Administration of KRAS inhibitors to treat cancer

Abstract

To provide methods of administering a KRAS G12C inhibitor, namely AMG-510, to a cancer subject.SOLUTION: A method comprises the steps for administering AMG-510 in a daily dose of 180 mg, 360 mg, 720 mg, or 960 mg.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 847,862, filed May 14, 2019, and U.S. Provisional Patent Application No. 62 / 867,747, filed June 27, 2019, both of which are incorporated by reference herein in their entirety and for all purposes as if fully set forth herein. [Background technology]

[0002] KRAS gene mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and bile duct cancer. KRAS mutations are also observed in approximately 25% of NSCLC patients, and some studies have shown that KRAS mutations are a negative prognostic factor for NSCLC patients. Recently, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations have been found to confer resistance to epidermal growth factor receptor (EGFR)-targeted therapy in colorectal cancer; therefore, KRAS mutation status can provide important information before prescribing TKI therapy. Overall, there is a need for novel medical treatments for patients with pancreatic cancer, lung adenocarcinoma, or colorectal cancer, especially those diagnosed with such cancers characterized by KRAS mutations and those who have progressed after chemotherapy. Oncogenic KRAS mutations at residues G12, G13, and Q61 represent the most common RAS mutations found in solid malignancies. Recently, we have developed a covalent small molecule inhibitor of KRAS that reacts with a mutant cysteine ​​adjacent to the switch II pocket (SIIP) and locks KRAS in its inactive GDP-bound state. G12C It has been demonstrated that it is possible to target

[0003] KRAS is the most frequently mutated oncogene in human cancers and encodes a signaling protein important within tumors. G12CThe mutants possess a cysteine ​​that has been exploited to design covalent inhibitors with promising preclinical activity. We have optimized a series of inhibitors with novel binding interactions and significantly enhanced potency and selectivity. These efforts represent the first KRAS inhibitors in clinical development. G12C This led to the discovery of the inhibitor AMG 510 (also referred to herein as Compound A). Preclinical AMG 510 treatment regressed KRAS p.G12C tumors and significantly improved the antitumor efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 led to a proinflammatory tumor microenvironment, which, in combination with immune checkpoint inhibition, resulted in durable cures. Cured mice repelled the growth of isogenic KRAS p.G12D tumors, suggesting adaptive immunity against a shared antigen. AMG 510 showed preliminary evidence of clinical antitumor activity in the first dosing cohort and represents a potentially transformative treatment for patients lacking effective treatments.

[0004] The KRAS oncoprotein is a GTPase that is an essential mediator of intracellular signaling pathways involved in tumor cell proliferation and survival. In normal cells, KRAS functions as a molecular switch, alternating between an inactive GDP-bound state and an active GTP-bound state. The transition between these states is facilitated by guanine nucleotide exchange factors (GEFs), which load GTP and activate KRAS, and GTP hydrolysis, catalyzed by GTPase-activating proteins (GAPs), which inactivate KRAS. GTP binding to KRAS promotes the binding of effectors that trigger a signaling pathway involving the RAF-MEK-ERK (MAPK) pathway. Somatic activating mutations in KRAS are a hallmark of cancer and prevent GAP assembly, thereby stabilizing effector binding and enhancing KRAS signaling. Patients with KRAS-mutant tumors have significantly poorer outcomes and a worse prognosis. Although clinically approved inhibitors of several MAPK pathway proteins (e.g., MEK, BRAF, EGFR) exist for a subset of tumor types, to date, no clinical molecules are selective for KRAS mutant tumors. Furthermore, several MAPK pathway-targeted therapies are contraindicated for the treatment of KRAS mutant tumors due to a lack of clinical efficacy. Furthermore, non-tumor or non-mutation selective therapies may introduce target toxicity due to inhibition of MAPK signaling in normal cells. This may limit the usefulness of combining such agents with standard therapies or immunotherapy. Thus, there is a significant unmet need for the development of tumor-selective therapies that do not spare normal cells.

[0005] KRAS p.G12C is present in approximately 13% of lung adenocarcinomas, 3% of colorectal cancers, and 2% of other solid tumors. G12C The mutant cysteine ​​in KRAS is adjacent to a pocket (P2) present in the inactive GDP-bound form of KRAS. The proximity of P2 to the mutant cysteine ​​has led to an extensive search for covalent inhibitors of KRAS. G12CAraxes Pharma's initially reported electrophilic screen led to the eventual identification of ARS-1620, which demonstrated in vivo efficacy in a preclinical KRAS p.G12C model. Araxes Pharma's ARS-1620 was a milestone for proof-of-concept, mutant-selective KRAS inhibition, positioning it as a tool compound for preclinical studies. The inventors have identified previously untapped KRAS inhibitors to substantially enhance efficacy and selectivity. G12C Intensive electrophilic screening and structure-based design have identified a series of novel acrylamide-based molecules that exploit the surface grooves of KRAS, the first to reach human clinical trials. G12C This led to the discovery of an inhibitor, AMG 510 (see www.clinicaltrials.gov NCT03600883). Herein, we demonstrate the overwhelming clinical activity of AMG 510. Summary of the Invention [Means for solving the problem]

[0006] Provided herein are methods of treating cancer, comprising administering to a subject in need thereof Compound A in a daily dose of 180 mg, 360 mg, 720 mg, or 960 mg. In various cases, the daily dose is 180 mg. In various cases, the daily dose is 360 mg. In various cases, the daily dose is 720 mg. In various cases, the daily dose is 960 mg. The dose can be administered orally. The dose can be administered as a single daily dose. In various cases, the subject is administered Compound A for at least 1 month, or at least 3 months, or at least 6 months.

[0007] The subject to whom the compound is administered in the method disclosed herein has cancer.Cancer can be solid tumor.Cancer can be KRAS G12C mutation cancer.In some cases, cancer is non-small cell lung cancer.In some cases, cancer is colorectal cancer.In some cases, cancer is prostate cancer.In various cases, the subject has received at least one (for example, at least two) other systemic cancer therapies before starting therapy with compound A.

[0008] In various cases, subjects administered Compound A for at least one month do not exhibit any Grade 3 or Grade 4 adverse events associated with Compound A therapy. In some cases, subjects do not exhibit any Grade 3 or Grade 4 adverse events associated with Compound A therapy after at least three months of administration of Compound A. In various cases, subjects exhibit at least stable disease after administration of Compound A. In some cases, subjects exhibit at least a partial response after administration of Compound A.

[0009] In various cases, the methods disclosed herein may further include administering a chemotherapeutic agent. In some cases, the chemotherapeutic agent includes an anti-PD1 antibody. In some cases, the anti-PD1 antibody is pembrolizumab (Keytruda), nivolumab, AUNP-12, AMG 404, or pidilizumab. In some cases, the chemotherapeutic agent includes an anti-PDL1 antibody. In some cases, the anti-PDL1 antibody is atezolizumab, MPDL3280A, avelumab, or durvalumab. In some cases, the chemotherapeutic agent includes a MEK inhibitor. In some cases, the MEK inhibitor is trametinib, pimasertib, PD-325901, MEK162, TAK-733, GDC-0973, or AZD8330. In some cases, the chemotherapeutic agent includes a CDK4 / 6 inhibitor. In some cases, the CDK4 / 6 inhibitor includes abemaciclib or palbociclib. In some cases, the chemotherapy agent comprises a PI3K inhibitor. In some cases, the PI3K inhibitor comprises AMG 511 or bupallisib.

[0010] In the figures below, PD refers to progressive disease, PR refers to partial response, and SD refers to stable disease. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 shows CA 19-9 and CAE biomarker responses in patients with metastatic colon adenocarcinoma who received Compound A at a total daily dose of 360 mg. [Figure 2] FIG. 1 shows non-small cell lung cancer (NSCLC) tumor response, as measured by radiographic scans every 6 weeks, in nine NSCLC patients receiving Compound A at various total daily doses as indicated. [Figure 3] FIG. 1 shows response and duration of treatment in NSCLC patients receiving Compound A at the following total daily doses: 960 mg for the top four bars; 720 mg for the next six bars; 360 mg for the next bar; and 180 mg for the bottom three bars. [Figure 4] FIG. 1 shows colorectal cancer (CRC) and other solid tumor response, as measured by X-ray scans every 6 weeks, in CRC and other solid tumor cancer patients receiving Compound A at various total daily doses as indicated. [Figure 5] FIG. 1 shows response and duration of treatment in patients with CRC and other solid tumors receiving Compound A at the following total daily doses: 960 mg for the top two bars; 720 mg for the next five bars; 360 mg for the next 11 bars; and 180 mg for the bottom three bars. [Figure 6] 1 shows the efficacy of Compound A in patients with NSCLC as percent change from baseline in tumor burden. A superscript "a" on the right bar indicates that the patient had a complete response to the target lesion. A superscript "b" indicates that one patient discontinued the study due to clinical PD before the first evaluation in the absence of available post-baseline tumor burden data and is therefore not shown on the graph. [Figure 7]Figure 1 shows the efficacy of Compound A in response time to treatment and duration of treatment in patients with NSCLC. Each bar on the 23 graphs represents a given patient (N=23) who received a specific total daily dose (counting from the top of the graph: bars 1-3 (180 mg), bar 4 (360 mg), bars 5-10 (720 mg), and bars 11-23 (960 mg)). The superscript "a" on bar 9 indicates that this graph was plotted based on data received from the participating sites at the data cutoff. Duration of treatment data from this patient (bar 9) may be missing from the study site. [Figure 8] FIG. 1 shows progression-free survival probability for CRC patients. [Figure 9] FIG. 1 shows overall survival probability for CRC patients. [Figure 10] FIG. 1 shows the percent change from baseline in tumor burden for CRC patients. [Figure 11] FIG. 1 shows the percent change from baseline in tumor burden over time for CRC patients across all four doses of Compound A (total daily doses of 180 mg, 360 mg, 720 mg, and 960 mg). [Figure 12] Figure 12 shows the percent change from baseline in tumor burden over time for a subset of CRC patients shown in Figure 11. In particular, Figure 12 shows patients who received a daily dose of 180 mg of Compound A. [Figure 13] Figure 13 shows the percent change from baseline in tumor burden over time for a subset of CRC patients shown in Figure 11. In particular, Figure 13 shows patients who received a daily dose of 360 mg of Compound A. [Figure 14] Figure 14 shows the percent change from baseline in tumor burden over time for a subset of CRC patients shown in Figure 11. In particular, Figure 14 shows patients who received a daily dose of 720 mg of Compound A. [Figure 15] Figure 15 shows the percent change from baseline in tumor burden over time for a subset of CRC patients shown in Figure 11. In particular, Figure 15 shows patients who received a daily dose of 960 mg of Compound A. [Figure 16] FIG. 1 shows response times and treatment over time for CRC patients administered Compound A (counting from the top of the graph: bars 1-4 (720 mg), bars 5-14 (360 mg), and bars 15-17 (180 mg)). [Figure 17] FIG. 1 shows response times and treatment over time for CRC patients administered 960 mg of Compound A daily. [Figure 18]

[0023] Figure 1 shows the efficacy of Compound A as percent change from baseline in tumor burden in patients with advanced solid tumors other than NSCLC and CRC. A superscript "a" above a given bar indicated that the patient had an unconfirmed PR. A superscript "b" above three given bars marked PR indicates that one patient with appendiceal cancer received a total daily dose of 720 mg of Compound A, and two other patients (endometrial cancer and melanoma) each received a total daily dose of 960 mg of Compound A. [Figure 19] FIG. 1 shows response times and treatment over time for patients with advanced solid tumors other than NSCLC and CRC. DETAILED DESCRIPTION OF THE INVENTION

[0012] Provided herein is a method of treating cancer by administering to a subject in need thereof Compound A. Compound A is: [ka] In some cases, Compound A is referred to as AMG 510. Compound A may be presented as a pharmaceutically acceptable isotopically labeled version, in which one or more atoms have the same atomic number, but are usually replaced by an atom having an atomic mass or mass number different from that found in nature. Examples of isotopes that can be incorporated into Compound A include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13N, 15 N, 15 O. 17 O. 18 O and 18 F. These radiolabeled compounds may be useful to help determine or measure the effectiveness of Compound A, for example, by characterizing its site or mode of action, or its binding affinity to a pharmacologically important site of action. Certain isotopically labeled versions of Compound A, for example, those incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. The radioisotope tritium, i.e. 3 H and carbon-14, i.e. 14 C is particularly useful for this purpose in view of its ease of incorporation and ready means of detection.

[0013] Deuterium, i.e. 2 Substitution with heavier isotopes such as H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances.

[0014] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of structure (I) can be prepared by conventional techniques generally known to those skilled in the art. Isotopically labeled compounds disclosed herein can be prepared by conventional techniques generally known to those skilled in the art.

[0015] Compound A can exist as stereoisomers (i.e., isomers that differ only in the spatial arrangement of atoms), including optical isomers and conformational isomers (or conformers). Unless otherwise specified, Compound A referred to herein includes both pure individual stereoisomer preparations and enriched preparations thereof, as well as racemic mixtures of such stereoisomers, and all stereoisomers of individual diastereomers and enantiomers that can be separated according to methods known to those skilled in the art. In some cases, Compound A is 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one: [ka] It is provided as.

[0016] Compound A can exist as atropisomers, which are conformational stereoisomers that arise when rotation around a single bond in a molecule is hindered or significantly slowed as a result of steric interactions with other parts of the molecule. Unless otherwise indicated, Compound A, when referred to herein, includes all atropisomers, both as pure individual atropisomer preparations, enriched preparations, or unspecified mixtures. If the rotation barrier around a single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of isomeric species may be possible. Separation and isolation of isomeric species is appropriately indicated by the well-known and commonly accepted symbols "M" or "P." In some cases, compound A is 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one and the M-atropisomer: [ka] In some cases, compound A is 4-((R)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one and the M-atropisomer: [ka] It is provided as.

[0017] In some cases, compound A is 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one and the P-atropisomer: [ka] In some cases, compound A is 4-((R)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one and the P-atropisomer: [ka] In some cases, Compound A is provided as a mixture of the above isomers.

[0018] Compound A can be prepared as previously reported, for example, generally as disclosed in WO 2018 / 119183 or as disclosed in WO 2018 / 217651.

[0019] Compound A may be provided as its pharmaceutically acceptable salt. Contemplated examples of pharmaceutically acceptable salts include base addition salts and acid addition salts. Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines. Pharmaceutically acceptable salts of compounds can also be prepared with pharmaceutically acceptable cations. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali, alkaline earth, ammonium, and quaternary ammonium cations. Carbonate or bicarbonate salts are also possible. Examples of metals used as cations include sodium, potassium, magnesium, ammonium, calcium, or iron. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine. Pharmaceutically acceptable acid addition salts include salts of inorganic or organic acids. Examples of suitable acid salts include hydrochlorides, formates, acetates, citrates, salicylates, nitrates, and phosphates.Other suitable pharmaceutically acceptable salts are well known to those skilled in the art, such as with formic acid, acetic acid, citric acid, oxalic acid, tartaric acid or mandelic acid, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; with organic carboxylic acids, sulfonic acids, sulfoacids or phosphoacids or N-substituted sulfamic acids, such as acetic acid, trifluoroacetic acid (TFA), propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid. and with amino acids such as glutamic acid or aspartic acid, and also with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane 1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene 2-sulfonic acid, naphthalene 1,5-disulfonic acid, 2- or 3-phosphoglyceric acid, glucose 6-phosphate, N-cyclohexylsulfamic acid (with the formation of cyclamates) or with other acid organic compounds such as ascorbic acid.

[0020] Compound A can be combined with a pharmaceutically acceptable excipient to provide a pharmaceutical formulation (also interchangeably referred to as a composition). The excipient may be a diluent or carrier. A suitable pharmaceutical formulation can be determined by one skilled in the art depending on the route of administration and the desired dosage. See, for example, Remington's Pharmaceutical Sciences, 1435-712 (18th ed., Mack Publishing Co., Easton, Pennsylvania, 1990). The formulation can affect the physical state, stability, in vivo release rate, and in vivo excretion rate of the administered drug. Depending on the route of administration, the suitable dose can be calculated according to body weight, body surface area, or organ size. Further refinement of the calculations required to determine the appropriate therapeutic dose can be routinely performed by one skilled in the art without undue experimentation, especially in light of the dosage information and assays disclosed herein and pharmacokinetic data obtained from animal or human clinical trials. The phrases "pharmaceutically acceptable" or "pharmacologically acceptable" refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans. As used herein, "pharmaceutically acceptable" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such excipients for pharmaceutically active substances is well known in the art. Except as otherwise incompatible with the therapeutic compositions, their use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.In an exemplary embodiment, the formulation comprises corn syrup solids, high oleic safflower oil, coconut oil, soybean oil, L-leucine, tricalcium phosphate, L-tyrosine, L-proline, L-lysine acetate, DATEM (emulsifier), L-glutamine, L-valine, dipotassium phosphate, L-isoleucine, L-arginine, L-alanine, glycine, L-asparagine monohydrate, L-serine, potassium citrate, L-threonine, sodium citrate, magnesium chloride, L-histidine, L-methionine, ascorbic acid, calcium carbonate, L-glutamic acid, L-cystine dihydrate. Hydrochloride, L-tryptophan, L-aspartic acid, choline chloride, taurine, m-inositol, ferrous sulfate, ascorbyl palmitate, zinc sulfate, L-carnitine, alpha tocopheryl acetate, sodium chloride, niacinamide, mixed tocopherols, calcium pantothenate, copper sulfate, thiamine chloride hydrochloride, vitamin A palmitate, manganese sulfate, riboflavin, pyridoxine hydrochloride, folic acid, beta-carotene, potassium iodide, phylloquinone, biotin, sodium selenate, chromium chloride, sodium molybdate, vitamin D3, and cyanocobalamin.

[0021] Pharmaceutical compositions containing Compound A can be manufactured in a conventional manner, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen.

[0022] For oral administration, suitable compositions can be easily formulated by combining Compound A with pharmaceutically acceptable excipients, such as carriers well known in the art. Such excipients and carriers allow Compound A to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding Compound A with solid excipients, optionally grinding the resulting mixture, and processing the granular mixture, after adding suitable auxiliary agents as needed, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. Disintegrants can be added as needed. Pharmaceutically acceptable ingredients are well known for various types of formulations and can be, for example, binders (e.g., natural or synthetic polymers), lubricants, surfactants, sweeteners and flavorings, coating agents, preservatives, dyes, thickeners, adjuvants, antibacterial agents, antioxidants, and carriers for various formulation types.

[0023] When a therapeutically effective amount of Compound A is administered orally, the composition is typically in the form of a solid (e.g., a tablet, capsule, pill, powder, or lozenge) or a liquid formulation (e.g., an aqueous suspension, solution, elixir, or syrup). In one embodiment, a therapeutically effective amount (e.g., 960 mg) of Compound A is administered orally in the form of a single tablet or multiple tablets (e.g., 8 x 120 mg tablets).

[0024] When administered in tablet form, the composition may further contain a functional solid and / or functional solid carrier such as gelatin or an adjuvant. The tablet, capsule, and powder may contain about 1 to about 95% Compound A, preferably about 15 to about 90% Compound A.

[0025] When administered in the form of a solution or suspension, a functional liquid and / or functional liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. Liquid formulations of the composition can further comprise saline solution, sugar alcohol solution, dextrose or other sugar solution, or glycol. When administered in the form of a solution or suspension, the composition can contain about 0.5 to about 90% by weight of Compound A, and preferably about 1 to about 50% of Compound A. In one contemplated embodiment, the liquid carrier is non-aqueous or substantially non-aqueous. For administration in liquid form, the composition can be supplied as a rapidly dissolving solid formulation that is dissolved or suspended immediately prior to administration.

[0026] When a therapeutically effective amount of Compound A is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, taking into due consideration pH, isotonicity, stability, and the like, is within the skill of the art. Preferred compositions for intravenous, cutaneous, or subcutaneous injection typically contain an isotonic vehicle in addition to Compound A. Such compositions can be prepared for administration as a solution of the free base or a pharmacologically acceptable salt in water appropriately mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, as well as in oils. Under ordinary conditions of storage and use, these preparations can optionally contain preservatives to prevent the growth of microorganisms.

[0027] Injectable compositions can include sterile aqueous solutions, suspensions, or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions, suspensions, or dispersions. In all embodiments, the form must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi, optionally by the inclusion of a preservative. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In one contemplated embodiment, the carrier is non-aqueous or substantially non-aqueous. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size of the compound in the case of dispersion embodiments, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many embodiments, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0028] Sterile injectable solutions are prepared by incorporating the required amount of Compound A in a suitable solvent with various other ingredients as listed above, followed by filtration sterilization. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other desired ingredients from those listed above. In sterile powder embodiments for preparing sterile injectable solutions, the preferred preparation method is vacuum drying and freeze-drying, which produces a powder of the active ingredient and any additional desired ingredients from a previously sterile-filtered solution thereof.

[0029] Slow-release or sustained-release formulations can also be prepared to control the release of Compound A in contact with body fluids in the gastrointestinal tract and provide a substantially constant and effective level of the active compound in plasma. For example, release can be controlled by one or more of dissolution, diffusion, and ion exchange. Furthermore, the slow-release approach can enhance absorption via saturable or controlled pathways in the gastrointestinal tract. For example, the compound can be embedded in a polymer matrix of a biodegradable polymer, a water-soluble polymer, or a mixture of both, and optionally a suitable surfactant for this purpose. In this context, embedding can refer to the incorporation of microparticles into a polymer matrix. Controlled-release formulations can also be obtained by encapsulating dispersed microparticles or emulsified microdroplets via known dispersion or emulsion coating techniques.

[0030] For administration by inhalation, Compound A is conveniently delivered in the form of an aerosol spray dispensed from a pressurized pack or nebulizer using a suitable propellant. In pressurized aerosol embodiments, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges, for example of gelatin, for use in an inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0031] Compound A can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Injectable preparations can be provided in unit dosage form (e.g., ampoules or multi-dose containers) with added preservatives. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending agents, stabilizers, and / or dispersing agents.

[0032] Pharmaceutical preparations for parenteral administration include aqueous solutions of Compound A in water-soluble form. Furthermore, suspensions can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of Compound A and allow for the preparation of highly concentrated solutions. Alternatively, the compositions of the present invention can be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use.

[0033] Compound A can also be formulated into rectal compositions such as suppositories or retention enemas (e.g., containing a conventional suppository base). In addition to the formulations described above, Compound A can also be formulated as a depot preparation. Such long-acting preparations can be administered by infusion (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, Compound A can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or can be formulated as a sparingly soluble derivative, e.g., a sparingly soluble salt.

[0034] In particular, Compound A can be administered orally, bucally, or sublingually in the form of tablets containing excipients such as starch or lactose, or in capsules or ovoids alone or in a mixture with excipients, or in the form of elixirs or suspensions containing flavorings or colorings. Such liquid preparations can be prepared using pharmaceutically acceptable additives such as suspending agents. Compound A can also be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the compound is best used in the form of a sterile aqueous solution, which may contain other substances, such as salts or sugar alcohols such as mannitol or glucose, to make the solution isotonic with blood.

[0035] For veterinary use, Compound A is administered in an appropriately tolerated formulation in accordance with normal veterinary practice. A veterinarian can readily determine the most appropriate dosing regimen and route of administration for a particular animal.

[0036] In some embodiments, all necessary components for the treatment of a KRAS-associated disorder with Compound A, either alone or in combination with another drug or intervention conventionally used for the treatment of such a disease, can be packaged into a kit. Specifically, the present disclosure provides kits for use in the therapeutic intervention of a disease, comprising Compound A and a packaged set of drugs, including buffers and other ingredients for preparing a deliverable form of the drug, and / or equipment for delivering such drugs, and / or any drugs to be used in combination therapy with Compound A, and / or instructions for treating the disease packaged with the drugs. The instructions can be fixed on any tangible medium, such as printed paper or a computer-readable magnetic or optical medium, or can be instructions that reference a remote computer data source, such as a World Wide Web page accessible via the Internet.

[0037] A "therapeutically effective amount" refers to an amount effective to treat, prevent progression of, or alleviate existing symptoms of the subject being treated. Determining an effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, a "therapeutically effective dose" refers to the amount of Compound A that produces the desired effect. For example, a therapeutically effective amount of Compound A reduces KRAS activity by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% compared to a control.

[0038] A "therapeutically effective amount" refers to an amount effective to treat, prevent progression of, or alleviate existing symptoms of the subject being treated. Determining an effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, a "therapeutically effective dose" refers to that amount of a compound that produces a desired effect. For example, in a preferred embodiment, a therapeutically effective amount of a compound disclosed herein reduces KRAS activity by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% compared to a control.

[0039] While individual needs vary, determination of optimal ranges for effective amounts of the compounds is within the skill of the art. For administration to humans in the curative or prophylactic treatment of the conditions and disorders identified herein, for example, a typical dosage of a compound of the present disclosure can be from about 0.05 mg / kg / day to about 50 mg / kg / day, e.g., at least 0.05 mg / kg, at least 0.08 mg / kg, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, or at least 0.5 mg / kg, and preferably not more than 50 mg / kg, not more than 40 mg / kg, not more than 30 mg / kg, not more than 20 mg / kg, or not more than 10 mg / kg, which can be, for example, about 2.5 mg / day (0.5 mg / kg x 5 kg) to about 5000 mg / day (50 mg / kg x 100 kg). For example, the dosage of the compound may be from about 0.1 mg / kg / day to about 50 mg / kg / day, from about 0.05 mg / kg / day to about 10 mg / kg / day, from about 0.05 mg / kg / day to about 5 mg / kg / day, from about 0.05 mg / kg / day to about 3 mg / kg / day, from about 0.07 mg / kg / day to about 3 mg / kg / day, from about 0.09 mg / kg / day to about 3 mg / kg / day, from about 0.05 mg / kg / day to about 0.1 mg / kg / day, from about 0.1 mg / kg / day to about 1 mg / kg / day. g / kg / day, about 1 mg / kg / day to about 10 mg / kg / day, about 1 mg / kg / day to about 5 mg / kg / day, about 1 mg / kg / day to about 3 mg / kg / day, about 1 mg / kg / day to about 960 mg / day, about 20 mg / day to about 720 mg / day, about 3 mg / day to about 500 mg / day, about 5 mg / day to about 360 mg / day, about 10 mg / day to about 100 mg / day, about 3 mg / day to about 10 mg / day, or about 100 mg / day to about 250 mg / day. Such doses can be administered in a single dose or divided into multiple doses.

[0040] In certain embodiments, Compound A is orally administered once daily to a subject in need thereof. In some cases, the subject is administered a total daily dose of 180 mg, 360 mg, 720 mg, or 960 mg. In some cases, the total daily dose of Compound A administered is 180 mg. In some cases, the total daily dose of Compound A administered is 360 mg. In some cases, the total daily dose of Compound A administered is 720 mg. In some cases, the total daily dose of Compound A administered is 960 mg. In some cases, Compound A is administered in divided daily doses two, three, four, five, or six times daily.

[0041] Embodiment In a first embodiment, the disclosure provides a method of treating cancer, comprising administering to a subject in need thereof Compound A at a daily dose of 180 mg, 360 mg, 720 mg, or 960 mg, wherein Compound A has the following structure: [ka] The present invention provides a method having the following structure:

[0042] In a second embodiment, the disclosure relates to the method of embodiment 1, wherein compound A has the structure: [ka] The present invention provides a method having the following structure:

[0043] In a third embodiment, the present disclosure relates to the method of embodiment 1, wherein compound A has the structure: [ka] The present invention provides a method having the following structure:

[0044] In a fourth embodiment, the present disclosure provides a method according to any one of embodiments 1, 2 or 3, wherein the cancer is a solid tumor.

[0045] In a fifth embodiment, the present disclosure provides a method according to any one of embodiments 1, 2, 3 or 4, wherein the cancer is non-small cell lung cancer.

[0046] In a sixth embodiment, the present disclosure provides a method according to any one of embodiments 1 to 4, wherein the cancer is colorectal cancer.

[0047] In a seventh embodiment, the present disclosure provides a method according to any one of embodiments 1 to 4, wherein the cancer is pancreatic cancer.

[0048] In an eighth embodiment, the present disclosure provides a method according to any one of embodiments 1 to 7, wherein the cancer is a KRAS G12C mutant cancer.

[0049] In a ninth embodiment, the present disclosure provides a method according to any one of embodiments 1 to 8, wherein the subject has received at least one other systemic cancer therapy prior to initiation of Compound A therapy.

[0050] In a tenth embodiment, the present disclosure provides a method according to embodiment 9, wherein the subject has received at least two other systemic cancer therapies.

[0051] In an eleventh embodiment, the present disclosure provides a method according to any one of embodiments 1 to 9, wherein compound A is administered orally.

[0052] In a twelfth embodiment, the present disclosure provides a method according to any one of embodiments 1 to 11, wherein Compound A is administered as a single daily dose.

[0053] In a thirteenth embodiment, the present disclosure provides a method according to any one of embodiments 1 to 12, wherein the subject does not exhibit any Grade 3 or Grade 4 adverse events associated with Compound A therapy after administration of Compound A for at least one month.

[0054] In a fourteenth embodiment, the present disclosure provides a method according to embodiment thirteen, wherein the subject does not exhibit any grade 3 or grade 4 adverse events associated with Compound A therapy after administration of Compound A for at least three months.

[0055] In a fifteenth embodiment, the present disclosure provides a method according to any one of embodiments 1 to 14, wherein the dose of Compound A is 180 mg.

[0056] In a sixteenth embodiment, the present disclosure provides a method according to any one of embodiments 1 to 14, wherein the dose of Compound A is 360 mg.

[0057] In a seventeenth embodiment, the present disclosure provides a method according to any one of embodiments 1 to 14, wherein the dose of Compound A is 720 mg.

[0058] In an eighteenth embodiment, the present disclosure provides a method according to any one of embodiments 1 to 14, wherein the dose of Compound A is 960 mg.

[0059] In a nineteenth embodiment, the present disclosure provides a method according to any one of embodiments 1 to 18, wherein the subject is administered Compound A for at least one month.

[0060] In a twentieth embodiment, the present disclosure provides a method according to any one of embodiments 1 to 18, wherein the subject is administered Compound A for at least 3 months.

[0061] In a twenty-first embodiment, the present disclosure provides a method according to any one of embodiments 1 to 18, wherein the subject is administered Compound A for at least 6 months.

[0062] In a twenty-second embodiment, the present disclosure provides a method according to any one of embodiments 19 to 21, wherein the subject exhibits at least stable disease (SD).

[0063] In a 23rd embodiment, the present disclosure provides a method according to embodiment 22, wherein the subject exhibits at least a partial response (PR).

[0064] In a twenty-fourth embodiment, the present disclosure provides a method according to any one of embodiments 1 to 23, wherein the subject does not exhibit dose-limiting toxicity (DLT).

[0065] In a twenty-fifth embodiment, the present disclosure provides the method of any one of embodiments 1 to 24, wherein compound A is as the M atropisomer.

[0066] In a twenty-sixth embodiment, the present disclosure provides a method according to any one of embodiments 1 to 25, further comprising administering to the subject a chemotherapeutic agent.

[0067] In a 27th embodiment, the present disclosure provides a method according to embodiment 24, wherein the chemotherapeutic agent comprises an anti-PD1 antibody.

[0068] In a 28th embodiment, the present disclosure provides the method of embodiment 25, wherein the anti-PD1 antibody is pembrolizumab (Keytruda), nivolumab, AUNP-12, AMG 404, or pidilizumab.

[0069] In a 29th embodiment, the present disclosure provides a method according to embodiment 26, wherein the chemotherapeutic agent comprises an anti-PDL1 antibody.

[0070] In a 30th embodiment, the present disclosure provides the method of embodiment 29, wherein the anti-PDL1 antibody is atezolizumab, MPDL3280A, abemaciclib, or durvalumab.

[0071] In a thirty-first embodiment, the present disclosure provides the method of embodiment 26, wherein the chemotherapeutic agent comprises a MEK inhibitor.

[0072] In a thirty-second embodiment, the present disclosure provides the method of embodiment 31, wherein the MEK inhibitor is trametinib, pimasertib, PD-325901, MEK162, TAK-733, GDC-0973, or AZD8330.

[0073] In a thirty-third embodiment, the present disclosure provides the method of embodiment 26, wherein the chemotherapeutic agent comprises a CDK4 / 6 inhibitor.

[0074] In a thirty-fourth embodiment, the present disclosure provides the method of embodiment 33, wherein the CDK4 / 6 inhibitor comprises abemaciclib or palbociclib.

[0075] In a thirty-fifth embodiment, the present disclosure provides the method of embodiment 26, wherein the chemotherapeutic agent comprises a PI3K inhibitor.

[0076] In a thirty-sixth embodiment, the present disclosure provides the method of embodiment 35, wherein the PI3K inhibitor comprises AMG 511 or buparisib.

[0077] In a thirty-seventh embodiment, the present disclosure provides a method according to embodiment 22, wherein the stability is neither sufficient contraction to qualify for PR nor sufficient increase to qualify for PD.

[0078] In a thirty-eighth embodiment, the present disclosure provides the method of embodiment 23, wherein the partial response is at least a 30% reduction in the sum of the diameters of the target lesions.

[0079] In an alternative first embodiment, the present disclosure provides Compound A in a daily dose of 180 mg, 360 mg, 720 mg, or 960 mg for use in treating cancer, wherein Compound A has the following structure: [ka] Compound A having the formula:

[0080] In another alternative first embodiment, the present disclosure relates to the use of Compound A in a daily dose of 180 mg, 360 mg, 720 mg, or 960 mg in the preparation of a medicament for treating cancer, wherein Compound A has the following structure: [ka] The present invention provides the use of a compound A having the formula:

[0081] Method of using Compound A In embodiments of the methods disclosed herein, the subject is administered Compound A at a dose disclosed herein for at least 1 month, at least 6 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

[0082] In some embodiments of the methods disclosed herein, the subject is orally administered Compound A at least once daily (QD) at a dose disclosed herein.

[0083] In some embodiments of the methods disclosed herein, the subject is administered Compound A orally at least twice daily (BID) at a dose disclosed herein.

[0084] The present disclosure provides a method for inhibiting RAS-mediated cell signaling, comprising contacting a cell with an effective amount of Compound A. Inhibition of RAS-mediated signaling can be assessed and demonstrated by a wide variety of methods known in the art. Non-limiting examples include: (a) a decrease in the GTPase activity of RAS; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in the kappa binding affinity of GTP; off increase in GDP or k off (d) decreased levels of downstream signaling molecules in the RAS pathway, such as decreased levels of pMEK, pERK, or pAKT; and / or (e) decreased binding of the RAS complex to downstream signaling molecules, including, but not limited to, Raf. Kits and commercially available assays are available to determine one or more of the above.

[0085] The present disclosure also provides methods of using Compound A or a pharmaceutical composition of the present disclosure to treat disease conditions, including, but not limited to, conditions caused by G12C KRAS, HRAS, or NRAS mutations (e.g., cancer).

[0086] In some embodiments, provided are methods for treating cancer, comprising administering an effective amount of Compound A as disclosed herein to a subject in need thereof. In some embodiments, the cancer is mediated by a KRAS, HRAS, or NRAS G12C mutation. In various embodiments, the cancer is pancreatic cancer, colorectal cancer, or lung cancer (e.g., non-small cell lung cancer (locally advanced or metastatic)). In some embodiments, the cancer is gallbladder cancer, thyroid cancer, and cholangiocarcinoma.

[0087] In some embodiments, the disclosure provides a method of treating a disease in a subject in need thereof, comprising determining whether the subject has a KRAS, HRAS, or NRAS G12C mutation, and if the subject is determined to have a KRAS, HRAS, or NRAS G12C mutation, then administering a therapeutically effective dose of Compound A, or a pharmaceutically acceptable salt thereof, to the subject.

[0088] The compounds disclosed herein have the potential to inhibit anchorage-independent cell growth and thus inhibit tumor metastasis. Accordingly, another embodiment of the present disclosure provides a method for inhibiting tumor metastasis, comprising administering an effective amount of Compound A.

[0089] KRAS, HRAS, or NRAS G12C mutations have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments are directed to administering Compound A (e.g., in the form of a pharmaceutical composition) to a patient in need of treatment for a hematological malignancy. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, Compound A can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other embodiments, Compound A is useful for treating lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma. In various embodiments, Compound A is useful in the treatment of plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom's macroglobulinemia.

[0090] Determining whether a tumor or cancer contains a G12C KRAS, HRAS, or NRAS mutation can be performed by evaluating the nucleotide sequence encoding the KRAS, HRAS, or NRAS protein, by evaluating the amino acid sequence of the KRAS, HRAS, or NRAS protein, or by evaluating the characteristics of a predicted KRAS, HRAS, or NRAS mutant protein. The sequence of wild-type human KRAS, HRAS, or NRAS is well known in the art (e.g., accession number NP203524).

[0091] Methods for detecting mutations in the nucleotide sequence of KRAS, HRAS, or NRAS are well known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequencing, mutant allele-specific PCR amplification (MASA) assay, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high-resolution melting assay, and microarray analysis. In some embodiments, samples are evaluated for G12C KRAS, HRAS, or NRAS mutations by real-time PCR. In real-time PCR, a fluorescent probe specific to the KRAS, HRAS, or NRAS G12C mutation is used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, KRAS, HRAS, or NRAS G12C mutations are identified using direct sequencing of specific regions in the KRAS, HRAS, or NRAS genes (e.g., exon 2 and / or exon 3). This technique identifies all possible mutations in the sequenced region.

[0092] Methods for detecting mutations in KRAS, HRAS, or NRAS proteins are known to those skilled in the art, including, but not limited to, detecting KRAS, HRAS, or NRAS mutants using binding agents (e.g., antibodies) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0093] The methods for determining whether a tumor or cancer contains a G12C KRAS, HRAS, or NRAS mutation can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, the sample is a circulating tumor cell (CTC) sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0094] The present disclosure also relates to a method of treating a hyperproliferative disease in a mammal, comprising administering to the mammal a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method is directed to treating a hyperproliferative disease, including acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, pediatric cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative Diseases, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), germinoma, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac tumor, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of unknown primary, midline duct cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer , ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, childhood anomalies, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.In some embodiments, the methods relate to the treatment of non-cancerous hyperproliferative diseases such as benign hyperplasia of the skin (eg, psoriasis), restenosis, or prostate (eg, benign prostatic hyperplasia (BPH)).

[0095] In some embodiments, the method for treatment is a method for treating lung cancer, comprising administering an effective amount of Compound A (or a pharmaceutical composition comprising same) to a subject in need thereof. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In some embodiments, the lung cancer is small cell lung cancer. Other lung cancers treatable by the disclosed compounds include, but are not limited to, ductal tumors, carcinoid tumors, and undifferentiated carcinomas.

[0096] The present disclosure further provides methods of modulating the activity of a G12C mutant KRAS, HRAS, or NRAS protein by contacting the protein with an effective amount of Compound A. Modulation can be inhibiting or activating protein activity. In some embodiments, the present disclosure provides methods of inhibiting the activity of a G12C mutant KRAS, HRAS, or NRAS protein by contacting the protein in solution with an effective amount of Compound A. In some embodiments, the present disclosure provides methods of inhibiting the activity of a G12C mutant KRAS, HRAS, or NRAS protein by contacting a cell, tissue, or organ expressing the protein of interest. In some embodiments, the present disclosure provides methods of inhibiting the activity of a protein in a subject, including, but not limited to, a rodent and a mammal (e.g., a human), by administering an effective amount of Compound A to the subject. In some embodiments, the percentage of modulation is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percentage of inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0097] In some embodiments, the disclosure provides a method of inhibiting the activity of KRAS, HRAS, or NRAS G12C in a cell by contacting the cell with Compound A in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the cell. In some embodiments, the disclosure provides a method of inhibiting the activity of KRAS, HRAS, or NRAS G12C in a tissue by contacting the tissue with Compound A in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the tissue. In some embodiments, the disclosure provides a method of inhibiting the activity of KRAS, HRAS, or NRAS G12C in an organ by contacting the organ with Compound A in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the organ. In some embodiments, the disclosure provides a method of inhibiting the activity of KRAS, HRAS, or NRAS G12C in an animal by contacting the animal with Compound A in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the animal. In some embodiments, the disclosure provides a method of inhibiting the activity of KRAS, HRAS, or NRAS G12C in a mammal by contacting the mammal with Compound A in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the mammal. In some embodiments, the disclosure provides a method of inhibiting the activity of KRAS, HRAS, or NRAS G12C in a human by contacting the human with Compound A in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the human. The disclosure provides a method of treating a disease mediated by KRAS, HRAS, or NRAS G12C activity in a subject in need of such treatment.

[0098] Subject Selection and Treatment Results In some embodiments, the subject treated with Compound A in the methods disclosed herein is a subject who has received at least one prior systemic cancer therapy (e.g., Compound A is a second-line or third-line therapy). In some embodiments, the subject treated with Compound A in the methods disclosed herein is a subject with disease progression after at least one prior systemic cancer therapy (i.e., Compound A is a second-line therapy). In some embodiments, the subject treated with Compound A in the methods disclosed herein is a subject with disease progression after at least two prior systemic cancer therapies (i.e., Compound A is a third-line therapy). The prior systemic cancer therapy can be any therapy approved by a regulatory authority (e.g., FDA or EMA) for the treatment of a given type and stage of cancer. In some cases, the prior systemic cancer therapy is a cancer therapy that has not yet been approved by a regulatory authority but is undergoing clinical trials. If the subject has received prior systemic cancer therapy, in some cases the subject has not received any systemic cancer therapy for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months prior to initiating therapy disclosed herein with Compound A.

[0099] In some embodiments, subjects will present with pathologically proven locally advanced or metastatic malignancies with a KRAS p.G12C mutation identified through molecular testing. The mutation will be confirmed by a central laboratory prior to enrollment.

[0100] In some embodiments, for NSCLC, the subject may have received platinum-based combination therapy and / or targeted therapy (i.e., if molecular testing identified a mutation in EGFR, ALK, or prototypic oncogene tyrosine protein kinase ROS [ROS1] or expression of programmed death-ligand [PD-L1]) prior to taking AMG 510 (Compound A).

[0101] In some embodiments, the subject's NSCLC must have progressed after receiving anti-PD1 or anti-PD-L1 immunotherapy (unless contraindicated) and / or platinum-based combination chemotherapy and targeted therapy (if a predisposing oncogenic driver mutation (i.e., EGFR, ALK, and ROS1) has been identified). The subject has received no more than three prior lines of therapy.

[0102] In some embodiments, for colorectal cancer (CRC), subjects must have received at least two prior systemic regimens in the metastatic setting. For those CRC subjects with tumors that are MSI-H, at least one of the prior systemic regimens must have been treatment with either nivolumab or pembrolizumab, provided they are clinically eligible to receive an inhibitor and one of these agents is approved for that indication in that region or country.

[0103] In some embodiments, the subject's CRC must have progressed after receiving a fluoropyrimidine, oxaliplatin, and irinotecan. For those CRC subjects with tumors that are MSI-H, at least one of the prior systemic regimens must have included anti-PD1 therapy if they are clinically able to receive an inhibitor and one of these agents is approved for that indication in that region or country.

[0104] In some embodiments, for advanced solid tumor types other than NSCLC or CRC, subjects must have received at least one prior systemic therapy that is intolerant or ineligible for available therapies known to provide clinical benefit.

[0105] In some embodiments, the dose of Compound A can be administered to a subject, optionally with food, such as a standard high-fat, high-calorie meal, or in a fasted state (no food or liquids, except water, for >= 10 hours). In one embodiment, a dose of Compound A (e.g., 960 mg once daily) is administered with or without food.

[0106] Subjects receiving therapy are monitored for adverse events (AEs) during the course of therapy. A treatment-related AE is an AE related to the therapeutic agent. A treatment-emergent AE is an AE that was not present before the start of therapy and develops while the subject is receiving treatment. In some cases, a treatment-emergent AE is not or is suspected to be unrelated to the treatment itself. AEs are characterized as one of five grades: Grade 1 is a mild AE; Grade 2 is a moderate AE; Grade 3 is a severe AE; Grade 4 is a life-threatening or disabling AE; and Grade 5 is death related to the AE. In some cases, subjects do not experience any Grade 3 AEs that are treatment-related. In some cases, subjects do not experience any Grade 3 AEs. In some cases, subjects do not experience any Grade 4 AEs that are treatment-related. In some cases, subjects do not experience any Grade 4 AEs. In various cases, subjects do not experience treatment-related Grade 3 or Grade 4 AEs after administration of Compound A for at least 1 month or at least 3 months.

[0107] In various cases, subjects treated with Compound A in the methods disclosed herein do not experience any dose-limiting toxicity (DLT) at the administered dose. A DLT is any AE meeting the criteria listed below that occurs during the first treatment cycle (Days 1-21) of Compound A, where a relationship to the drug cannot be ruled out. AE grading is based on the guidelines provided in CTCAE version 5.0. AEs for DLT evaluation: Hematologic toxicities: Febrile neutropenia; neutropenic infection; Grade 4 neutropenia; Grade ≥3 thrombocytopenia for >7 days; Grade 3 thrombocytopenia with Grade ≥2 bleeding; Grade 4 thrombocytopenia; Grade 4 anemia Non-hematologic toxicity: Grade ≥ 4 vomiting or diarrhea; Grade 3 diarrhea or Grade 3 vomiting persisting for ≥ 4 days despite best medical support; Grade ≥ 3 nausea lasting ≥ 3 days despite best medical support; any other Grade ≥ 3 AE

[0108] In various cases, subjects of the methods disclosed herein show a response to therapy. In some cases, subjects show at least stable disease (SD) due to the administration of Compound A. In some cases, subjects show at least a partial response (PR) due to the administration of Compound A. Subject response is evaluated by the criteria defined by RECIST 1.1, for example, as discussed in Eisenhauer et al., Eur J Cancer, 45:228-247 (2009). A complete response (CR) is the disappearance of all target lesions, and any pathological lymph nodes have a reduction to less than 10 mm in a single axis. A partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking the sum of the diameters at baseline as reference. Progression is at least a 20% increase in the sum of the diameters of target lesions (including the baseline sum if it is the smallest in the study), taking the smallest sum in the study as reference, and must be an absolute increase of at least 5 mm in addition to a 20% relative increase. Stable disease is neither a significant shrinkage that qualifies for PR nor a significant increase that qualifies for PD. Controlled disease is when a patient may have repeated periods of stable disease and partial response. Tumor location can be determined by radiographic examination.

[0109] Combination therapy The present disclosure also provides methods of combination therapy in which agents known to regulate other pathways or other components of the same pathway or even overlapping sets of target enzymes are used in combination with Compound A or a pharmaceutically acceptable salt thereof. In one aspect, such therapy includes, but is not limited to, the combination of Compound A disclosed herein with chemotherapeutic agents to provide a synergistic or additive therapeutic effect.

[0110] Numerous chemotherapeutic agents are currently known in the art and can be used in combination with Compound A. In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec® (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), Venclexta™ (venetoclax), and Adriamycin™ (doxorubicin), as well as a host of other chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (Cytoxan™); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, chlorocyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Aclacinomycin, actinomycin, austramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potrophilomycin, puromycin, ketoconazole ... Antibiotics such as ramycin, rhodrubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, etc.; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate, etc.; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, etc.; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, etc. Pyrimidine analogues; androgens such as calsterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomitine; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone ;Mitoxantrone;Mopidamol;Nitracrine;Pentostatin;Fenamet;Pirarubicin;Podophyllic acid;2-Ethylhydrazide;Procarbazine;PSK;Razoxane;Sizofiran;Spirogermanium;Tenuazonic acid;Triaziquone;2,2',2''-Trichlorotriethylamine;Urethane;Vindesine;Dacarbazine;Mannomustine;Mitobronitol;Mitolactol;Pipobroman;Gacytosine;Arabinoside ("Ara-C");Cyclophosphamide;Thiotepa;Taxanes, such as paclitaxel and docetaxel;Retinoic acid; esperamycin; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0111] Additionally, suitable chemotherapy cell conditioners include those that act to regulate or inhibit hormone action on tumors, such as tamoxifen, (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifen, ketoxifen, LY. Antihormonal agents such as antiestrogens, including 117018, onapristone, and toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, luprolide, and goserelin; and chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); the topoisomerase inhibitor RFS 2000; and difluoromethylornithine (DMFO).

[0112] Compound A is an active ingredient in Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfalazine, alvocidib, 3-aminopyridine-2- Carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic drugs, antitumor herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle non-specific antitumor agents, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothion Lon, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesin, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucantone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortaxel, PAC-1, pawpaw, pixantrone, pro It can be used in combination with commonly prescribed anticancer drugs such as teasome inhibitors, rebecamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosuquidar.

[0113] Compound A includes acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestine, ARGLABIN, arsenic trioxide, BAM002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA3030 (Dong-A), daclizumab, denileukin dif Chitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon α, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, efornithine, emiteflu, epirubicin, epoetin β, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fudrabin phosphate Salt, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumabzogamicin, dimeracil / oteracil / tegafur combination, glycopin, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronate, idarubicin, (imiquimod, interferon alpha, natural interferon alpha, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-N1, interferon alpha-n3, interferon alfacon-1, natural interferon Interferon α, interferon β, interferon β-1a, interferon β-1b, interferon γ, natural interferon γ-1a, interferon γ-1b, interleukin-1β, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leucocyte α interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melasoprol,Metoclopramide, mifepristone, miltefosine, millimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis-stimulating protein, NSC 631570, octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon α-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon α-2a, porfimer sodium, raloxifene, raltitrexed, rasbriemboment, rhenium Re186, etidrone acetaminophen, RII retinamide, rituximab, romurtide, samarium (153Sm) lexidronam, sargramotim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine-131, trastuzumab, treosulfan, tresulfan Chinoin, trilostane, trimetrexate, triptorelin, native tumor necrosis factor alpha, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer or zoledronic acid; abarelix; AE941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, dextromethorphan Citabine, dexaminoglutethimide, diazicon, EL532 (Elan), EM800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytran),Interleukin 2, iproxifen, LDI200 (Milkhaus), religistim, lintuzumab, CA125MAb (Biomira), cancer MAb (Nihon Yakuhin Kaihatsu Co., Ltd.), HER-2 and Fc MAb (Medarex), idiotype 105AD7MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering) The use of combination therapy with anti-tumor chemotherapeutic agents such as valspodar, melanoma oncolysate vaccine (New York Medical College), viral melanoma lysate vaccine (Royal Newcastle Hospital), or valspodar is contemplated.

[0114] Compound A can be used in combination with a chemotherapeutic agent that is a PD1 inhibitor, a PDL1 inhibitor, a MEK inhibitor, a PI3K inhibitor, or a CDK4 / 6 inhibitor.

[0115] KRAS of the present disclosure G12C Inhibitors can be used in combination with MEK inhibitors. Specific MEK inhibitors that can be used in the combinations of the present disclosure include PD-325901, trametinib, pimasertib, MEK162 (also known as binimetinib), TAK-733, GDC-0973, and AZD8330. The combinations of the present disclosure can also inhibit KRAS G12CA particular MEK inhibitor that can be used in combination with the inhibitor is trametinib (trade name: Mekinist®, commercially available from Novartis Pharmaceuticals Corp.). Another particular MEK inhibitor is N-(((2R)-2,3-dihydroxypropyl)oxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide, also known as AMG1009089, 1009089, or PD-325901. Another particular MEK inhibitor that can be used in the combinations of the present disclosure includes cobimetinib. In some cases, the MEK inhibitor is CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, or PD-325901.

[0116] In another embodiment, Compound A can be used in combination with one or more agents that are inhibitors of proteins in the phosphatidylinositol 3-kinase (PI3K) pathway. Examples of proteins in the PI3K pathway include PI3K, mTOR, and PKB (also known as Akt or AKT). PI3K proteins exist in several isoforms, including α, β, δ, and γ. It is contemplated that a PI3K inhibitor may be selective for one or more isoforms. By selective, it is meant that a compound inhibits one or more isoforms over other isoforms. Selectivity is a well-known concept to those skilled in the art and can be measured using well-known in vitro or cell-based activity assays. Preferred selectivity includes greater than 2-fold, preferably 10-fold, or more preferably 100-fold selectivity for one or more isoforms over other isoforms. In one embodiment, the PI3K inhibitor that can be used in combination with Compound A is a PI3K α-selective inhibitor. In another embodiment, the compound is a PI3K δ-selective inhibitor. In yet another embodiment, the compound is a PI3Kβ selective inhibitor.

[0117] Examples of PI3K inhibitors that can be used in combination with Compound A include those disclosed in: WO 2010 / 151791; WO 2010 / 151737; WO 2010 / 151735; WO 2010151740; WO 2008 / 118455; WO 2008 / 118454; WO 2008 / 118468; U.S. Pat. Patent Application Publication Nos. 20100331293; 20100331306; 20090023761; 20090030002; 20090137581; 2009 / 0054405; 2009 / 0163489; 2010 / 0273764; 2011 / 0092504; or International Publication No. WO 2010 / 108074.

[0118] In particular, PI3K inhibitors include wortmannin, the 17-hydroxywortmannin analogs described in WO 06 / 044453, 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC0941 and described in WO 09 / 036,082 and WO 09 / 055,730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine, and the like. (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO 2008 / 070740), LY294002 (Axon 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one available from Medchem), PI103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride available from Axon Medchem), PIK 75 (N'-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfono-hydrazide hydrochloride available from Axon Medchem), PIK90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide available from Axon Medchem), GDC-0941 bismesylate (Axon 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine bismesylate), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione available from Axon Medchem) and TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one available from Axon Medchem), XL-765 and XL-147. Other PI3K inhibitors include demethoxyviridine, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0119] Preferred PI3K inhibitors for use in combination with compounds of the present disclosure include the following investigational small molecules from Novartis Pharmaceuticals: [ka] , also known as buparlisib, is one of the following: [ka] or a pharmaceutically acceptable salt thereof.

[0120] More preferred are compounds of the following formula IIa: [ka] (In the formula, X 1 is fluorine or hydrogen; Y 1 is hydrogen or methyl; and Z 1is hydrogen or methyl), or a pharmaceutically acceptable salt thereof. A particular PI3K inhibitor that can be used in combination is AMG 511 (also known as AMG 2539965 or 2539965), which is Example 148 of WO 2010 / 126895.

[0121] Other PI3K inhibitors that can be used in combination with Compound A in the combinations disclosed herein include pan-PI3K inhibitors such as BKM120 and GDC-0941; PI3K alpha-selective inhibitors such as AMG 511 and YL719; and PI3K beta-selective inhibitors such as GSK-2636771.

[0122] Compounds that inhibit both PI3K and mTOR (dual inhibitors) are known. In yet another aspect, the present disclosure provides compounds that inhibit KRAS G12C The present invention provides the use of a dual PI3K and mTOR inhibitor in combination with an inhibitor. An example of a specific dual inhibitor is GDC-0980.

[0123] mTOR is a protein in the PI3K pathway. G12C Combination with an inhibitor is another aspect of the present disclosure. mTOR inhibitors that can be used in combination with Compound A include those disclosed in the following documents: WO 2010 / 132598 and WO 2010 / 096314. mTOR inhibitors that can be used in combination with Compound A include AZD2014 and MLN0128.

[0124] PKB (AKT) is also a protein in the PI3K pathway. Combining an AKT inhibitor with Compound A is another embodiment. AKT inhibitors that can be used include those disclosed in the following documents: U.S. Pat. Nos. 7,354,944; 7,700,636; 7,919,514; 7,514,566; U.S. Patent Application Publication No. 2009 / 0270445A1; U.S. Pat. No. 7,919,504; 7,897,619; or WO 2010 / 083246A1. Specific AKT inhibitors that can be used in combination include MK-2206, GDC-0068, and AZD5363.

[0125] Compound A can also be used in combination with a CDK4 and / or 6 inhibitor. CDK4 and / or 6 inhibitors that can be used in the combinations of the present invention include, but are not limited to, those disclosed in the following documents: WO 2009 / 085185 or U.S. Patent Application Publication No. 2011 / 0097305.

[0126] Anti-PD-1 antibodies include, but are not limited to, pembrolizumab (Keytruda™), nivolumab, AUNP-12, AMG401, and pidilizumab. Exemplary anti-PD-1 antibodies and their methods of use are described in Goldberg et al., Blood 110(1):186-192 (2007), Thompson et al., Clin. Cancer Res. 13(6):1757-1761 (2007), and Korman et al., International Application No. PCT / JP2006 / 309606 (International Publication No. WO 2006 / 121168A1), each of which is expressly incorporated herein by reference.

[0127] Compound A can be used in combination with the drugs disclosed herein or other suitable drugs, depending on the condition being treated. Thus, in some embodiments, Compound A will be co-administered with the other drug. When used in combination therapy, Compound A is administered simultaneously with the second drug or separately. This combination administration can include simultaneous administration of the two drugs in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, Compound A and any of the drugs can be formulated together in the same dosage form and administered simultaneously. Alternatively, Compound A and any of the drugs can be administered simultaneously, but where both drugs are present in separate formulations. In another alternative, Compound A can be administered followed by any of the drugs, or the reverse order can be used. In some embodiments of the separate administration protocol, Compound A and any of the drugs can be administered minutes, hours, or days apart. [Example]

[0128] Phase 1 clinical trial of Compound A A. First results Compound A Treatment Study: This study enrolled patients identified as having cancer with a KRAS G12C mutation. Patients were adults with locally advanced or metastatic KRAS G12C-mutated solid tumors. All patients had previously received prior standard therapy depending on tumor type and disease stage. No patients presented with progressive brain metastases. Patients in the treatment study had the following diagnoses: 14 with non-small cell lung cancer (NSCLC), 10 with colorectal cancer (CRC), and 2 with another KRAS G12C-mutated solid tumor. Compound A was administered orally once daily at the designated dose. Patients received Compound A at doses of 180 mg, 360 mg, 720 mg, or 960 mg and underwent radiological follow-up every 6 weeks.

[0129] Adverse events reported while taking Compound A are shown in Tables 1 and 2 below. Of the six serious adverse events reported, none were reported to be related to Compound A. Of the six serious adverse events, there were two Grade 3 (one pneumonia, one malignant bile duct obstruction); one Grade 4 (pericardial effusion); and three fatal cases (one dyspnea; two metastatic colorectal cancer). There were no DLTs, Grade 4-related adverse events, or serious related adverse events.

[0130] [Table 1]

[0131] [Table 2]

[0132] Individual Response to Compound A Therapy: Case #1: A 61-year-old woman diagnosed with KRAS G12C metastatic NSCLC in 2010 received prior therapy with carboplatin / Taxol from August 2010 to October 2010; then carboplatin / pemetrexed from October 2016 to June 2017; then nivolumab from August 2017 to April 2018; subsequently, Compound A was administered at a dose of 180 mg. She demonstrated a partial response (-34%) at the 180 mg dose at one of her 6-weekly evaluations. She tolerated the agent and has continued for over 27 weeks.

[0133] Case #2: A 59-year-old man diagnosed with KRAS G12C metastatic NSCLC in 2013 received prior therapy with carboplatin / pemetrexed from February 2014 to February 2015; erlotinib from April 2015 to June 2015; nivolumab from August 2015 to August 2017; dasatinib from July 2016 to August 2017; and M3541 (Targeted Biologics) from October 2017 to November 2017; subsequently, Compound A was administered at a dose of 360 mg. He demonstrated a partial response (-80%) at one of his 6-weekly evaluations. He tolerated the medication and has continued it for over 14 weeks.

[0134] Case #3: A 34-year-old woman diagnosed with KRAS G12C metastatic colon adenocarcinoma in 2014 received upfront therapy with FOLFOX and HIPEC in August 2015, followed by FOLFIRI therapy with PD in August 2016, HIPEC in October 2016, and upfront therapy with capecitabine and bevacizumab in August 2017. She underwent a phase I clinical trial from March to June 2018. She was subsequently enrolled in a phase I clinical trial for Compound A in October 2018 and received Compound A at a dose of 360 mg. She demonstrated stable disease (-18%) at one of her 6-weekly evaluations. She also demonstrated a biochemical response, with biomarkers CA 19-9 and CAE rapidly decreasing after Compound A administration and remaining at lower levels throughout the course of Compound A therapy (Figure 1). She tolerated the medication well and has been on treatment for over 22 weeks.

[0135] NSCLC Tumor Response: Patients with KRAS G12C NSCLC were administered daily doses of 180 mg, 360 mg, 720 mg, or 960 mg, and 9 of 10 patients demonstrated at least a stable response to therapy based on radiographic review performed every 6 weeks - the results are shown in Figure 2, with the designated dose noted below each histogram. The study period and treatment of interest in the NSCLC trial are shown in Figure 3, where the top four bars represent patients receiving a 960 mg total daily dose, the next six bars represent patients receiving a 720 mg total daily dose, the next bar represents patients receiving a 360 mg total daily dose, and the bottom three bars represent patients receiving a 180 mg total daily dose.

[0136] CRC and Other Solid Tumor Responses: Patients with KRAS G12C CRC or other solid tumors were administered daily doses of 180 mg, 360 mg, 720 mg, or 960 mg, and results for 17 of 19 patients studied are shown in Figure 4 (two patients did not progress before week 6 and did not undergo the initial 6-weekly evaluation). The results in Figure 4 are based on radiographic workup performed at the 6-weekly evaluation. Study duration and treatment of interest in the CRC / Other study are shown in Figure 5, where the top two bars are for patients receiving a 960 mg total daily dose, the next five bars are for patients receiving a 720 mg total daily dose, the next 11 bars are for patients receiving a 360 mg total daily dose, and the bottom three bars are for patients receiving a 180 mg total daily dose.

[0137] Phase 1 Clinical Trial Results of Compound A: Thirty-five patients with KRAS G12C cancers (19 CRC, 14 NSCLC, 2 other cancers - appendiceal cancer) were enrolled in a Phase 1 clinical trial for Compound A. All had received two or more prior lines of therapy. No DLTs were reported. Sixteen patients reported Compound A-related adverse events, and two reported Grade 3 related adverse events (anemia and diarrhea). Best tumor responses were tabulated, with 26 patients still on study. The results are shown in Table 3 below.

[0138] [Table 3]

[0139] The pharmacokinetics of 960 mg of Compound A administered orally is as follows: C of 7.84 μg mL max (SD of 8.09); AUC 0~24hr 140 h*μg / mL (SD of 117); and t 1 / 2,z 6.5 hours (SD 4.2–8.0).

[0140] Updated Results Updated results from this study were presented at the European Society of Medical Oncology (ESMO) Congress held September 27-October 1, 2019, in Barcelona, ​​Spain, at Govindan, R., et. al., "Phase 1 Study of AMG 510, a Novel KRAS G12C The detailed results of this study were presented as a poster by Fakih, MG, et al., "CodeBreak 100: activity of AMG 510, a novel small molecule inhibitor of KRAS," at the American Society of Ophthalmology (ASCO) virtual meeting, May 29-31, 2020, the contents of which are incorporated herein in their entirety. G12C , in patients with advanced colorectal cancer'' and Hong, DS, et al., ``CodeBreak 100: Phase 1 study of AMG 510, a novel KRASG12C inhibitor, in patients with advanced solid tumors other than non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC)''.

[0141] This study has also been published as “A Phase 1 / 2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects with a Specific KRAS Mutation (CodeBreak 100),” Clinicaltrials.gov Identifier No. NCT03600883, https: / / clinicaltrials.gov / ct2 / show / NCT03600883 (last accessed May 3, 2020), the contents of which are hereby incorporated herein in their entirety.

[0142] The data below demonstrate early promising anti-tumor activity of Compound A in patients with advanced solid tumors harboring the KRAS p.G12C mutation, such as NSCLC, CRC, and other tumor types.

[0143] The scheme below briefly describes the clinical trial design.

[0144] [Table 4]

[0145] [Table 5]

[0146] I. Patients with non-small cell lung cancer (NSCLC) The first patient was enrolled on August 27, 2018. As of the cutoff date of July 17, 2019, 76 patients had been enrolled, of which 34 had NSCLC (1 patient with SCLC; this patient was recorded as having SCLC ("other tumor type" category) as of the cutoff date, but was changed to NSCLC by the participating institution after the cutoff). 45 patients were enrolled in dose-escalation cohorts (180 mg total daily dose (N=6), 360 mg total daily dose (N=13), and 720 mg total daily dose (N=14). Thirty-one patients were enrolled in the dose-expansion cohort (total daily dose 960 mg (N=11) and 960 mg (N=15)), and 31 patients were enrolled in the dose-expansion cohort (total daily dose 960 mg (N=31)). 55 patients who underwent initial 6-weekly follow-ups or showed early progressive disease (PD) were evaluable. Of the 76 enrolled patients, 52 remained on treatment, while 24 discontinued treatment due to PD (N=22) and death (N=2). It is noteworthy that no treatment-related adverse events induced treatment discontinuation.

[0147] [Table 6]

[0148] The table below summarizes the patient incidence of adverse events (AEs). No dose-limiting toxicities were reported. Furthermore, no treatment-related serious or fatal AEs were reported. Most importantly, no treatment-related AEs led to treatment discontinuation. As a result, a total daily dose of 960 mg of Compound A was identified as the expansion dose and the recommended Phase 2 dose.

[0149] [Table 7]

[0150] The patient incidence of treatment-related adverse events (AEs) is detailed in the table below. In summary, 26 of 76 patients (34.2%) reported treatment-related AEs, the majority of which were grade 1 or 2. Six of 76 patients (7.9%) reported one or more grade 3 treatment-related adverse events (diarrhea and anemia). There were no treatment-related adverse events of grade 4 or higher.

[0151] [Table 8]

[0152] The pharmacokinetic (PK) profile of Compound A (960 mg oral total daily dose) (N=32, including patients with NSCLC and CRC) as of the PK cutoff date of July 24, 2019, was as follows (geometric mean; percent coefficient of variation (CV)): peak serum concentration (C max )7.50 μg / mL (98.3%), area under the curve (AUC) 65.3 h*μg / mL (81.7%) and elimination half-life (t 1 / 2,z ) 5.5 hours (1.8). Serum concentrations after administration were consistent for at least 22 hours, and exceeded the 90% inhibitory concentration (IC) in vitro in a 2-hour cellular phosphorylated extracellular signal-regulated kinase (pERK) assay. 90 ) remains above.

[0153] All dose levels and best tumor responses for NSCLC patients receiving the 960 mg dose are reported in the table below.

[0154] [Table 9]

[0155] The efficacy of Compound A in NSCLC patients is shown in Figure 6 (% change from baseline in sum of longest diameters for all evaluable NSCLC patients with available post-baseline tumor data (N=22)). Of note, the patient treated with a total daily dose of 960 mg, represented by the right-most bar, had a complete response to target lesions.

[0156] Figure 7 shows the efficacy of Compound A in NSCLC patients, focusing on time to response and duration of treatment (evaluable NSCLC patients (N=23) vs. duration of treatment (weeks)). Eleven patients had a partial response (PR) with a median duration of treatment of 15.1 weeks (range 4.1-42.3 weeks). Eight of these 11 patients remain on the study. Additionally, 11 patients had stable disease (SD) with a median duration of treatment of 10.0 weeks (range 4.1-35.1 weeks). Eight of these 11 patients remain on the study.

[0157] In conclusion, Compound A has demonstrated early promising antitumor activity in patients with advanced solid tumors harboring the KRAS p.G12C mutation, such as NSCRC. Furthermore, Compound A has been found to have a favorable safety profile at the dose levels tested—no dose-limiting toxicities were observed, and no cumulative toxicity was noted with extended treatment.

[0158] II. Colorectal cancer (CRC) patients As of the cutoff date of January 8, 2020, 42 patients with CRC were enrolled (Cohort 1, 180 mg total daily dose: 3 patients; Cohort 2, 360 mg total daily dose: 10 patients; Cohort 3, 720 mg total daily dose: 4 patients; and Cohort 4, 960 mg total daily dose: 25 patients). The median follow-up period was 7.9 months (range: 4.2-15.9 months). Eight patients continued treatment. Thirty-four patients discontinued treatment due to disease progression (32 patients) and patient request (2 patients). All enrolled patients had received prior systemic anticancer therapy. 45% of patients received four or more lines of therapy.

[0159] [Table 10]

[0160] The two tables below summarize the patient incidence of adverse events (AEs). Twenty of 42 patients reported treatment-related AEs, the majority of which were Grade 2 or less. Diarrhea and anemia were reported as Grade 3 treatment-related AEs occurring in one patient each. No dose-limiting toxicities occurred. As discussed above, a total daily dose of 960 mg of Compound A was identified as the expansion dose and recommended Phase 2 dose.

[0161] [Table 11]

[0162] [Table 12]

[0163] Tumor responses for CRC patients receiving all dose levels and a total daily dose of 960 mg are reported in the table below. Regarding efficacy, confirmed partial responses were observed in three patients, all receiving the 960 mg dose. Responses were durable and were still ongoing as of the data cutoff. Additionally, 29 patients had stable disease, resulting in a disease control rate of 76.2%.

[0164] [Table 13]

[0165] Progression-free survival (PFS) is shown in Figure 8. Progression-free survival across all dose levels was 4.0 months (median (min, max), 0.7, 11.0) and 4.2 months at 960 mg (median (min, max), 1.2, 5.7+; +: censored). The 3-month and 6-month PFS rates for all doses were 58.5% and 20.6%, respectively. The 3-month PFS rate for the 960 mg total daily dose was 59.7%. Overall survival (OS) is shown in Figure 9. Overall survival across all dose levels was 10.1 months (median (min, max), 1.3+, 11.4+; +: censored; NR: not reached)) and NE at 960 mg (2.3, 8.0+). The 6-month OS rate was 76.4% for all doses and 82.9% for the 960 mg total daily dose.

[0166] The efficacy of Compound A in CRC patients is shown in Figure 10 (% change from baseline in sum of longest diameters for all evaluable CRC patients with available post-baseline tumor data (N=39)). Three patients are not included in the graph in Figure 10 due to missing post-baseline tumor data (one PD, one SD, one not performed due to clinical progression).

[0167] Figures 11-15 show the change in tumor burden from baseline over time for CRC patients for all four doses of Compound A (Figure 11; total daily doses of 180 mg, 360 mg, 720 mg, and 960 mg), and for individual doses (Figures 12-15).

[0168] Figures 16 and 17 show the time to response and treatment over time for CRC patients administered Compound A at various doses.

[0169] In conclusion, 3 of 42 patients (7.1%) with heavily pretreated KRAS p.G12C-mutated metastatic CRC had durable partial responses to Compound A. In addition to the 3 responders, 29 patients achieved disease control, resulting in a disease control rate of 76.2% and a median progression-free survival (PFS) of 4.0 months (range: 0.7-11.0 months). Furthermore, Compound A was well tolerated in CRC patients with mild treatment-related toxicities, consistent with previous results.

[0170] III. Patients with advanced solid tumors other than NSCLC and CRC By the cutoff date of January 8, 2020, 25 patients with the following tumor types had been enrolled: pancreatic cancer (10 cases), appendiceal cancer (4 cases), endometrial cancer (2 cases), cancer of unknown primary site (2 cases), bile duct cancer (1 case), paranasal sinus cancer (1 case), ampulla of the ampulla (1 case), small intestine cancer (1 case), melanoma (1 case), small cell lung cancer (1 case), and esophageal cancer (1 case). Two patients with appendiceal cancer received total daily doses of 360 and 720 mg of Compound A, respectively. The remaining 23 patients received a total daily dose of 960 mg of Compound A. The median follow-up period was 4.3 months (range: 0.1 to 12.6 months). Twenty-two patients had ≥7 weeks of follow-up and were evaluable for response. By the cutoff date, 12 patients had progression as the most common cause and discontinued treatment. All enrolled patients had received prior lines of systemic anticancer therapy, and 84% had received two or more prior lines.

[0171] [Table 14]

[0172] The table below summarizes the patient incidence of adverse events (AEs). Treatment-related TEAEs reported in two or more patients were diarrhea (2 of 25 patients) and fatigue (2 of 25 patients). Grade 3 treatment-related AEs reported were diarrhea (1 of 25 patients) and pneumonia (1 of 25 patients). There were no dose-limiting toxicities or treatment-related adverse events that led to treatment discontinuation. As discussed above, a total daily dose of 960 mg of Compound A was identified as the expansion dose and recommended Phase 2 dose.

[0173] [Table 15]

[0174] The tumor responses of these patients are reported in the table below. Twenty-two patients were evaluable for tumor response. Three had a confirmed partial response, 13 had stable disease, and six had progressive disease. The three partial responders had appendiceal cancer, melanoma, and endometrial cancer, respectively. The 13 patients who achieved stable disease included six with pancreatic cancer, two with appendiceal cancer, one with ampullary cancer, one with bile duct cancer, one with endometrial cancer, one with paranasal sinus cancer, and one with cancer of unknown primary site. Three patients with pancreatic cancer who achieved stable disease had nearly a 30% reduction by RECIST 1.1.

[0175] [Table 16]

[0176] The efficacy of Compound A in these patients is shown in Figure 18 (% change from baseline in sum of longest diameters for the total number of evaluable patients with available post-baseline tumor data (N=19)). Three patients are not included in the graph in Figure 18 due to missing post-baseline tumor data: two patients with appendiceal cancer (one PD, one SD) and one patient with pancreatic cancer (PD).

[0177] Figure 19 shows the time to response and treatment over time for these patients.

[0178] In conclusion, promising anticancer activity has been observed in multiple tumor types with KRAS G12C. Confirmed partial responses were observed in three patients with appendiceal cancer, melanoma, and endometrial cancer, respectively. Six of eight evaluable patients with pancreatic cancer achieved stable disease—three of them with a 30% reduction in tumor burden. Compound A-associated toxicity was mild and manageable, consistent with previous study results.

[0179] While the invention has been described and illustrated with reference to certain specific embodiments, those skilled in the art will recognize that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit of the invention. It is therefore intended that the invention be defined by the claims which follow and that such claims be interpreted as broadly as reasonably possible.

Claims

1. The following formula: 【Chemical 1】 1. A pharmaceutical composition for treating a KRAS G12C mutant cancer in a patient, wherein said cancer is appendiceal cancer, endometrial cancer, pancreatic cancer, or melanoma, said treatment comprising administering to said patient 960 mg of said compound once daily.

2. 10. The method of claim 1, wherein the patient has undergone at least one systemic cancer therapy prior to the first administration of the compound.

3. 10. The method of claim 1, wherein the patient has received at least two systemic cancer therapies prior to the first administration of the compound.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the compound is administered orally.

5. 5. The pharmaceutical composition of claim 4, wherein the compound is administered as a tablet.

6. In the preparation of a medicament for treating KRAS G12C mutant cancer in a patient, a compound of the following formula: 【Chemistry 2】 wherein the cancer is appendiceal cancer, endometrial cancer, pancreatic cancer or melanoma, and the treatment comprises administering to the patient 960 mg of the compound once daily.

7. 7. The use of claim 6, wherein the patient has undergone at least one systemic cancer therapy prior to first administration of the compound.

8. 7. The use of claim 6, wherein the patient has received at least two systemic cancer therapies prior to the first administration of the compound.

9. The use according to any one of claims 6 to 8, wherein the compound is administered orally.

10. 10. The use of claim 9, wherein the compound is administered as a tablet.

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