, at a daily dose of 480 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally twice daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 480 mg. Preferably, in these embodiments, each of the two daily administrations is 240 mg.

[0571] In some embodiments, the solid dispersion is administered orally twice daily, preferably as a tablet, at a daily dose of 500 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally twice daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 500 mg. Preferably, in these embodiments, each of the two daily administrations is 250 mg.

[0572] In some embodiments, the solid dispersion is administered orally twice daily, preferably as a tablet, at a daily dose of 540 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally twice daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 540 mg. Preferably, in these embodiments, each of the two daily administrations is 270 mg.

[0573] In some embodiments, the solid dispersion is administered orally twice daily, preferably as a tablet, at a daily dose of 600 mg of compound (1). Alternatively, the method of treating a patient suffering from cancer comprises administering the solid dispersion orally twice daily, preferably as a tablet, wherein compound (1) is administered at a daily dose of 600 mg. Preferably, in these embodiments, each of the two daily administrations is 300 mg.

[0574] In a preferred embodiment, the above-defined dosage regimens of the solid dispersions can also be combined and the daily dose of compound (1) can be varied during the course of treatment. Thus, for example, treatment can be started by administering a daily dose of 30 mg of compound (1) (once or twice a day) and the dose can be switched to a higher or lower daily dose (once or twice a day).

[0575] The doses and dosage regimens described in this paragraph are also applicable to situations in which the patient has already received one or more systemic anti-cancer treatments or therapies.

[0576] The doses and dosage regimens described in this paragraph also apply to the pharmaceutical compositions as described herein. Accordingly, provided herein are embodiments corresponding to those described in this section, wherein the expression "solid dispersion" is replaced by the expression "pharmaceutical composition".

[0577] Second-line or additional-line administration

[0578] It has unexpectedly been found that the use of compound (1), a solid dispersion as described herein, or a pharmaceutical composition as described herein, following cancer therapy with at least one systemic anti-cancer therapeutic has the potential to improve or stabilize clinical outcomes.

[0579] In a preferred embodiment, at least one additional therapeutic agent is administered before or in a previous line of treatment at the doses and dosage regimens described herein. Alternatively, the method of treating a patient having cancer as described above comprises administering compound (1) in a subsequent line of treatment at the doses and dosage regimens described herein after or in a subsequent line of treatment.

[0580] In a preferred embodiment, at least one additional therapeutic agent is administered prior to or in a prior line of treatment at the doses and dosage regimens described herein for a solid dispersion as described herein or a pharmaceutical composition as described herein. Alternatively, the method of treating a patient suffering from cancer as described above comprises administering a solid dispersion as described herein or a pharmaceutical composition as described herein in a dose and dosage regimen described herein after or in a subsequent line of treatment after administration of at least one additional therapeutic agent.

[0581] In a preferred embodiment, the additional therapeutic agent administered in the line of treatment prior to the administration of compound (1), a solid dispersion as described herein, or a pharmaceutical composition as described herein is selected from chemotherapy and systemic anticancer therapeutic agents. In addition to the administration of compound (1), additional therapeutic agents may also be used for cancer treatment.

[0582] In a preferred embodiment, a systemic anticancer therapeutic is administered before or in a previous treatment line of compound (1). In particular, one or more systemic anticancer therapeutics can be administered in a treatment line before compound (1). In other words, it is preferred that compound (1) be used to treat cancer in a treatment line after or after administration of a treatment line containing one or more systemic anticancer therapeutics. These systemic anticancer therapeutics can be administered as a separate treatment line or in combination with each other in the same line. Additionally or alternatively, one or more systemic anticancer agents administered in a treatment line before compound (1) can be used in combination with any other anticancer therapy (whether or not systemic) other than compound (1). This means that compound (1) can be administered as a second-line treatment (in the case of administering only one treatment line containing at least one systemic anticancer therapy before compound (1)) or as a treatment line of another line (in the case of administering more than one treatment line containing at least one systemic anticancer therapy before compound (1)). In this embodiment, compound (1) is preferably administered in a solid dispersion at a dose and dosing regimen as described herein.

[0583] In a preferred embodiment, a systemic anticancer therapeutic is administered before or in a previous line of treatment of a solid dispersion as described herein or a pharmaceutical composition as described herein. In particular, one or more systemic anticancer therapeutics can be administered in a line of treatment before a solid dispersion as described herein or a pharmaceutical composition as described herein. In other words, it is preferred that a solid dispersion as described herein or a pharmaceutical composition as described herein be used to treat cancer in a line of treatment after or after administration of a line of treatment comprising administration of one or more systemic anticancer therapeutics. These systemic anticancer therapeutics can be administered as a separate line of treatment or in combination with each other in the same line. Additionally or alternatively, one or more systemic anticancer agents administered in a line of treatment before a solid dispersion as described herein or a pharmaceutical composition as described herein can be used in combination with any other anticancer therapy (whether or not systemic) other than compound (1). This means that the solid dispersion as described herein or the pharmaceutical composition as described herein can be administered as a second line of treatment (in case only one line of treatment comprising at least one systemic anticancer therapy is administered before the solid dispersion as described herein or the pharmaceutical composition as described herein) or in addition (in case more than one line of treatment comprising at least one systemic anticancer therapy is administered before the solid dispersion as described herein or the pharmaceutical composition as described herein) line of treatment. In this embodiment, the solid dispersion may be as defined herein in any aspect or embodiment. In this embodiment, compound (1) is preferably administered in the doses and dosing regimens described herein.

[0584] In this context, the terms "after" and "afterwards" mean that the additional therapeutic agent (especially a chemotherapeutic agent or a systemic anti-cancer therapeutic agent) is administered in one or more doses in a first-line therapy or a previous line of therapy during a first time period (e.g., over the course of hours, days, or a week or more weeks), and subsequently the compound (1) is administered in one or more doses in a second-line therapy or an additional line of therapy during a second time period (e.g., over the course of hours, days, or a week or more weeks), optionally as a solid dispersion or pharmaceutical composition as described herein, with the proviso that there is no overlap between the first time period and the second time period.

[0585] The systemic anticancer therapeutic 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 anticancer therapeutic or chemotherapeutic agent is not restarted at the same dose (of the single systemic anticancer therapeutic or chemotherapeutic agent).

[0586] The systemic anticancer therapeutic or chemotherapeutic agent is not administered on the same day as the solid dispersion as described herein or the pharmaceutical composition as described herein. In particular, once the solid dispersion as described herein or the pharmaceutical composition as described herein is administered, the administration of the single systemic anticancer therapeutic or chemotherapeutic agent is not restarted at the same dosing (of the single systemic anticancer therapeutic or chemotherapeutic agent).

[0587] The terms "after" and "afterwards" do not require that compound (1), a solid dispersion as described herein, or a pharmaceutical composition as described herein be administered in a line of therapy immediately after or after a line of therapy with one or more systemic anticancer therapeutics. Thus, another line of therapy may be administered between a systemic anticancer therapeutic or chemotherapy and compound (1), optionally formulated in a solid dispersion or pharmaceutical composition as described herein, as long as the systemic anticancer therapy or chemotherapy is administered in a line of therapy prior to compound (1), optionally formulated in a solid dispersion or pharmaceutical composition as described herein. Preferably, the systemically detectable dose of the anticancer therapeutic in the prior anticancer therapy is lower than the therapeutically effective amount established prior to administration of compound (1). In further preferred embodiments, the selected daily dose and daily administration schedule of compound (1), optionally formulated in a solid dispersion or pharmaceutical composition as described herein, may also be selected as a function of one or all pre-treatments with systemic anticancer therapeutics.

[0588] Those skilled in the art will recognize that the terms "before," "before," "after," and "after" are used herein to refer to different and / or separate lines of therapy. In other words, any reference to administering compound (1), solid dispersion, or pharmaceutical composition after or following systemic anticancer therapy or chemotherapy corresponds to a reference to administering compound (1), solid dispersion, or pharmaceutical composition as a second or additional line after administration of systemic anticancer therapy or chemotherapy, even when not explicitly stated.

[0589] As used herein, "second or additional line" and its grammatical variants have the meaning known in the art. In particular, "second or additional line" and its grammatical variants may refer to the administration of compound (1), optionally formulated in a solid dispersion or pharmaceutical composition as described herein, after or following a first-line therapy or previous line of therapy that has failed, ceased to work, has reduced efficacy, developed intolerable side effects, or has only partially been successful, at the discretion of the attending physician, especially wherein the patient is no longer being administered the first-line therapy or previous line of therapy. The expression "second or additional line administration" may be read as "second-line administration or additional line administration".

[0590] As used herein, a "systemic anticancer therapeutic agent" may be present and administered in the form of only a single drug compound or a single active ingredient. The agent may also be present and administered in the form of a combination of two or more drug compounds or active ingredients. The drug compound may include small or large molecules, chemical elements (such as Pt), biological agents, and combinations thereof.

[0591] 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.

[0592] As used herein, a "chemotherapeutic agent" or "chemotherapeutic agent" can be present and administered in the form of only a single pharmaceutical compound or a single active ingredient. The agent can also be present and administered in the form of a combination of two or more pharmaceutical compounds or active ingredients.

[0593] 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.

[0594] Preferably, the chemotherapy is administered systemically, ie, it is systemic chemotherapy.

[0595] In a preferred embodiment, chemotherapy or systemic anticancer therapeutic agents are selected from platinum-based chemotherapy, anti-HER2 antibody-drug conjugates, taxanes, antimetabolites, immunotherapeutics and combinations thereof. Preferably, the term "combination thereof" can include administering two or more members of the list separately at different time intervals or at different time points as different therapy lines, or administering two or more members of the list in combination in the same therapy line. The combination can be before the treatment based on compound (1), for example, including first-line treatment (including platinum-based chemotherapy agents) and subsequent second-line treatment based on ADC (preferably anti-HER2-ADC) or vice versa. The combination can be a planned sequence or can be carried out as the treatment outcome changes.

[0596] Preferred platinum-based chemotherapy includes carboplatin and / or cisplatin. Preferred anti-HER2 antibody-drug conjugates include: trastuzumab derugiperda and / or emtansine-trastuzumab. Preferred taxanes include docetaxel and / or paclitaxel. Preferred antimetabolites include: gemcitabine, pemetrexed and / or tegafur. Preferred immunotherapeutics include: pembrolizumab, durvalumab, atezolizumab, nivolumab, ipilimumab, tremelimumab and / or ramucirumab.

[0597] As used herein, the term "antibody drug conjugate" (also abbreviated herein as "ADC") is well known in the art and describes a group of therapeutic agents that combine the specificity of a tumor-targeting binding agent (e.g., an antibody) with the potency of a highly cytotoxic agent. 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)).

[0598] In particular, as used herein, "anti-HER2 antibody-drug conjugate" refers to an ADC whose tumor-targeting binding agent is an antibody against, targeting and / or binding to HER2 (such as trastuzumab).

[0599] In a preferred embodiment, the chemotherapy or systemic anti-cancer therapeutic is selected from the group consisting of carboplatin, cisplatin, trastuzumab delutec, emtansine-trastuzumab, pemetrexed, docetaxel, paclitaxel, gemcitabine, pembrolizumab, durvalumab, tremelimumab, ramucirumab, atezolizumab, tegafur, nivolumab, and ipilimumab.

[0600] In a further preferred embodiment, the compound (1) as defined below

[0601]

[0602] For the treatment of cancer, wherein compound (1) is administered in the treatment line after the administration of chemotherapy or systemic anticancer therapeutics. Alternatively, in a preferred embodiment, the method for treating a patient with cancer comprises administering compound (1), wherein compound (1) is administered in the treatment line after the administration of chemotherapy or systemic anticancer therapeutics. Preferably, in these embodiments, compound (1) is administered according to the dosage and dosage regimen described above. Additionally or alternatively, in these embodiments, the cancer and / or systemic anticancer therapeutics can be as defined herein. Preferably, the systemic anticancer therapeutic is a specific anti-HER2 systemic anticancer therapeutic, such as an anti-HER2 antibody-drug conjugate.

[0603] In a preferred embodiment, compound (1) can be used to treat cancer at least 21 days after the last day of administration of chemotherapy or systemic anticancer therapy. Alternatively, in a preferred embodiment, the method of treating a patient suffering from cancer comprises administering compound (1), wherein compound (1) is administered at least 21 days after the last day of administration of chemotherapy or systemic anticancer therapy.

[0604] In a further preferred embodiment, a solid dispersion comprising a compound (1) as defined herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier is used to treat cancer, wherein the solid dispersion is administered in the treatment line after the administration of chemotherapy or a systemic anticancer therapeutic. Alternatively, in a preferred embodiment, a method for treating a patient with cancer comprises administering a solid dispersion comprising a compound (1) as defined herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier, wherein the solid dispersion is administered in the treatment line after the administration of chemotherapy or a systemic anticancer therapeutic. Preferably, in these embodiments, the solid dispersion is administered according to the dose and dosage regimen described above. Additionally or alternatively, in these embodiments, the cancer and / or systemic anticancer therapeutic may be as defined herein. Preferably, the systemic anticancer therapeutic is a specific anti-HER2 systemic anticancer therapeutic, such as an anti-HER2 antibody-drug conjugate.

[0605] In a preferred embodiment, the solid dispersion comprising compound (1) as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable dispersion carrier is used to treat cancer at least 21 days after the last day of administration of chemotherapy or systemic anticancer therapy. Alternatively, in a preferred embodiment, the method of treating a patient suffering from cancer comprises administering 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 at least 21 days after the last day of administration of chemotherapy or systemic anticancer therapy.

[0606] Method for preparing solid dispersion

[0607] 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 SVBhujbal et al., Acta Pharmaceutica Sinica B 2021; 11(8): 2505e2536, which is incorporated herein by reference. According to the present invention, the solid dispersion is generally prepared by dissolving the active substance and a pharmaceutically acceptable dispersion carrier in a solvent or solvent mixture to form a feed solution, and then removing the solvent from the feed solution (such as by spray drying) to form a solid dispersion.

[0608] In an embodiment, there is provided a method of preparing a solid dispersion as described herein, the method comprising the steps of:

[0609] 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; and

[0610] b) removing the solvent from the solution or suspension to form a solid dispersion as described herein.

[0611] This method may further comprise the step of drying the solid dispersion obtained in step b).

[0612] In an embodiment, there is provided a method of preparing a solid dispersion as described herein, the method comprising the steps of:

[0613] 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; and

[0614] b) removing the solvent from the solution or suspension to form a solid dispersion as described herein; and

[0615] c) Optionally, drying the solid dispersion obtained in b).

[0616] The solution or suspension according to step a) of any of the above methods may be referred to as feed solution.

[0617] In an embodiment, the removal of the solvent in step b) of the method defined above is performed 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 performed by spray drying.

[0618] The term "spray drying" as used herein is conventional and widely used and generally refers to any method that involves atomizing a solution, suspension, slurry or emulsion containing one or more components of the desired product into droplets by spraying, and then rapidly evaporating the sprayed droplets into a solid powder by hot air at a certain temperature and pressure. Spray drying is a method known to those skilled in the art.

[0619] Spray drying is typically performed by dissolving compound (1) and a pharmaceutically acceptable dispersion carrier in a solvent to prepare a feed solution. The feed solution can be pumped into a drying chamber by 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 a solid dispersion. Typical drying chambers use hot gases such as forced air, nitrogen, nitrogen-enriched air, or argon to dry the particles. The size of the drying chamber can be adjusted to achieve particle characteristics or throughput.

[0620] Although solid dispersions are preferably prepared by conventional spray drying techniques, other techniques known in the art such as melt extrusion, freeze drying, rotary evaporation, coprecipitation, Dispersion technology (KSD), fluidized bed technology, drum drying, vacuum drying or other solvent removal methods.

[0621] The above method for preparing a solid dispersion as described herein may comprise the additional step between steps a) and b) of spraying the solution or suspension obtained in step a) onto an inert excipient core. This method belongs to fluidized bed technology, in particular fluidized bed granulation technology.

[0622] In an embodiment, there is provided a method of preparing a solid dispersion as described herein, the method comprising the steps of:

[0623] (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; and

[0624] (a') spraying the solution or suspension provided in (a) onto an inert excipient core; and

[0625] (b') removing the solvent from the inert excipient core; and

[0626] (c') Optionally, drying the excipient core comprising the solid dispersion obtained in (c').

[0627] 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.

[0628] Any solvent or solvent mixture that at least partially dissolves compound (1) can be used. Examples of suitable solvents that can be used alone 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; and various other solvents such as dichloromethane (DCM), chloroform, tetrahydrofuran, acetonitrile, toluene, and 1,1,1-trichloroethane. In an embodiment, the solvent mentioned in any of the above methods and embodiments thereof is selected from water, alcohols, ketones, esters, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, toluene, 1,1,1-trichloroethane, and mixtures thereof. In an embodiment, the solvent mentioned in any of the above methods and embodiments thereof is selected from the group consisting of alcohols (particularly methanol, ethanol, n-propanol, isopropanol and butanols such as n-butanol, 2-butanol, isobutanol and tert-butanol), ketones (particularly acetone, methyl ethyl ketone and methyl isobutyl ketone), esters (particularly 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 the solvent and water may also be used.

[0629] In embodiments, the solvent is a mixture of dichloromethane (DCM) and methanol (MeOH). The relative amounts of DCM and MeOH in the mixture can vary. Preferably, the mixture comprises at least 25wt% MeOH based on a total weight of 100wt% of the mixture. In embodiments, the mixture comprises an excess of DCM. Still preferably, the weight of DCM:MeOH: weight ratio ranges from 25:75 to 95:5 (w / w). Preferably, the weight of DCM and MeOH: weight ratio is approximately 25:75, 50:50, 70:30, 75:25, 80:20, 85:15 or 90:10. Advantageously, it has been found that a solvent mixture of DCM:MeOH with a ratio of approximately 90:10 (w / w) can achieve higher spray drying throughput.

[0630] In an embodiment, the concentration of solids in the feed solution (particularly a suspension or solution as defined in step a) above) ranges from about 1 wt% to 20 wt% based on 100 wt% of the total weight of the feed solution. Preferably, the concentration of solids in the feed solution ranges from about 5 wt% to 15 wt%, more preferably from about 8 wt% to 12 wt%, based on 100 wt% of the total weight of the feed solution. For example, the concentration of solids in the feed solution is about 8 wt% or 10 wt%, based on 100 wt% of the total weight of the feed solution.

[0631] After the solvent is removed by spray drying, the obtained solid dispersion can optionally be subjected to a drying method 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 from about 30°C to 60°C, more preferably from about 35°C to 45°C. For example, drying is carried out at a temperature of about 40°C. In other embodiments, drying is carried out at ambient pressure and / or under reduced pressure. For example, drying is carried out at ambient pressure or at a pressure of about 900 mbar or lower, more preferably from about 100 mbar or lower and most preferably from about 50 mbar or lower, such as from about 20 mbar or lower. In still other embodiments, drying is carried out over a period of about 6 to 72 hours, preferably from about 12 to 48 hours.

[0632] Another aspect relates to a solid dispersion obtainable by a process comprising the steps of:

[0633] a) providing a mixture of compound (1) as defined above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier, and adding a solvent to obtain a solution or suspension; and

[0634] b) removing the solvent from the solution or suspension to form a solid dispersion, preferably wherein the removal of the solvent in step b) is performed by spray drying.

[0635] Another aspect relates to a solid dispersion obtainable by a process comprising the steps of:

[0636] 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; and

[0637] b) removing the solvent from the solution or suspension to form a solid dispersion as described herein; and

[0638] c) Optionally, drying the solid dispersion obtained in b).

[0639] Another aspect relates to a solid dispersion obtainable by a process comprising the steps of:

[0640] (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; and

[0641] (a') spraying the solution or suspension provided in (a) onto an inert excipient core; and

[0642] (b') removing the solvent from the inert excipient core; and

[0643] (c') Optionally, drying the excipient core comprising the solid dispersion obtained in (c').

[0644] In those aspects relating to a solid dispersion obtainable by a process, the process steps can be performed as described above with reference to the process for preparing a solid dispersion.

[0645] Pharmaceutical compositions (such as tablets, preferably film-coated tablets) can be manufactured according to conventional methods known to the skilled person. In an embodiment, the manufacturing method may include the following steps: 1) preparing a solid dispersion, such as by spray drying as described herein, 2) dry granulating the solid dispersion with one or more suitable excipients, 3) blending the granules with one or more suitable disintegrants and / or one or more lubricants and / or glidants, 4) compressing the blend into tablet cores, and 5) optionally film coating the tablet cores.

[0646] In the present invention, any aspect or embodiment referring to a feature (e.g., compound (1) is amorphous in the solid dispersion) can be combined with any one or more aspects or embodiments referring to another feature or multiple other features (e.g., the weight ratio of compound (1) in the solid dispersion: pharmaceutically acceptable dispersion carrier is 1:1, and / or the pharmaceutically acceptable dispersion carrier is HPMCAS) to provide additional aspects or embodiments of the present invention, for example

[0647] 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 pharmaceutically acceptable dispersion carrier in the solid dispersion is 1:1;

[0648] 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;

[0649] 3) A solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable dispersion carrier, wherein compound (1) is amorphous, the weight ratio of compound (1) to pharmaceutically acceptable dispersion carrier in the solid dispersion is 1:1, and the pharmaceutically acceptable dispersion carrier is HPMCAS.

[0650] The expressions "as defined herein," "as disclosed herein," "as described herein," "as used herein," and variations thereof in each instance thereof include all aspects, embodiments, sub-aspects, sub-embodiments, etc., of the features or terms to which they refer.

[0651] In some embodiments, numerical values are recited, sometimes as part of a range. Even when the term "about" or "approximately" is not explicitly recited, the numerical values should be considered as approximate values.

[0652] Unless defined otherwise, 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.

[0653] The following examples are used to illustrate the present invention in more detail, but are not intended to limit the present invention.

[0654] Example 1 - Preparation of solid dispersions containing compound (1) and different dispersion polymers

[0655] In this example, dispersions containing 25 wt% or 50 wt% of compound (1) and, respectively, 75 wt% or 50 wt% of carrier HPMCAS-M (Shin-Etsu AQOAT), PVP-VA, Solid dispersion of L100 or HPMC HME 15LV.

[0656] 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 comprising compound (1), a dispersion carrier, and a DCM:MeOH (1:1 (w / w)) solvent system (solid content of 8 wt% total solids). The solid dispersion is prepared using a Procept 4M8TRX spray dryer having a 2-fluid nozzle type and a 1.0 mm / 1.0 mm nozzle cap / tip size, an inlet temperature of 85°C-90°C, an outlet temperature of 45°C-50°C, atomization at 3.0 bar, and a drying gas air flow rate of 0.50 m 3 / min, and the solution feed rate was about 15 g / min. Secondary drying of the dispersion was performed in a tray dryer type vacuum dryer in a collecting vessel at 40°C for 22.5 hours.

[0657] The spray drying yield results obtained according to the protocol in the preceding paragraph are summarized in Table 1, where gA represents grams of API (active pharmaceutical ingredient, ie, compound (1)).

[0658] Table 1: Compound (1) and dispersion carriers HPMCAS-M, PVP-VA, Batch size and yield of solid dispersions of L100 or HPMC HME 15LV

[0659]

[0660] Example 2 - Characterization of solid dispersions by X-ray powder diffraction (XRPD) and modulated differential scanning calorimetry (mDSC)

[0661] 2.1 X-ray powder diffraction (XRPD)

[0662] XRPD can be obtained according to the following protocol: XRPD analysis was performed using a Rigaku Miniflexx 600 diffractometer. An amount of approximately 10 mg of compound (1) was mixed with a dispersion carrier (e.g., HPMCAS-M, PVP-VA, Solid dispersion samples of either HPMC® L100 or HPMC® HME 15LV were placed on a zero background sample pan and placed in the autosampler of a Rigaku Miniflex 600. The samples were analyzed using the instrument parameters described in Table 2 below.

[0663] Table 2: Summary of XRPD Collection Parameters

[0664]

[0665] XRPDs obtained using various solid dispersions prepared according to Example 1 and following the protocol in the preceding paragraph are shown in Figures 1 to 4 Comparison of these with the XRPD of crystalline compound (1) in the same figure shows that no crystalline material is present in the sample. Specifically, 25 wt% or 50 wt% of compound (1) with the dispersion carrier HPMCAS-M, PVP-VA, The XRPD of the solid dispersions of L100 or HPMC HME 15LV exhibited a lack of sharp peaks and the presence of an amorphous halo. The lack of sharp diffraction peaks indicated that the solid dispersions were consistent with the amorphous form of compound (1).

[0666] 2.2 Modulated differential scanning calorimetry (mDSC)

[0667] The mDSC characterization of the compound (1) of Example 1 and the dispersion carriers HPMCAS-M, PVP-VA, Solid dispersions of HPMC HME 15LV or HPMC L100 were prepared to determine the glass transition temperature (Tg).

[0668] mDSC can be performed according to the following protocol: mDSC analysis was performed on a Thermoanalytical DSC 2500 with a Thermoanalytical Cryocooling System 90. Samples in an amount of 2-5 mg were placed in a non-sealed pan. A Tzero non-sealed lid was attached to the pan, and the samples were analyzed in modulation mode over a scan range of 20°C to 250°C (unless otherwise specified), with a modulation amplitude of 1°C / min and a ramp rate (heating rate) of 3.0°C / min.

[0669] A summary of the glass transition temperatures (Tg) obtained following the protocol of the previous paragraph is presented in Table 3.

[0670] Table 3: Measured results of compound (1) of Example 1 and HPMCAS-M, PVP-VA, Summary of glass transition temperatures (Tg) of solid dispersions of L100 and HPMC HME15LV

[0671]

[0672] As can be seen from Table 3, all solid dispersions exhibited a single glass transition temperature, indicating a homogeneous dispersion with no signs of phase separation. The glass transition temperature values followed the expected trend with the loading of polymer and compound (1). For L100, the glass transition temperature decreased with increasing drug loading. For 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.

[0673] Example 3 - Production of solid dispersions using different process parameters

[0674] Solid dispersions of compound (1) were tested under different spray drying conditions such as solvent, inlet temperature and spray drying parameters.

[0675] 3.1 Solvent selection

[0676] The solubility of compound (1) was measured in a solvent blend of dichloromethane (DCM):methanol.

[0677] To this end, the following protocol can be followed: a solution of compound (1) is prepared at a high concentration and then diluted with a solvent until compound (1) dissolves or until the concentration drops below 1 wt%. The solubility is determined by visual observation.

[0678] The solubility data for compound (1) obtained according to this protocol are shown in Table 4 below.

[0679] Table 4: Organic solubility screening results of compound (1)

[0680]

[0681] Thus, the 90:10 DCM:methanol solvent blend provides high solubility of compound (1) compared to DCM:methanol solvent blends with higher methanol ratios and has the highest potential flux due to the lower concentration of methanol in the solvent system.

[0682] 3.2 Inlet temperature

[0683] Solid dispersions comprising 50 wt% compound (1) and 50 wt% HPMCAS-M or 25 wt% compound (1) and 75 wt% HPMCHME 15LV were produced on a larger scale using lower inlet temperatures than in Example 1.

[0684] To this end, the following protocol can be followed: a solid dispersion is spray dried from a spray solution composition (solid content of 8 wt% total solids) comprising compound (1) and HPMCAS-M or HPMC HME 15LV) using a DCM:MeOH (1:1 (w / w)) solvent system. The solid dispersion is prepared using a Procept 4M8TRX spray dryer having a 2-fluid nozzle type and a 1.0 mm / 1.0 mm nozzle cap / tip size, an inlet temperature of 55°C-70°C, an outlet temperature of 45°C-50°C, atomization at 3.0 bar, and a drying gas air flow rate of 0.50 m 3 / min, and the solution feed rate was about 10-15 g / min. Secondary drying of the dispersion was performed in a tray dryer type vacuum dryer in a collection vessel at 40°C for about 24 hours.

[0685] The spray drying yields obtained according to this protocol are summarized in Table 5, where gA represents grams of API (active pharmaceutical ingredient, i.e., compound (1)). The mDSC results (non-sealed pan, heating 3°C / min, conditioning 1°C / min) are summarized in Table 6.

[0686] Table 5: Batch size and yield of solid dispersions with larger batch size and lower inlet temperature

[0687] <![CDATA[ Preparations ]]> <![CDATA[ Batch size [gA] ]]> <![CDATA[ Yield [%] / gA ]]> 50wt%: 50wt% Compound (1): HPMCAS-M 12gA 67% (8.0gA) 25wt%:75wt% Compound (1): HPMC HME 15LV 15gA 73 (10.9 gA)

[0688] Table 6: mDSC results

[0689] <![CDATA[ Preparations ]]> <![CDATA[ Tg ]]> Amorphous compounds (1) 156℃ 50wt%: 50wt% Compound (1): HPMCAS-M 115℃ 25wt%:75wt% Compound (1): HPMC HME 15LV 92℃

[0690] 3.3 Spray drying parameters

[0691] The effects of flow rate (=liquid feed rate), dryer outlet temperature, and drying environment on the spray-dried solid dispersion were tested. For the test, a composition containing 50 wt% compound (1) and 50 wt% of the dispersion carrier HPMCAS-M was used. The composition was spray-dried from a spray solution composition (solids content of 10 wt% total solids) containing compound (1) and HPMCAS-M using a 90:10 (w / w) DCM:MeOH solvent ratio. The solid dispersion was produced using an open-loop custom-developed spray dryer SD-90 with an SK 79-16 spray system nozzle. Liquid feed rates between 291 and 317 g / min and outlet temperatures between 35°C and 45°C were tested. The process parameters are summarized in Table 7 below.

[0692] Table 7: Spray drying process parameters

[0693]

[0694] acfm…actual cubic feet per minute

[0695] Yield increases from the first spray batch (3.3-A) to the last spray batch (3.3-C). Batch A has a lower yield due to fixed losses, which reduce the yield percentage for smaller batch sizes relative to larger batches. Yield increases with spraying of each batch due to the reduced effect of carryover and fixed losses from previous batches on subsequent batches.

[0696] 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). The PSD was determined by laser diffraction.

[0697] XRPDs can be obtained according to the following protocol: XRPD analysis was performed using a Rigaku Miniflex 600 diffractometer. Approximately 10 mg amounts of samples 3.3-A, 3.3-B, and 3.3-C were placed on a zero-background sample pan and loaded into the autosampler of the Rigaku Miniflex 600. The samples were analyzed using the instrument parameters described in Table 8 below.

[0698] Table 8: Summary of XRPD Collection Parameters

[0699]

[0700] The XRPDs of the solid dispersions of samples 3.3-A, 3.3-B and 3.3-C obtained according to the protocol in the above paragraph are shown in Figure 5 The absence of sharp peaks and the presence of an amorphous halo were observed, indicating that all samples contained amorphous compound (1).

[0701] For mDSC measurements, the following protocol can be used: 2-5 mg of samples 3.3-A, 3.3-B, and 3.3-C were placed in a Tzero pan. The Tzero non-sealing lid was attached to the pan, and the samples were analyzed in modulation mode over a scan range of 0°C to 250°C, with a modulation amplitude of 1°C / min, a modulation period of 60 seconds, and a ramp rate (heating rate) of 3°C / min. A summary of the glass transition temperatures is given in Table 9.

[0702] Table 9: Summary of Glass Transition Temperatures (Tg) for Samples 3.3-A, 3.3-B, and 3.3-C

[0703] <![CDATA[ Preparations ]]> <![CDATA[ Average midpoint Tg ]]> 3.3-A 116℃ 3.3-B 117℃ 3.3-C 116℃

[0704] Thermograms obtained from the solid dispersions of samples 3.3-A, 3.3-B, and 3.3-C following the protocol in the previous paragraph all showed a single glass transition at approximately 116°C, with no apparent melting or recrystallization events. This indicates that the solid dispersions are single-phase and contain amorphous compound (1).

[0705] The particle size distribution (PSD) of the solid dispersions of samples 3.3-A, 3.3-B, and 3.3-C was measured by laser diffraction of the dry dispersed powders using a Sympatec HELOS laser diffraction system and a RODOS dry powder feeding system. The system can be operated at a dispersion pressure of 3 bar using an R4 lens. The results of this method are summarized in Table 10.

[0706] Table 10: Particle Size Distribution (PSD) of Samples 3.3-A, 3.3-B, and 3.3-C

[0707]

[0708] 3.4 Spray drying parameters

[0709] The spray drying parameters were further tested for larger batch sizes. For the tests, a mixture containing 50 wt% compound (1) and 50 wt% dispersion carrier HPMCAS-M was used. The mixture was spray dried from a spray solution composition (solid loading of 10 wt%) using a solvent ratio of DCM:MeOH of 90:10 (w / w). The solid dispersion was produced using an open-loop custom-developed spray dryer SD-90 with an SK 79-16 spray system nozzle. Feed rates of 300 and 325 g / min and outlet temperatures of 44° C. and 40° C. were tested. The process parameters are summarized in Table 11 below.

[0710] Table 11: Spray drying process parameters

[0711]

[0712] acfm…actual cubic feet per minute

[0713] It is hypothesized that the low yield of sample 3.4-A is due to the presence of fixed losses in the small batch size. Fixed losses are independent of batch size, but account for a higher proportion in smaller batches. Therefore, the larger batch size of sample 3.4-B results in a higher yield. Both samples were characterized using XRPD, mDSC, and PSD. PSD was determined by laser diffraction.

[0714] XRPD scans of samples 3.4-A and 3.4-B were performed as described above in Example 3.3. The diffraction patterns of the solid dispersions of samples 3.4-A and 3.4-B are shown in Figure 6 and showed an amorphous halo without sharp peaks, which indicated that compound (1) was in an amorphous state in both samples.

[0715] For mDSC measurements, 2-5 mg amounts of samples 3.4-A and 3.4-B were placed in a Tzero pan and measured as described above in Example 3.3, except that a scan range of 0°C to 200°C was used for sample 3.4-B. A summary of the glass transition temperatures is given in Table 12 below.

[0716] Table 12: Summary of Glass Transition Temperatures (Tg) for Samples 3.4-A and 3.4-B

[0717] <![CDATA[ Preparations ]]> <![CDATA[ Average midpoint Tg ]]> 3.4-A 114℃ 3.4-B 111℃

[0718] The thermograms of the solid dispersions of samples 3.4-A and 3.4-B exhibited a single glass transition, indicating a single-phase amorphous material, with no distinct peaks in the mDSC thermogram (distinct peaks would indicate crystalline material). The difference in glass transition temperature compared to sample 3.3 may be attributed to different batches of compound (1) used for SDD manufacturing and / or noise in the instrument measurement.

[0719] The mDSC results were consistent with the XRPD results, indicating that the solid dispersion contained compound (1) in an amorphous form by two orthogonal methods.

[0720] The particle size distribution (PSD) of the solid dispersions of samples 3.4-A and 3.4-B was measured by laser diffraction of the dry dispersed powder using a Sympatec HELOS laser diffraction system and a RODOS dry powder feeding system. The system was operated at a dispersion pressure of 3 bar using an R4 lens. The results of this method are summarized in Table 13.

[0721] Table 13: Particle Size Distribution (PSD) of Samples 3.4-A and 3.4-B

[0722]

[0723] Example 4 - Physical Stability of Amorphous Solid Dispersion

[0724] 4.1 Study on stress stability under accelerated stress conditions

[0725] The physical stability of amorphous solid dispersion formulations of compound (1) equivalent to samples 3.3-A, 3.3-B, and 3.3-C obtained in Example 3.3 was evaluated in an accelerated stability study. Each sample was incubated in an open vial under the following conditions: (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 obtained by using a saturated salt solution (sodium bromide - approximately 60% RH at ambient temperature, sodium chloride - 75% RH at 40°C). After two and four weeks, samples were removed for analysis and characterized via XRPD to evaluate potential recrystallization.

[0726] No changes in physical properties were observed. After four weeks under all storage conditions, the diffraction patterns of all amorphous solid dispersions remained consistent with the amorphous form of compound (1).

[0727] 4.2 Study on stress stability under severe stress conditions

[0728] An amorphous solid dispersion (50 wt%:50 wt% Compound (1):HPMCAS-M, prepared, for example, according to the procedure of Example 1) was exposed to 75°C / 79% relative humidity and 80°C / 76% relative humidity in an open container for three weeks. The corresponding XRPDs are shown in Figure 7 After three weeks of exposure to these extreme stress conditions, no morphological changes were observed.

[0729] Example 5 - pH Dependent Solubility and In Vitro Dissolution

[0730] 5.1 Comparative study of solubility in biorelevant media and aqueous media at different pH

[0731] The solubility of amorphous solid dispersions 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) in various aqueous media at room temperature and in biorelevant media at 37° C. was measured. The culture media used for the solubility measurements are listed in Table 14 below.

[0732] Table 14: Media used for solubility determination

[0733]

[0734] *SIF…Simulated intestinal fluid (3.402g KH2PO4 + 448mg NaOH + 49ml ultrapure water). Adjust to pH 6.8 with 1N NaOH, then make up to 50ml with ultrapure water.

[0735] Use the following protocol to prepare samples for solubility measurements:

[0736] ■ Weigh an appropriate amount of crystalline Compound (1) or amorphous solid dispersion of Compound (1) to achieve the desired target concentration.

[0737] ■Add the selected medium to achieve the selected target concentration at room temperature.

[0738] ■ Orbital stirring for 24 h at room temperature or vortex stirring at 37°C in the dark.

[0739] ■ Separate the soluble and insoluble fractions by centrifugation (15 min at 18000 rpm) and filter on a PTFE 0.45 μm membrane. Discard the first portion of about 3.5 mL and then collect 3 aliquots (about 0.5 mL) for analysis.

[0740] ■ Quantification of three aliquots was performed by UPLC-UV-MS and an appropriate calibration curve.

[0741] UPLC-UV-MS method:

[0742] Instrument: Waters Acquity H-Class with PDA and QDa detector

[0743] Column: Waters Acquity BEH C18, 1.7μm, 2.1x 50mm

[0744] Flow rate: 0.65 mL / min

[0745] UV detection: 254nm or 410nm

[0746] Column temperature: 40℃±2℃

[0747] Sample temperature: 23℃±2℃

[0748] Injection volume: 0.4 μL (for concentrations between 1-500 μg / mL) and 9 μL (for concentrations between 0.050-1 μg / mL)

[0749] Mobile phase: Prepare a gradient of solutions A and B as follows

[0750]

[0751] Ionization mode: ESI+ / ESI-

[0752] Source temperature: 600°C

[0753] Capillary voltage: 0.8kV

[0754] Cone voltage: +20V / -20V

[0755] For each solid form and solid dispersion, two standard calibration curves (chromatographic UV peak area versus concentration) were established in DMSO at 254 nm or 410 nm, one between 0.025 or 0.050 μg / mL and 1 μg / mL (injection volume = 9 μL), and the other between 1 μg / mL and 500 μg / mL (injection volume = 0.4 μL). The calibration curves were linear over the entire concentration range studied.

[0756] The results of the solubility assays obtained following the protocol of the previous paragraph are summarized in Table 15 and are presented in Figure 8 middle.

[0757] Table 15: Equilibrium solubility of amorphous solid dispersions of compound (1) and HPMCAS-M (50 wt%:50 wt%) and the crystalline form of compound (1) in various media

[0758]

[0759] It has been found that both crystalline forms of compound (1) are soluble in strongly acidic media, but the solubility decreases at pH ≥ 5. In addition, the solubility of the crystalline form of compound (1) is poor in biologically relevant fasted and fed simulated intestinal fluids (FaSSIF and FeSSIF). It has been found that when compound (1) is formulated as an amorphous solid dispersion using HPMCAS-M, the solubility of compound (1) at pH ≥ 5 and in biologically relevant media is significantly improved. 5.2 In vitro dissolution of amorphous solid dispersions of compound (1) compared to crystalline compound (1)

[0760] The crystalline compound (1) and the polymer selected from HPMCAS-M, HPMC HME 15LV, PVP-VA, Kinetic solubility of various amorphous solid dispersion formulations prepared with L100 polymer.

[0761] For this reason, the following scheme can be used: first the sample is delivered in simulated gastric fluid (SGF), then transferred to simulated intestinal fluid (SIF) via a dilution step. In 0.01N HCl, using 3mg / mL as SGF (first stage), then after 30 minutes in FaSSIF (pH 6.5,+33mM sodium phosphate is used for other buffering capacity), 3x is diluted to target 1mg / mL and tested. " Total drug " and " dissolved drug " are evaluated. By sampling the supernatant of non-sedimentation (saturated) sample after bench centrifugation (approximately 19000rcf, 3-5min), total drug is determined. Total drug includes free drug, bile salt micelle (in SIF) and the colloid species formed by drug-polymer interaction. By filtering the total drug supernatant by 0.22 μm filter to remove large colloid species, determine the drug dissolved. Dissolved drug includes free drug and bile salt micelle.

[0762] Following this protocol, it was observed that while all formulations were completely dissolved in simulated gastric fluid at 3 mg / mL (data not shown), the amorphous solid dispersion formulation showed significantly more dissolved drug in simulated intestinal fluid relative to the crystalline API (see Figure 9 and Figure 10 It should be noted that it is generally expected that for a given polymer, as drug loading increases in an amorphous solid dispersion formulation, performance as assessed by increases in dissolved drug and / or colloid species formation will be unaffected or reduced. However, in the case of compound (1): HPMCAS-MSDD formulations, increases in drug loading resulted in consistent increases in dissolved drug.

[0763] Example 6 - Pharmaceutical Composition

[0764] 6.1 Method for manufacturing tablets comprising a spray-dried solid dispersion of compound (1)

[0765] Unless otherwise stated, film-coated tablets comprising a solid dispersion of Compound (1) were generally prepared according to the following protocol.

[0766] Step 1: Preparation of solid dispersion by spray drying

[0767] Compound (1) and HPMCAS-MG (hydroxypropylmethylcellulose 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 instead of HPMCAS-MG, or in addition to HPMCAS-MG. The solution is spray-dried using a suitable spray drying machine to produce a spray-dried solid dispersion. This spray drying step can be performed as described in detail in Examples 1 and 3. The spray-dried solid dispersion is then further dried in a suitable dryer to remove residual solvent, as described in detail in Examples 1 and 3.

[0768] Step 2: Dry granulation of solid dispersion with excipients

[0769] The dry solid dispersion is mixed with the part of microcrystalline cellulose, mannitol, croscarmellose sodium and colloidal silicon dioxide, and then the mixture of solid dispersion and filler, disintegrant and glidant is pre-blended and screened / de-agglomerated. Sodium stearyl fumarate as lubricant is added to the pre-blend. Then the intragranular blend is granulated using a roller press equipped with a 1.0mm screen. The dry granules screened are collected for subsequent final blending.

[0770] Step 3: Blending

[0771] The granules were blended together with the pre-screened extragranular mixture of croscarmellose sodium and colloidal silicon dioxide in a blender. Sodium stearyl fumarate was added and blended to produce the final blend.

[0772] Step 4: Tablet pressing

[0773] The final blend is then compressed into tablet cores.

[0774] Steps 1 to 4 were performed using the ingredients given in Table 16 below.

[0775] Table 16: Summary of core tablet ingredients

[0776]

[0777] 6.2 Preparation of film-coated tablets containing 15 mg or 60 mg of compound (1)

[0778] Steps 1-4 may be followed by an optional film coating step, which may be performed as outlined below.

[0779] Step 5: Film coating

[0780] Use a blender and a bowl to mix the film coating mixture AMB II yellow is dispersed in water for injection. The cores are coated with the film coating suspension in a suitable coating pan to obtain film coated tablets comprising a solid dispersion of compound (1) and a dispersion carrier. Step 5 is optional. Alternative film coating mixtures may be used instead. AMB II yellow.

[0781] Film-coated tablets containing a spray-dried solid dispersion of compound (1) and HPMCAS MG (hypromellose acetate succinate, where MG refers to a grade that is 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. A summary of the ingredients is given in Table 17 below.

[0782] Table 17: Summary of ingredients of film-coated tablets

[0783]

[0784] The film-coated tablets contained either 15 mg or 60 mg of compound (1). Dichloromethane and methanol were used as solvents for the solid dispersions and nitrogen was used as the drying gas for the solid dispersions, but were removed during the process and therefore did not appear in the final product. In addition, water for injection was used as solvent for the film coating mixture, but was also removed during drying and therefore was not analyzed.

[0785] The film coating mixture used was AMB II Yellow 88A120087. It contains partially hydrolyzed polyvinyl alcohol as a film former, talc as an anti-adhesive agent, sodium lauryl sulfate as a lubricant, and titanium dioxide, monocaprylocaprylin and dicaprylocaprin (GMDCC), and yellow iron oxide as pigments.

[0786] 6.3 Preparation of Tablets Containing 400 mg or 200 mg of Compound (1)

[0787] Uncoated tablet formulations comprising spray-dried solid dispersions of Compound (1) and HPMCAS-M in a ratio of 25:75 wt% or 50:50 wt% were prepared as described in Example 6.1 above. A summary of the ingredients is given in Tables 18 and 19 below.

[0788] Table 18: Summary of ingredients of tablets containing 25 wt% of a spray-dried solid dispersion of compound (1) and 75 wt% of HPMCAS-M

[0789]

[0790] Table 19: Summary of ingredients of tablets containing 50 wt% of a spray-dried solid dispersion of compound (1) and 50 wt% of HPMCAS-M

[0791]

[0792] 6.4 Preparation of Tablets Containing Solid Dispersion of Compound (1) and HPMC

[0793] Solid dispersion formulations with non-enteric polymers such as HPMC are known to gel easily and therefore disintegrate slowly when formulated into tablets. Knowing this potential challenge, an initial feasibility assessment of a solid dispersion comprising 25 wt% of compound (1) and 75 wt% of HPMC HME 15LV spray-dried solid dispersion was completed. A summary of the starting ingredients is given in Table 20 below.

[0794] Table 20: Summary of ingredients of tablets containing 25 wt% of the spray-dried solid dispersion of compound (1) and 75 wt% of HPMC HME 15LV

[0795]

[0796] The formulation described in Table 20 did not disintegrate as expected. A formulation to improve disintegration was formulated by diluting the intragranular blend of Table 20 by 50%, increasing the amount of microcrystalline cellulose and mannitol (24 wt% each), only 2 wt% croscarmellose sodium, and using a tablet structure that utilized both granulation components and extragranular components. The final formulation contained 50 mg of compound (1) in a 700 mg tablet.

[0797] 6.5 Characterization of Core and Film-Coated Tablets by X-Ray Powder Diffraction (XRPD)

[0798] Tablet cores (Example 6.1-C) and film-coated tablets (Example 6.2-C) were studied by XRPD in order to confirm the absence of crystalline compound (1), such as Form III and Form IV. To this end, the following protocol was followed: the sample was prepared by lightly grinding the tablet cores or film-coated tablets in a mortar with a pestle and then uniformly mixing the obtained powder with a spatula. The obtained powder was then measured by XRPD using an X'pert PRO diffractometer and applying the following settings and measurement parameters:

[0799] Table 21: Experimental parameters for XRPD measurements

[0800]

[0801] The core of Example 6.1-C and Example 6.2-C were obtained according to the procedure of the preceding paragraph.

[0802] The XRPD of the film-coated tablet of 6.2-C is shown in Figure 15 and Figure 16Both formulations contain crystalline excipients in combination with an amorphous solid dispersion containing compound (1). The diffraction peaks present in the XRPD are attributed to those excipients. The absence of Form IV is indicated by the absence of a peak at, for example, (5.8 ± 0.2)°, and the absence of Form III is indicated by the absence of a peak at, for example, (6.2 ± 0.2)°.

[0803] Example 7 - Determination of the properties of tablets containing a spray-dried solid dispersion of compound (1)

[0804] 7.1 In vitro dissolution profile in phosphate buffer pH 2.0

[0805] A dissolution test was performed to compare conventional film-coated tablets containing a total of 15 mg of crystalline Compound (1) and film-coated tablets of Example 6.2-B containing 15 mg of Compound (1) together with HPMCAS MG as a spray-dried solid dispersion.

[0806] Comparative film-coated tablets with 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, 4.5 mg of a film-coating mixture (e.g. Yellow 03B120053). For testing, three 5 mg tablets were used.

[0807] For dissolution test comparison, the following protocol can be used: dissolution testing is performed at 37°C in 20 mM phosphate buffer (NaH2PO4) at pH 2.0 using an Agilent 708-DS apparatus 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 totaling 15 mg of compound (1) in crystalline form are suspended in the buffer solution. The dissolution profile is evaluated under the following conditions: shaft rotation 50 rpm, medium volume 900 mL, sample volume 3 mL. The amount of compound (1) in the buffer is measured regularly by HPLC over 60 minutes. The dissolution % is calculated by the following equation (A):

[0808] Dissolved % = ((A smp x C S1 x DF smp ) / (A S1 x LC))x 100(A)

[0809] in:

[0810] A smp is the sample peak area

[0811] C S1 The concentration of standard 1 is 0.017 mg / mL compound (1).

[0812] DF smp is the sample dilution factor, 900mLA S1 is the average peak area response of the first five injections of Standard 1 and is the tablet label declared content; 15 mg.

[0813] The results of the in vitro dissolution comparison of conventional tablets and solid dispersion tablets obtained according to the protocol described in the previous paragraph in pH 2.0 buffer are shown in Figure 11 As can be observed, the tablets containing the solid dispersion showed a faster initial drug release compared to the tablets containing crystalline Compound (1).

[0814] 7.2 In vitro dissolution profile of phosphate buffer containing 0.1% SDS, pH 6.8

[0815] Dissolution tests were conducted to compare conventional film-coated tablets containing a total of 60 mg (3 x 20 mg) of crystalline compound (1), film-coated tablets containing a total of 60 mg (4 x 15 mg) of compound (1) as a spray-dried solid dispersion with HPMCAS MG of Example 6.2-A, and film-coated tablets containing 60 mg of compound (1) as a spray-dried solid dispersion with HPMCAS MG of Example 6.2-C.

[0816] Conventional film-coated tablets with crystalline compound (1) contain 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, 4.5 mg of a film-coating mixture (e.g. Yellow 03B120053). For testing, three 20 mg tablets were used.

[0817] Dissolution testing was performed under the conditions outlined in Table 22.

[0818] Table 22: In vitro dissolution conditions

[0819]

[0820] The % dissolution (same as % dissolved) was calculated as described above in Example 7.1. The results of the in vitro dissolution comparison of the conventional tablets and the solid dispersion tablets in pH 6.8 buffer are shown in Figure 12 As can be seen, the tablets containing the solid dispersion had a similar dissolution profile and showed a faster initial drug release than the tablets containing the crystalline compound (1). In addition, the tablets containing the solid dispersion completely dissolved compared to the tablets containing the crystalline compound (1).

[0821] 7.3 In vitro bioaccessibility determination

[0822] Bioavailability in humans was evaluated using a dynamic in vitro gastrointestinal model that mimics the physiological processes occurring in the human stomach and small intestine tiny-TIM.

[0823] Conventional tablets of crystalline Compound (1) (conventional formulation) and tablets containing a solid dispersion of Compound (1) (SDD formulation) were tested in the tiny-TIM model.

[0824] A conventional formulation includes 100 mg of compound (1), 247.5 mg of silicified microcrystalline cellulose and 105 mg of anhydrous lactose as fillers, 25 mg of hydroxypropyl cellulose as a binder, 15 mg of sodium starch glycolate as a disintegrant, 2.5 mg of colloidal silicon dioxide as a glidant, and 5 mg of magnesium stearate as a lubricant.

[0825] The SDD formulation tested in the tiny-TIM model corresponds to Example 6.2-A, as shown in Table 17.

[0826] Tiny-TIM Research Plan:

[0827] Dietary substrates in the tiny-TIM setup

[0828] To simulate fasting state conditions, a glass of water (240 mL) was administered to the tiny-TIM system. tiny-TIM test system:

[0829] This study was performed in a TNO dynamic multicompartmental in vitro system (tiny-TIM) of the stomach and small intestine.

[0830] The tiny-TIM system consists of a gastric compartment and a small intestinal compartment ( Figure 13This compartment is constructed from two glass units with a flexible silicone inner wall enclosing the lumen material. The space between the inner and outer walls is filled with water. Peristaltic mixing of the chyme is a result of alternating compression and relaxation of the flexible inner wall. The compartments are connected by a peristaltic valve pump that opens and closes continuously, allowing chyme to be transported through the compartments over time. In this way, with the tiny-TIM, the oral dosage form / API is exposed to the locally varying and physiologically relevant conditions of the stomach and small intestine.

[0831] The tiny-TIM system simulates the gastrointestinal transport of intraluminal pH, enzyme activity, bile salt concentration, peristaltic motility, and contents. The set point of the gastrointestinal simulation is controlled and monitored by a specific computer program. The released and dissolved drug molecules are removed from the intestinal lumen by a semipermeable membrane unit connected to the small intestinal compartment. This allows the so-called bioaccessible fraction, i.e., the portion of the drug that can be used for small intestinal absorption, to be assessed.

[0832] Simulated gastrointestinal conditions:

[0833] The experiments in tiny-TIM were carried out under average physiological conditions that simulate the gastrointestinal tract as described for people in a fasting state. These conditions included, among other things, gastric emptying kinetics and pH drop, intestinal transit time, housekeeping waves, gastric and intestinal pH values (Table 23 and Table 24), and the composition and activity of secretory products. Digestible and soluble (low molecular) compounds were continuously removed from the intestinal compartment via a special membrane system.

[0834] Before each experiment was performed, secretions (eg, gastric juice containing enzymes, electrolytes, bile, and pancreatic juice) were freshly prepared, pH electrodes were calibrated, and semipermeable membrane (hollow fiber) units were installed.

[0835] Table 23: Parameters simulated in tiny-TIM, describing average gastrointestinal physiological conditions in healthy young adults in the fasting state

[0836] Tiny-TIM Fasting state <![CDATA[ Gastric compartment tiny-TIM ]]> Intake (total) 270g Water and artificial saliva 240g Gastric priming solution 30g Gastric emptying T1 / 2 20min Guan Jiabo 60min Gastric pH 3.0 to 1.8 within 30 minutes <![CDATA[ Small intestinal compartment tiny-TIM ]]> pH intestinal compartment 6.5 Experiment duration 5 hours

[0837] Table 24: Parameters simulated in tiny-TIM, describing the average gastrointestinal physiological conditions in healthy young adults in the fasting state plus PPI

[0838] Tiny-TIM Fasting state + PPI 1 <![CDATA[ Gastric compartment tiny-TIM ]]> Intake (total) 270g Meal (HFM) Water and artificial saliva 240g Gastric priming solution 30g Gastric emptying T1 / 2 20min Guan Jiabo 60min Gastric pH Continuous 5.0 <![CDATA[ Small intestinal compartment tiny-TIM ]]> pH intestinal compartment 6.5 Experiment duration 5 hours

[0839] Guan Jiabo

[0840] After 60 minutes, a housekeeping wave (HKW) was simulated by the automatic transfer of residual material from the gastric compartment to the intestinal compartment.

[0841] experiment

[0842] The experiments were performed as replicates. All runs were performed under yellow light to prevent degradation of compound (1).

[0843] sampling

[0844] filtrate

[0845] Through a semipermeable membrane unit (Fresenius Filtration of the released and dissolved / solubilized drug molecules from the intestinal lumen (P1dry) allows the assessment of the so-called bioaccessible fraction, i.e. the fraction of the drug available for absorption in the small intestine. Filtrates were collected at the following time intervals: 0-30, 30-60, 60-90, 90-120, 120-180, 180-240 and 240-300 min from the start of the experiment ( Figure 13 , sampling point H). Analysis of these samples yields data on the bioavailability and absorption availability of compound (1). The collection volume for each time period is measured, and subsamples are collected, immediately diluted in an organic solvent, and stored at 2°C-10°C in the dark until analysis.

[0846] Residue

[0847] At the end of each experiment, the residual fractions from the gastric and small intestinal compartments plus the filtration unit were collected, measured, and analyzed. These residual fractions represent the non-bioaccessible fraction. This rinse was combined with the residual fraction samples from the same compartments, the volumes were measured, and the cells were stored protected from light at 2°C-10°C until analysis.

[0848] Storage of backup samples

[0849] After the research report is completed, the backup samples will be stored in the dark at ≤-18℃ for 1 month, after which the samples will be destroyed.

[0850] Sample analysis

[0851] The collected samples were analyzed for the concentration of compound (1).

[0852] Calculation of results

[0853] The absolute amount of API in the sample was calculated by multiplying the assay concentration in the sample by the collected volume (Equation 1).

[0854] A(mg)=C 样品 (μg / mL)·10 -3 ·V 样品 [mL] (1)

[0855] The recovery of the API was determined by the sum of the filtrate fraction from the intestinal compartment and the residual and flush fractions from the gastric and intestinal compartments and all amounts recovered in the drug product. The total recovery was expressed as a % of the amount added (Equation 2).

[0856]

[0857] Bioaccessibility (% uptake) was calculated by expressing the amount of API recovered from the filtrate as a percentage of uptake (Equation 3).

[0858]

[0859] The results of repeated runs are expressed as mean ± SD. For SD, Use the STDEVP function (Equation 4) in

[0860]

[0861] Statistics

[0862] No statistical analysis was performed in this study.

[0863] result

[0864] The bioaccessibility profiles obtained from the above tiny-TIM protocol for conventional (conv.) and SDD formulations under two conditions (fasted state and simulated PPI conditions (i.e., higher gastric pH)) are presented in Figure 14 Under fasting conditions of low gastric pH (3.0 to 1.8 within 30 min), comparable bioaccessibility was observed between conventional tablets and SDD tablets. Under PPI conditions (fasting, gastric pH 5), conventional tablets showed an approximately 5-fold decrease in bioaccessibility, while SDD tablets were unaffected. Therefore, the performance of the SDD formulation is pH-independent compared to conventional tablets. The tablets of Examples 6.2-B and 6.2-C described in Table 17 have been tested under the same tiny-TIM study protocol and show comparable results.

[0865] 7.4 In vivo relative bioavailability clinical studies

[0866] A clinical study was conducted to evaluate the relative bioavailability of compound (1) in two different oral formulations, namely a conventional tablet comprising a crystalline form of compound (1) and a tablet comprising a solid dispersion of compound (1) according to 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) were investigated following oral administration of the solid dispersion formulation in healthy male subjects.

[0867] 7.4.1 Plan

[0868] Age 18 to 45 years (inclusive) and body mass index (BMI) 18.5 to 29.9 kg / m 2Sixteen healthy male subjects (including end values) were enrolled in the 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) of compound (1) from time 0 (t0), corresponding to the time point of drug administration, to time z (tz), corresponding to the last quantifiable time point. 0-tz ) and the maximum concentration in plasma (C max The secondary endpoint was the area under the plasma concentration-time curve (AUC) of compound (1) extrapolated from t0 to infinity. 0-∞ ).

[0869] Therefore, the purpose of this study is to investigate

[0870] Test 1: Relative bioavailability of two different tablet formulations of Compound (1) in crystalline form and as a solid dispersion under fasting conditions,

[0871] Test 2: Relative bioavailability of compound (1) formulated as a solid dispersion under fasting and fed conditions, and

[0872] Test 3: Relative bioavailability of compound (1) formulated as a solid dispersion administered alone and together with rabeprazole under fasting conditions.

[0873] Test product 1: comparative film-coated tablets with crystalline compound (1), containing 5 mg or 20 mg of compound (1) and 64.5 or 49.5 mg, respectively, of silicified microcrystalline cellulose consisting 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, 4.5 mg of a film-coating mixture (e.g. Yellow 03B120053).

[0874] Test product 2: a film-coated tablet as defined in Example 6.2-A, comprising 15 mg of compound (1) as a spray-dried solid dispersion with HPMCAS MG.

[0875] Test Product 3: 20 mg strength proton pump inhibitor rabeprazole gastro-resistant tablets

[0876] The reference treatment (R or TF1) consisted of oral administration of a total dose of 30 mg of crystalline Compound (1) in the form of Test Product 1 (1 tablet, 20 mg each; and 2 tablets, 5 mg each) with 240 mL of water on Day 1 after an overnight fast of at least 10 h.

[0877] Test Treatment 1 (T1 or NF1) consisted of a total dose of 30 mg of Compound (1) as Test Product 2 in solid dispersion form (2 tablets, 15 mg each) administered orally with 240 mL of water on Day 1 after an overnight fast of at least 10 h.

[0878] Test treatment 2 (T2) consisted of a total dose of 30 mg of compound (1) in the form of a solid dispersion as test product 2 (2 tablets, 15 mg each) administered on day 1 after a high-fat, high-calorie breakfast followed by feeding. The total caloric content of the high-fat, high-calorie breakfast was approximately as follows: protein 150 kcal, carbohydrates 250 kcal, and fat 500 to 600 kcal; ingredients: 2 eggs (whole contents) for scrambled eggs 192 kcal; 10 g butter for scrambled eggs 75 kcal, 35 g fried bacon 186 kcal, 2 slices of toasted wheat bread 130 kcal, 15 g butter for spreading toast 113 kcal, 115 g mashed potatoes 132 kcal, 240 mL whole milk (3.5% fat) 156 kcal; total 984 kcal.

[0879] Test treatment 3 (T3) consisted of a total dose of 30 mg of compound (1) in the form of a solid dispersion as test product 2 (2 tablets, 15 mg each) administered under fasting conditions. Four days prior to and on the day of administration of compound (1), subjects in T3 further received test product 3 at a total dose of 200 mg of rabeprazole at a daily dose of 40 mg once daily (2 tablets, 20 mg each).

[0880] For all treatments, blood sampling was performed up to 118 h after administration of compound (1) to analyze the plasma concentration of compound (1). The plasma concentration time curve was evaluated by non-compartmental analysis to calculate the corresponding PK parameters. Relative bioavailability was estimated by the ratio of the geometric means (T1 / R, T2 / T1 and T3 / T1) of the primary and secondary endpoints. In addition, their two-sided 90% confidence intervals (CI) were also provided. This method corresponds to two one-sided t-test procedures, each with a significance level of 5%. Since the main focus was estimation rather than testing, formal hypothesis testing and associated acceptable ranges were not specified. The statistical model was a logarithmic scale analysis of variance (ANOVA) including the effects of sequence, subjects nested within the sequence, period and treatment. CI was 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). No formal interim analysis was planned or performed.

[0881] 7.4.2 Results

[0882] Of the 16 subjects planned for inclusion in the trial, 13 completed the study. For treatment comparisons, the relative bioavailability comparison of T1 versus R was evaluable for 12 subjects, the food effect evaluation (T2 versus T1) was evaluable for 9 subjects, and the drug-drug interaction between compound (1) and rabeprazole (T3 versus T1) was evaluable for 11 subjects. The relative bioavailability comparison showed that the variability of the tablet containing the solid dispersion of compound (1) (T1) was reduced compared to the tablet containing crystalline compound (1) (R). The exposure of T1 increased by an average of 3% (Cmax) and 35% (AUC0-tz) compared to R. The food effect evaluation showed that the exposure under fed conditions (T2) was reduced compared to fasting (T1), with an average decrease of 46% in Cmax and an average decrease of 26% in AUC0-tz. Pretreatment with rabeprazole did not relevantly alter the exposure of the tablet containing the solid dispersion of compound (1) (mean change in Cmax -13% and mean change in AUC0-tz -3%), suggesting that there is no relevant DDI between compound (1) and proton pump inhibitors or other concomitant drugs that increase pH.

[0883] The results of the experiments are discussed in more detail below.

[0884] Trial subjects and compliance with the clinical trial protocol

[0885] A total of 13 subjects received the trial drug and completed the planned observation period. No major protocol violations were reported. Of the 13 healthy male subjects treated in the trial, 12 subjects (92.3%) were white 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); the age range was 25 to 45 years. The mean BMI was 25.49 kg / m 2 (SD=3.03kg / m 2 ); BMI ranged from 20.7 to 29.5 kg / m 2 The treatment groups were similar with respect to demographics and baseline characteristics.

[0886] Twelve subjects received the reference treatment (R), twelve subjects received test treatment 1 (T1), nine subjects received test treatment 2 (T2), and eleven subjects received test treatment 3 (T3) in a randomized manner, with at least a 14-day washout interval separating administration of compound (1) and subsequent treatment.

[0887] The relative bioavailability of formulations NF(T1) and TF1(R) under fasting conditions is given in Table 25. The adjusted geometric mean ratios for the primary and secondary endpoints in subjects treated with T1 / R ranged from 129.1% to 139.3%, with 90% CIs ranging from 87.7% to 221.3% (Table 25). max (geometric coefficient of variation [gCV] 37.3%), AUC 0-tz (gCV 18.8%) and AUC 0-∞ (gCV 19.2%)) compared to the pharmacokinetic (PK) parameters C in subjects receiving treatment R. max (gCV 93.1%), AUC0-tz (gCV 52.7%) and AUC 0-∞ The variability was higher for NF (gCV 52.7%). A trend toward increased NF bioavailability was not consistently observed across all subjects, however a general trend toward increased oral bioavailability was shown.

[0888] Table 25: Adjusted geometric mean and relative bioavailability-pharmacokinetic set of compound (1) NF fasting (T1) compared to TF1 fasting (R) with subject as random effect

[0889]

[0890] The results of the analysis of variance comparing the primary and secondary endpoints of the NF formulation when administered fasting (T1) or after a high-fat, high-calorie meal (T2) are provided in Table 26. The adjusted g mean ratios for the primary and secondary endpoints in subjects treated 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-∞ Lower values indicate a negative food effect.

[0891] Table 26: Adjusted geometric mean and relative bioavailability-pharmacokinetic set of compound (1) NF fed (T2) compared to NF fasted (T1) with subject as random effect

[0892] Abbreviations: adj = adjusted, gCV = geometric coefficient of variation, gmean = geometric mean, gSE = geometric standard error, ind = individual

[0893] The results of the analysis of variance comparing the primary and secondary endpoints of the NF formulation when administered fasting in the absence (T1) and presence of co-administration with the proton pump inhibitor (PPI) rabeprazole (T3) are presented in Table 27. The adjusted geometric mean (g mean) ratios of the endpoints in subjects undergoing treatment T3 / T1 ranged from 87.0% to 97.1%, with 90% CIs ranging from 66.8% to 113.2% (Table 27). The PK parameters and profiles for T1 and T3 were similar, but in the presence of rabeprazole, the PK levels in the plasma were significantly increased from the (last) dose to the (last) dose.

[0894] The time of maximum measured concentration of the analyte (t max In summary, the results indicate that rabeprazole does not interfere with the PK of compound (1).

[0895] Table 27: Adjusted geometric mean and relative bioavailability-pharmacokinetic set of compound (1) NF fasted + rabeprazole (T3) compared to NF fasted (T1) with subject as random effect

[0896]

[0897] Abbreviations: adj = adjusted, gCV = geometric coefficient of variation, gmean = geometric mean, gSE = geometric standard error, ind = individual

[0898] Example 8 - Open-label, Phase I, dose-escalation trial with dose confirmation and expansion of compound (1) as monotherapy in patients with advanced or metastatic solid tumors with HER2 aberrations

[0899] 8.1 Plan:

[0900] This is a first-in-human dose-escalation and expansion trial to determine the maximum tolerated dose (MTD) of compound (1) as monotherapy in patients with HER2 aberration-positive advanced and / or metastatic solid tumors and to explore its safety, pharmacokinetics, pharmacodynamics and preliminary signs of efficacy.

[0901] The dose escalation portion of the trial (also known as Phase Ia) includes successive cohorts of patients treated with increasing doses of compound (1).

[0902] 8.1.1 Purpose:

[0903] The objectives of the dose-escalation portion of the trial are to:

[0904] - To investigate the safety, tolerability and pharmacokinetics (PK) of increasing doses of compound (1) administered orally twice daily (BID) or once daily (QD) as monotherapy in patients with advanced and / or metastatic solid tumors with HER2 aberrations;

[0905] - For each study regimen, determine the MTD and / or recommended Phase II dose (RP2D) of orally administered compound (1) monotherapy.

[0906] 8.1.2 End point:

[0907] The primary endpoints of the dose-escalation portion of the trial are:

[0908] -MTD, defined as the highest dose at which the risk of a true dose-limiting toxicity (DLT) rate equal to or greater than 33% during the MTD evaluation period for any study regimen is less than 25%;

[0909] - Number of patients with DLT during the MTD evaluation period.

[0910] The MTD evaluation period was defined as the first 21 days of treatment (cycle 1).

[0911] Secondary endpoints for the dose-escalation portion of the trial are:

[0912] - the number of patients who experienced a DLT during the entire treatment period;

[0913] - The following PK parameters of Compound (1) after administration of the first dose and multiple doses of the compound on Day 1 and Day 15 (if applicable):

[0914] ·C max : Maximum measured concentration of compound (1) in plasma;

[0915] AUC 0-t2 : Area under the concentration-time curve of compound (1) in plasma.

[0916] If evaluable and applicable, the following additional endpoints were evaluated:

[0917] - Number of patients experiencing adverse events (AEs) during the on-treatment period

[0918] - Objective response (OR), defined as the best overall response of complete response (CR) or partial response (PR), where the best overall response is determined according to RECIST version 1.1 as assessed by the investigator from the first treatment administration until the earliest of the following:

[0919] disease progression, death, or last evaluable tumor assessment before initiation of subsequent anticancer therapy, loss to follow-up, or withdrawal of consent.

[0920] - Disease control (DC), defined as a best overall response of complete response (CR) or partial response (PR) or stable disease (SD), where best overall response was defined according to RECIST version 1.1 as assessed by the investigator from the earliest of: disease progression, death, or the last evaluable tumor assessment before the start of subsequent anticancer therapy, loss to follow-up, or withdrawal of consent.

[0921] - Duration of objective response (DoR), defined as the time from the first documented complete response (CR) or partial response (PR) until the earliest of disease progression or death in patients with an objective response.

[0922] - Duration of disease control (DoDC), defined as the time from the first treatment administration until the earliest of disease progression or death in patients with disease control.

[0923] - PK parameters calculated for compound (1) as monotherapy, if data permit

[0924] include:

[0925] AUC 0-∞ : The area under the plasma concentration-time curve for the time interval extrapolated from 0 to infinity.

[0926] AUC 0-tz : From 0 to the last measurement time point (t z ) is the area under the plasma concentration-time curve during the time interval.

[0927] ·C min : Minimum measurable plasma concentration in plasma.

[0928] ·t 1 / 2 : Terminal half-life of the analyte in plasma.

[0929] ·t max : Administered to plasma C max time.

[0930] 8.1.3 Dose Escalation

[0931] Dose escalation is carried out according to open label design.Based on Bayesian logistic regression model (BLRM) in combination with excessive control, the data obtained from the trial determine MTD estimated value (Neuenschwander B, Branson M, Gsponer T.Critical aspects of the Bayesian approach to phase I cancer trials.Stat Med.2008; 27: 2420-2439). When patient information is available, considering the updated DLT information from two arrangement schemes, BLRM estimates MTD by observing the estimated value of the probability of DLT in the MTD evaluation phase for each dose level in the update trial. At any time in the trial, it is not allowed to escalate the dose to the dosage that does not meet the excessive control escalation (EWOC) principle. Dose escalation is limited to the maximum increment relative to previous dose 100%. Dose escalation and cohort size are guided by BLRM based on the decision made by the dose escalation committee (DEC)

[0932] The dose escalation portion of the trial tested two different dosing schedules for compound (1) within a BLRM with a covariate that distinguishes BID from QD. In the BID schedule, the duration of the cycle was 3 weeks, and compound (1) was administered twice a day (BID), while in the QD schedule, the duration of the cycle was 3 weeks, and compound (1) was administered once a day (QD). The trial began with the BID schedule; after a dose level higher than the predicted human therapeutic dose was determined to be safe by DEC, the QD schedule was initiated. When this QD cohort was deemed safe, the next BID dose level was opened.

[0933] After this time, all dose level cohorts will alternate between BID and QD schedules, with the BID dose cohort filling first and then transitioning to the equivalent QD cohort.

[0934] Successive cohorts of patients receive escalating doses of compound (1) until the MTD is reached. After all patients in the cohort have experienced a DLT or have been observed for 21 days without experiencing a DLT, the BLRM is updated with newly accumulated data from both schedules. The overdose risk for each dose is then calculated, and dose escalation is allowed for all doses that meet the EWOC criteria. For each dosing schedule, based on the model and additional information (PK, pharmacodynamics, patient profile, information from other dosing schedules), the DEC members reach a joint decision on the next dose level to be studied and the size of the next cohort. The pre-specified dose levels are provisional, and the DEC may explore intermediate levels if deemed necessary.

[0935] All cohorts included at least 3 patients. If only two patients in a cohort were evaluable (i.e., one patient was not evaluable) and neither patient experienced a DLT during the MTD evaluation period, dose escalation could be performed based on these two patients.

[0936] If a DLT is observed in the first two consecutive patients at a dose level not previously tested, further enrollment in that cohort is stopped. The BLRM is updated to confirm that the dose level still meets the EWOC principles. Based on this information, the DEC evaluates whether the next patient should be enrolled at the same dose level or at a lower dose level.

[0937] After meeting the criteria for MTD, no further dose escalation is performed. Additional patients can be included to confirm this MTD estimate, i.e., to confirm that the EWOC criteria are still met. DEC can declare any dose that meets the EWOC criteria as RP2D, regardless of the MTD estimate. RP2D will not exceed MTD. Any DLT that occurs after the MTD evaluation period is considered for evaluating the RP2D of compound (1). If no DLT is observed, DEC can decide to declare RP2D based on PK / pharmacodynamic endpoints and overall safety profile. The MTD and RP2D of the two arrangements are defined separately.

[0938] At the end of dose escalation, when the selected dose or doses for dose expansion are announced, if agreed by the DEC, dose escalation remains open in the participating sites to enroll patients who are not eligible for dose expansion but receive the selected dose or doses.

[0939] One or more RP2Ds for compound (1) administered BID and QD as a monotherapy are defined based on DLT / MTD (if reached), all safety data, and (if data permit) PK, PK / PD collected during the study. If DLT or MTD is not reached, one or more RP2Ds are determined based on safety data (i.e., overall tolerability and incidence of severe toxicity) and (if data permit) PK, PK / PD. The RP2Ds in the two schedules (BID, QD) do not need to be the same. A BLRM is run based on all DLT-like events during the entire treatment period and on extended data for the treatment schedule only to further guide the selection of one or more RP2Ds.

[0940] An RP2D can be defined and the dose expansion portion initiated before reaching the MTD / ending dose escalation.

[0941] Patients can continue to receive treatment with compound (1) until progressive disease (PD) according to RECIST or until another reason for discontinuation of treatment occurs (see Section 3.3.4).

[0942] 8.1.4 Dosage:

[0943] The starting doses for the dose-escalation portion of the trial are:

[0944] -BID schedule: 15 mg twice daily

[0945] -QD schedule: 60 mg once daily (if not otherwise recommended by DEC). Dose escalation steps will be determined by DEC.

[0946] The predicted human dose of compound (1) was derived from a quantitative pharmacokinetic / tumor growth inhibition (PK / TGI) model. This preclinical mathematical model was built using input data from internal in vitro and in vivo data from efficacy experiments with PC-9YVMA xenografts. The model was trained using plasma exposure and tumor growth inhibition data from mice. The predicted human PK parameters were used to predict the human plasma profile in the preclinical PK / TGI model. In this case, the PK / TGI model was used to identify the required dose in humans necessary to achieve a TGI>100%. This was predicted at 40 mg BID.

[0947] 8.1.5 Patients

[0948] In the dose escalation portion, patients with advanced, unresectable and / or metastatic solid tumors who are refractory to or inadequate for standard therapy for their disease are eligible. Patients must also have exhausted treatment options known to prolong their disease survival. These patients should also show a confirmed positive diagnosis of HER2 aberration (described as overexpression according to standard diagnostic criteria, or as gene amplification according to standard diagnostic criteria, or as non-synonymous somatic mutation or gene rearrangement for HER2 or NRG1).

[0949] Based on the interim dose levels and escalation schedule, approximately 66 patients are planned to be enrolled in the dose escalation portion of the trial (approximately 36 patients for the BID dosing schedule and approximately 30 patients for the QD dosing schedule). The total number of patients will depend on the number of dose escalations necessary.

[0950] All patients, including those eligible for study entry based on local testing, must provide a tumor sample to confirm their HER2 status.

[0951] Main inclusion criteria:

[0952] - Patients diagnosed with advanced, unresectable and / or metastatic non-hematologic malignancies with at least one measurable or evaluable lesion. Patients must show the presence of at least one measurable lesion according to RECIST 1.1.

[0953] - Eastern Cooperative Oncology Group score of 0 or 1.

[0954] - Availability and willingness to provide a sample of archival formalin-fixed paraffin-embedded (FFPE) tumor tissue material for confirmation of the patient's HER2 status.

[0955] - Patients must be willing and able to comply with blood sampling and tumor biopsy requests for PK, pharmacodynamic (PD), and biomarker analyses.

[0956] - Adequacy of organ function as measured routinely in the art.

[0957] - Recovery from any prior therapy-related toxicity to ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the start of treatment (except alopecia, stable sensory neuropathy, and hypothyroidism (in patients on thyroid replacement therapy), which must be ≤ CTCAE Grade 2).

[0958] - Life expectancy at the start of treatment is at least 12 weeks in the investigator's opinion.

[0959] - Be at least 18 years of age at the time of informed consent, or over the legal age of consent in countries where the legal age of consent is greater than 18.

[0960] - Before entering the trial, according to the International Committee for Harmonization - Good Clinical Practice

[0961] Sign and date the written informed consent in accordance with ICH-GCP and local regulations.

[0962] - Male or female patients. Women of childbearing potential (WOCBP) and men of childbearing potential must be ready and able to use highly effective birth control methods per ICH M3(R2) that have a low failure rate of less than 1% per year when used consistently and correctly.

[0963] - Patients with documented HER2 gene aberrations, including overexpression by immunohistochemistry (IHC), gene copy number gain by in situ hybridization (ISH), nonsynonymous gene mutations, or gene fusions for either the HER2 or NRG-1 genes.

[0964] - Patients for whom conventional treatment has failed, for whom there is no therapy with proven efficacy, or who are ineligible for established treatment options. Patients must have exhausted available treatment options known to prolong survival with their disease or be inappropriate candidates for these available treatment options.

[0965] Patients may discontinue trial treatment or withdraw consent for overall trial participation.

[0966] 8.1.6 Compounds:

[0967] 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.

[0968] 8.1.7 Evaluation of efficacy:

[0969] Tumor assessments should include a computed tomography (CT) scan (or PET / CT) of the chest, abdomen / pelvis, and brain MRI at screening. If clinically indicated, imaging of any other known or suspected sites of disease (e.g., bone) should be performed using appropriate modalities (CT scan, MRI, PET / CT, or bone scan). The same radiological procedures must be used throughout the trial. Assessments will be performed by the investigator at screening (≤28 days before treatment initiation), every two cycles (6 weeks ± 5 days), at the end-of-treatment (EOT) visit (if not performed within the first 3 weeks), and at the investigator's discretion, with copies available to the sponsor or designee. Whenever possible, the assessment schedule should not be altered; however, if treatment is interrupted or delayed, changes to the tumor assessment schedule are permitted to align with clinical assessments. Additional unscheduled tumor assessments may be performed at the investigator's discretion. If a patient discontinues trial drug for reasons other than progression, tumor assessments will continue according to RECIST v1.1 until progression (or until one of the following occurs: death, loss to follow-up, or end of trial).

[0970] The patient's clinical status was assessed locally by each investigator. Any worsening of clinical status must be attributed to underlying tumor progression and not to comorbidities or concomitant medications. In the event of tumor-related clinical worsening, every effort should be made to confirm disease progression with imaging tests.

[0971] According to RECIST 1.1 version, tumor response was evaluated (Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al. New response evaluation criteria in solid tumors:revised RECIST guideline (1.1 version). Eur J Cancer. 2009; 45: 228-247). RECIST 1.1 was used for a) systemic assessment (classical RECIST 1.1) and b) tumor assessment in non-CNS areas. The assessment performed by researchers and / or local radiologists according to classic RECIST 1.1 was the basis for individual patients to continue or discontinue the trial (also considering safety). Systemic RECIST assessment was not performed in the dose escalation portion.

[0972] Baseline imaging should include imaging of all known or suspected sites of disease using appropriate methods. The investigator (or designee) should record target and non-target lesions in the case report form (CRF or eCRF). Lesions in previously irradiated areas should not be considered measurable lesions at baseline unless they occurred after irradiation. Each reported lesion must be characterized using the same assessment method and the same imaging technique at each subsequent time point throughout treatment and follow-up.

[0973] 8.1.8 Safety Assessment:

[0974] Physical examinations, including measurements of height (at screening only) and weight, were performed at screening, on Day 1 of each treatment cycle, at the end-of-treatment visit, and at the 30-day safety follow-up visit. However, a brief physical examination (focused on specific ailments, as determined by the investigator) was performed on Day 1 of Cycle 1 (if the previous physical examination was performed within 72 hours of treatment initiation) and Day 15 of Cycle 1.

[0975] A comprehensive physical examination is performed to assess general health and also serves as a clinical tumor assessment and may include, but is not limited to, a cardiopulmonary examination, regional lymph node examination, abdominal examination, and assessment of mental and neurological status. Additional symptoms not reported during the previous examination should be clarified. Whenever possible, this examination should be performed by the same investigator.

[0976] A limited physical examination should include a cardiopulmonary examination, clinical tumor assessment, regional lymph node examination, and abdominal examination.

[0977] 8.1.9 Assessment of Adverse Events:

[0978] An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and not necessarily causally related to the treatment.

[0979] Thus, an AE can be any unfavorable and unexpected sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product.

[0980] A serious adverse event (SAE) was defined as any AE that met at least one of the following criteria:

[0981] - results in death,

[0982] - Life-threatening, which means an event in which the patient is at risk of death at the time of the event; it does not mean an event that, assuming it were more severe, could result in death,

[0983] - Requires hospitalization or prolongs existing hospitalization

[0984] - causes persistent or substantial disability or incapacity,

[0985] - is a congenital anomaly / birth defect,

[0986] - A condition considered serious for any other reason is a medically important event that, based on appropriate medical judgment, could endanger the patient and might require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. Examples of such events are intensive treatment in the emergency department or at home for allergic bronchospasm, blood dyscrasias, or convulsions that does not result in hospitalization or the development of dependence or abuse.

[0987] 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 pattern of response, temporal relationship, dechallenge or rechallenge, and confounding factors such as concomitant medications, concomitant illnesses, and relevant medical history.

[0988] Grounds that may indicate a reasonable possibility of a causal relationship could be:

[0989] -The event is consistent with the known pharmacology of the drug.

[0990] - The event is known to be caused by or attributable to the drug class.

[0991] - The plausible timing of the event relative to the timing of drug exposure.

[0992] - Evidence of recurrence of the event when the drug is reintroduced.

[0993] - There is no medically reasonable alternative etiology that could explain the event (e.g., pre-existing or concomitant disease, or concomitant medication).

[0994] -The event is typically drug-related and uncommon in the general population not exposed to the drug (eg, Stevens-Johnson syndrome).

[0995] - An indication of dose-response (ie, if the dose is increased, the magnitude of the effect is greater, if the dose is decreased, the magnitude of the effect is smaller).

[0996] Reasons that may indicate that there is no reasonable possibility of a causal relationship could be:

[0997] -The plausible timing of the event relative to drug exposure is unclear (e.g., pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of drug administration; allergic reaction occurring weeks after discontinuation of the relevant drug).

[0998] - The event persists despite discontinuation of the drug, taking into account the pharmacological properties of the compound (e.g., after 5 half-lives).

[0999] -Of note, this criterion may not apply to events whose time course is prolonged despite removal of the original trigger.

[1000] - Additional reasons to the above, such as alternative explanations (e.g., situations where other drugs or underlying conditions appear more likely to explain the observed event than the drug in question).

[1001] - The event disappears even though trial drug treatment is continued or maintained.

[1002] The investigator maintained and saved detailed records of all AEs in the patient files.

[1003] 8.1.10 Pharmacokinetic Assessment:

[1004] The pharmacokinetic (PK) characteristics of compound (1) were studied after the first dose and after repeated doses. Standard PK parameters were calculated if the data allowed and if scientifically justified.

[1005] Individual concentration data and their calculated PK parameters were tabulated and displayed graphically. Statistical analysis was performed. In the event of protocol violations related to PK evaluation (decided no later than in the report planning meeting), or in the event of PK being unevaluable (as revealed during data analysis based on the criteria specified below), the patient's PK data was flagged and excluded from the statistical analysis. The reasons for excluding the patient's data were recorded in the clinical trial report (CTR).

[1006] If data permit, estimate the pharmacokinetic parameters C of compound (1) max (,ss),AUC 0-t 2(,ss) dose proportionality to determine whether steady state is achieved. If deemed necessary, further PK parameters can be used in these assessments.

[1007] A preliminary PK analysis may be performed as needed by the DEC. A final primary analysis is performed at the end of the dose-escalation phase before proceeding to the dose-expansion phase. In contrast to...

Claims

1. A solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof as defined below 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) or a pharmaceutically acceptable salt thereof is administered in a daily dose of at least 30 mg.

2. A solid dispersion comprising compound (1) or a pharmaceutically acceptable salt thereof as defined below 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) or a pharmaceutically acceptable salt thereof is administered after administration of a systemic anticancer therapeutic agent.

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

4. The solid dispersion for use according to any one of claims 1 to 3, wherein the polymer is enteric or non-enteric.

5. The solid dispersion for use according to any one of claims 1 to 4, wherein the pharmaceutically acceptable dispersion carrier is a polymer selected from the group consisting of hydroxypropyl methylcellulose and its esters, polyvinyl pyrrolidone and its copolymers, and polymethacrylate and its copolymers.

6. The solid dispersion for use according to claim 5, wherein the hydroxypropyl methylcellulose and its esters are selected from hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose, in particular hot melt extrusion grade hydroxypropyl methylcellulose.

7. The solid dispersion for use according to any one of claims 5 or 6, wherein the polyvinyl pyrrolidone and its copolymer is a polyvinyl pyrrolidone vinyl acetate copolymer.

8. The solid dispersion for use according to any one of claims 5 to 7, wherein the polymethacrylate and copolymer thereof is a methyl methacrylate copolymer.

9. The solid dispersion for use according to any one of claims 1 to 8, wherein the pharmaceutically acceptable dispersion carrier is a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, polyvinyl pyrrolidone vinyl acetate copolymer, methacrylic acid methyl methacrylate copolymer and hot melt extrusion grade hydroxypropyl methylcellulose.

10. The solid dispersion for use according to any one of claims 1 to 9, wherein compound (1) is amorphous.

11. The solid dispersion for use according to any one of claims 1 to 10, wherein 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.

12. The solid dispersion for use according to any one of claims 1 to 11, wherein 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.

13. The solid dispersion for use according to any one of claims 1 to 12, wherein the weight ratio of compound (1) to the pharmaceutically acceptable dispersion carrier in the solid dispersion is 1:1 to 1:

3.

14. The solid dispersion for use according to any one of claims 1 to 13, characterized in that when subjected to a temperature in the range of 20°C to 30°C and with a wavelength of or An X-ray powder diffraction pattern having no diffraction peak at a 2θ angle equal to or lower than 40.0° when measured using Cu-Kα radiation.

15. A pharmaceutical composition comprising the solid dispersion according to any one of claims 1 to 14 and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is for use in a method for preventing and / or treating cancer, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in a daily dose of at least 30 mg.

16. The pharmaceutical composition for use according to claim 15, wherein the one or more pharmaceutically acceptable excipients are selected from fillers, disintegrants, glidants, lubricants and coating agents.

17. The pharmaceutical composition for use according to claim 16, wherein the filler is selected from microcrystalline cellulose, mannitol and mixtures thereof.

18. The pharmaceutical composition for use according to claim 16 or 17, wherein the disintegrant is selected from the group consisting of cross-linked carboxymethylcellulose sodium, sodium bicarbonate, crospovidone, sodium starch glycolate, and mixtures thereof.

19. The pharmaceutical composition for use according to any one of claims 16 to 18, wherein the glidant is colloidal silicon dioxide.

20. The pharmaceutical composition for use according to any one of claims 16 to 19, wherein the lubricant is selected from stearyl fumarate, magnesium stearate and mixtures thereof.

21. The pharmaceutical composition for use according to any one of claims 15 to 20, wherein the one or more pharmaceutically acceptable excipients comprise mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and sodium stearyl fumarate.

22. The pharmaceutical composition for use according to any one of claims 15 to 21, wherein based on 100 wt% of the total weight of the pharmaceutical composition, the pharmaceutical composition comprises: - in the range of 25 wt% to 65 wt% of the solid dispersion according to any one of claims 1 to 14; and / or - in the range of 25 wt% to 65 wt% of one or more fillers; and / or - in the range of 4 wt% to 10 wt% of a disintegrant; and / or - in the range of 1 wt% to 2 wt% of a glidant; and / or - in the range of 1 wt% to 2 wt% of a lubricant; and / or - Optionally in the range of 2 wt% to 5 wt% of a coating agent.

23. The pharmaceutical composition for use according to any one of claims 15 to 22, wherein the composition is in the form of tablets, granules or capsules.

24. The pharmaceutical composition for use according to any one of claims 15 to 23, comprising: (i) a tablet core comprising the solid dispersion according to any one of claims 1 to 14, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate; and (ii) Film coating.

25. The pharmaceutical composition for use according to any one of claims 15 to 24, characterized in that the pharmaceutical composition is or An X-ray powder diffraction pattern having no diffraction peak at a 2θ angle equal to or lower than 6.5° when measured using Cu-Kα radiation.

26. The solid dispersion for use according to any one of claims 1 to 14 or the pharmaceutical composition for use according to any one of claims 15 to 25, wherein the cancer is selected from brain cancer, breast cancer, bile duct 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.

27. The solid dispersion or pharmaceutical composition for use according to claims 1 to 26, wherein the cancer is HER2 overexpressing, HER2 amplified and / or HER2 mutated.

28. The solid dispersion or pharmaceutical composition for use according to claims 1 to 27, wherein the cancer is advanced cancer or metastatic cancer.

29. The solid dispersion or pharmaceutical composition for use according to claims 1 to 28, wherein the solid dispersion or the pharmaceutical composition is administered to a fasting subject.

30. The solid dispersion or pharmaceutical composition for use according to claims 1 to 28, wherein the solid dispersion or the pharmaceutical composition is administered in combination with an agent that increases gastric pH.

31. The solid dispersion or pharmaceutical composition for use according to claim 30, wherein the agent that increases gastric pH is selected from the group consisting of proton pump inhibitors, antacids and antihistamines.

32. The solid dispersion or pharmaceutical composition for use according to claims 1 to 31, wherein compound (1) is administered in a daily dose of 30 mg to 600 mg.

33. The solid dispersion or pharmaceutical composition for use according to claims 1 to 32, 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.

34. The solid dispersion or pharmaceutical composition for use according to claims 1 to 33, wherein compound (1) is administered once or twice a day.

35. The solid dispersion or pharmaceutical composition for use according to claims 1 to 34, wherein compound (1) is administered once a day 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.

36. The solid dispersion or pharmaceutical composition for use according to claims 1 to 35, wherein compound (1) is administered twice a day 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.

37. The solid dispersion or pharmaceutical composition for use according to any one of claims 2 to 36, wherein the systemic anti-cancer therapeutic is selected from platinum-based chemotherapy, anti-HER2 antibody-drug conjugates, and combinations thereof.

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