Methods of treating solid tumors using (19R)-5-chloro-3-ethyl-16-fluoro-10, 19-dimethyl-20-oxa-3, 4, 10, 11, 23-pentaazaplane [19.3.1. 02, 6.08, 12.013, 18] pentacosa-1 (24), 2 (6), 4, 8, 11, 13, 15, 17, 21 (25), 22-decen-22-amine

Abstract

Provided herein are methods of treating, preventing, or managing solid tumors using a heteroaromatic macrocyclic ether compound (e.g., Compound 1), or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

Description

[0001] This application claims priority to U.S. Serial No. 63 / 328,609 filed on April 7, 2022, U.S. Serial No. 63 / 328,620 filed on April 7, 2022, U.S. Serial No. 63 / 356,702 filed on June 29, 2022, and U.S. Serial No. 63 / 376,962 filed on September 23, 2022, all of which are incorporated herein by reference in their entirety. Background Art

[0002] Receptor tyrosine kinase (RTK) is a cell surface enzyme that receives external signals (such as whether to grow and divide) and transmits these signals inside the cell through kinase activity. Many RTKs are proto-oncogenes; abnormal RTK activity can drive cell survival, growth and proliferation, leading to cancer and related conditions. This abnormal kinase activity may be caused by mutations (such as activating mutations in the kinase domain), gene rearrangements (leading to fusion proteins containing complete kinase domains), amplifications and other means. RTK proto-oncogenes include ROS1, anaplastic lymphoma kinase (ALK), NTRK1 (encoding TRKA), NTRK2 (encoding TRKB) and NTRK3 (encoding TRKC).

[0003] ALK is an RTK proto-oncogene, and ALK rearrangements have been detected in many cancers, including non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumor (IMT), diffuse large B-cell lymphoma (DLBCL), esophageal squamous cell carcinoma (ESCC), renal medullary carcinoma, renal cell carcinoma, breast cancer, colon cancer, serous ovarian cancer, papillary thyroid cancer, cholangiocarcinoma, and Spitz-like tumors, and ALK activating mutations have been detected in neuroblastoma and anaplastic thyroid cancer. Oncogenic ALK gene fusions contain the kinase domain (3' region) of ALK fused to the 5' region of more than 20 different partner genes, the most common of which are EML4 in NSCLC and NPM in ALCL. Other partner genes include TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, ATIC, and KIF5B kinase.

[0004] NTRK1, NTRK2, and NTRK3 are RTK proto-oncogenes encoding TRK family kinases, of which NTRK1, NTRK2, and NTRK3 chromosomal rearrangements are detected at low frequencies in many cancers. However, for the treatment of ROS1-positive or ALK-positive patients, TRK inhibition, especially in the central nervous system (CNS), is associated with adverse reactions, including dizziness / ataxia / gait disturbance, paresthesia, weight gain, and cognitive changes.

[0005] Existing drugs for the treatment of oncogenic ROS1 and ALK have significant deficiencies. These deficiencies may represent one or more of the following: associated TRK inhibition, limited CNS activity, and insufficient activity against antagonistic mutations. Treatment of ROS1-positive or ALK-positive patients with concomitant TRK inhibition has been associated with adverse effects, particularly in the CNS, including dizziness / ataxia / gait disturbance, paresthesias, weight gain, and cognitive changes. Alternatively, there is a need for CNS penetrant and TRK-retaining inhibitors of wild-type ROS1 kinase domain and ROS1 with acquired resistance mutations occurring alone or in combination, including G2032R, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, and L2086F. Likewise, there is a need for CNS penetrant and TRK-retaining inhibitors of ALK inhibitors with acquired resistance mutations. A variety of ALK drug resistance mutations have been reported, including G1202R, F1174C, F1174L, I1171N, I1171S, I1171T, L1196M, V1180L, C1156Y, G1202del, G1202K, G1269A, F1174L, F1174S, S1206Y, E1210K, T1151M, T1151_L1152insT, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T and F1245V, or a combination thereof. Summary of the invention

[0006] Provided herein are methods of treating, preventing, or managing solid tumors using a heteroaromatic macrocyclic ether compound (eg, Compound 1) or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0007] In one embodiment, provided herein is a method of treating a solid tumor, comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1:

[0008]

[0009] or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is Compound 1.

[0010] In one embodiment, the solid tumor is an advanced ALK-positive solid tumor. In one embodiment, the solid tumor is a locally advanced or metastatic solid tumor. In one embodiment, the solid tumor is an advanced ALK-positive non-small cell lung cancer (NSCLC).

[0011] In one embodiment, the solid tumor is a metastatic ALK-positive solid tumor. In one embodiment, the solid tumor is a central nervous system (CNS) (e.g., brain) metastatic ALK-positive solid tumor. In one embodiment, the solid tumor is a metastatic ALK-positive NSCLC. In one embodiment, the solid tumor is a CNS (e.g., brain) metastatic ALK-positive NSCLC.

[0012] In one embodiment, the subject has not received tyrosine kinase inhibitor (TKI) therapy. In one embodiment, the subject has been treated with one or more previous TKI therapies. In one embodiment, the subject has been treated with a previous ALK TKI therapy (e.g., crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib). In one embodiment, the subject has been treated with at least one previous ALK TKI therapy. In one embodiment, the subject has been treated with at least two previous ALK TKI therapies. In one embodiment, the subject has been treated with at least one previous ALK TKI therapy selected from the group consisting of ceritinib, alectinib, brigatinib, or lorlatinib. In one embodiment, a subject with ALK fusion-positive NSCLC has been treated with at least one previous ALK TKI therapy, one of which is a second or third generation TKI selected from the group consisting of ceritinib, alectinib, brigatinib, or lorlatinib. In one embodiment, a subject with ALK-positive solid tumors (e.g., NSCLC) has been treated with at least one previous systemic anticancer therapy. In one embodiment, the subject has an ALK-positive solid tumor (e.g., NSCLC) for which there is no satisfactory standard therapy. In one embodiment, a subject with advanced ALK-positive NSCLC has received a previous first-generation ALK TKI therapy (e.g., crizotinib) treatment. In one embodiment, a subject with advanced ALK-positive NSCLC has received a previous second-generation ALK TKI therapy selected from ceritinib, alectinib and brigatinib. In one embodiment, a subject with advanced ALK-positive NSCLC has received a previous first-generation or second-generation ALK TKI therapy selected from crizotinib, ceritinib, alectinib and brigatinib. In one embodiment, a subject with advanced ALK-positive NSCLC has received two or three previous ALK TKI therapy treatments, wherein lorlatinib is a second-line or third-line therapy. In one embodiment, a subject with a solid tumor carrying an ALK rearrangement or activating ALK mutation has received at least one previous systemic anticancer therapy treatment. In one embodiment, the subject with a solid tumor carrying an ALK rearrangement or activating ALK mutation has no existing satisfactory standard therapy. In certain embodiments, the subject has an ALK resistance mutation (e.g., a single mutation and / or a compound mutation). In certain embodiments, the subject has ALK G1202R. In one embodiment, the solid tumor is a locally advanced or metastatic solid tumor. In certain embodiments, the late or metastatic ALK positive NSCLC is a locally advanced or metastatic ALK positive NSCLC.In certain embodiments, the advanced or metastatic ALK-positive NSCLC is locally advanced or metastatic ALK-positive NSCLC carrying an ALK rearrangement.

[0013] In one embodiment, the compound is administered in an amount from about 5 mg to about 400 mg once a day (QD) or twice (BID). In one embodiment, the compound is administered in an amount from about 15 mg to about 200 mg once a day (QD) or twice (BID) (by weight of compound 1). In one embodiment, the compound is administered in an amount from about 15 mg to about 200 mg once a day (QD) (by weight of compound 1). In one embodiment, the compound is administered in an amount from about 15 mg, 25 mg, 50 mg, 100 mg, 150 mg or 200 mg once a day (QD) (by weight of compound 1).

[0014] In one embodiment, the compound is administered in an amount from about 10 mg to about 150 mg once a day (QD) or twice a day (BID) (based on the weight of Compound 1). In one embodiment, the compound is administered in an amount from about 10 mg to about 150 mg once a day (QD) (based on the weight of Compound 1). In one embodiment, the compound is administered in an amount from about 10 mg, 15 mg, 25 mg, 50 mg, 100 mg, or 150 mg once a day (QD) (based on the weight of Compound 1).

[0015] In one embodiment, the compound is administered in an amount from about 10 mg to about 100 mg once a day (QD) or twice a day (BID) (based on the weight of Compound 1). In one embodiment, the compound is administered in an amount from about 10 mg to about 100 mg once a day (QD) (based on the weight of Compound 1). In one embodiment, the compound is administered in an amount from about 10 mg, 15 mg, 25 mg, 50 mg or 100 mg once a day (QD) (based on the weight of Compound 1).

[0016] In one embodiment, the compound is administered in an amount from about 25 mg to about 250 mg once a day (QD) or twice a day (BID) (based on the weight of Compound 1). In one embodiment, the compound is administered in an amount from about 25 mg to about 250 mg once a day (QD) (based on the weight of Compound 1). In one embodiment, the compound is administered in an amount from about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg once a day (QD) (based on the weight of Compound 1).

[0017] In one embodiment, the compound is administered to a subject on an empty stomach (e.g., at least 1 hour before and no earlier than 2 hours after ingestion of food and / or beverages other than water). In one embodiment, the compound is administered after the subject ingests food and / or beverages. In one embodiment, the compound is administered in the absence of a strong inhibitor of CYP3A4 or a sensitive substrate of CYP3A4. In one embodiment, the compound is administered in the presence of a strong inhibitor of CYP3A4 or a sensitive substrate of CYP3A4. In one embodiment, the compound is administered in the absence of a sensitive substrate of CYP2C8. In one embodiment, the compound is administered in the presence of a sensitive substrate of CYP2C8. In one embodiment, the compound is administered in the absence of a substrate of P-gp / multidrug resistance protein 1 (MDR1), a substrate of BCRP / breast cancer resistance protein (ABCG2), OATP1B1, OATP1B3, or MATE1. In one embodiment, the compound is administered in the presence of a substrate for P-gp / multidrug resistance protein 1 (MDR1), a substrate for BCRP / breast cancer resistance protein (ABCG2), OATP1B1, OATP1B3, or MATE1. In one embodiment, the compound is administered in the absence of a gastric acid reducing agent (e.g., a proton pump inhibitor). In one embodiment, the compound is administered in the presence of a gastric acid reducing agent. In one embodiment, the compound is administered in the absence of a strong inducer of CYP3A4. In one embodiment, the compound is administered in the presence of a strong inducer of CYP3A4. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Phase 1 and Phase 2 study designs are shown.

[0020] Figure 2Compound 1 is shown to induce regression of a patient-derived xenograft model of MR619 cholangiocarcinoma (STRN-ALK G1202R) implanted subcutaneously in NSG mice. The vehicle was 20% HP-β-CD and was used to formulate Compound 1. Lorlatinib was tested at 5 mg / kg - a dose selected to approximate the free drug exposure of the 100 mg QD human dose (Shaw et al., Lancet Oncol 2017; 18(12): 1590; Yamazaki et al., J Pharm Exp Ther 2014; 351(1): 67) and formulated in 2 equivalents of HCl + 20% HP-β-CD in water. All treatments were well tolerated. No dosing was performed on weekends; in other words, 5 days of dosing and 2 days of rest. Mean ± SEM are plotted. BID = twice a day; PO = oral administration.

[0021] Figure 3 The activity of various inhibitors against ALK activating mutations in neuroblastoma is shown. Biochemical analysis was performed using purified ALK kinase and fluorescent substrate (PhosphoSens Assay, Shults and Imperiali. J Am Chem Soc 2003; 125(47): 14248). Cell viability assays (3 days) were performed using Kelly (ALK F1174L), SH-SY5Y (ALK F1174L) and NB-1 (ALKEx2-3del) human neuroblastoma cell lines. NB-1 is known to have ALK overexpression, but it has been determined that it also has a partial deletion of ALK near exon 2-3 (Okubo et al., Oncogene 2012; 31(44): 4667). All data are from n≥2 replicates. Average values ​​are plotted.

[0022] Figure 4 Shown are the activities of various ALK inhibitors against the human anaplastic large cell lymphoma cell line Karpas299 carrying the NPM1-ALK fusion in a 3-day cell viability assay or an ALK phosphorylation ELISA assay. 50 Values ​​are indicated above the bars. All data are from n ≥ 2 replicates. Mean values ​​are plotted.

[0023] Figure 5 Figure 2 shows the activity of various ALK inhibitors against Aska-SS with ALK deletion surrounding exons 2-17 in a 3-day cell viability assay and ALK phosphorylation ELISA assay. 50 Values ​​are indicated above the bars. All data are from n ≥ 2 replicates. Mean values ​​are plotted.

[0024] Figure 6The inhibition of cell viability by various inhibitors in the MR448re cell line carrying the EML4-ALK v3 G1202R / T1151M mutation is shown. 50 Values ​​are in nM.

[0025] Figure 7 Inhibition of cell viability by various inhibitors in different cells carrying EML4-ALK fusion (with or without resistance mutations), ETV6-TRKB fusion or TPM3-TRKA fusion. 50 (nM) values ​​were plotted as a heat map.

[0026] FIG. 8A to FIG. 8D Inhibition of pALK in PDX tumors bearing HIP1-ALK is shown. Abbreviations: β2m = β2-microglobulin; BID = twice daily; HP-β-CD = 2-hydroxypropyl-β-cyclodextrin; PO = oral; QD = once daily; SEM = standard error of the mean. Mice bearing PDX tumors bearing HIP1-ALK received a single dose (QD×1) or BID×5 days (BID×5) of oral vehicle (20% HP-β-CD), compound 1, or lorlatinib, and then tumors were collected at designated time points (n=2 or 3) and analyzed by Western blotting. Fig. 8A Quantification of pALK after QD x 1 administration is shown. Figure 8B Quantification of pALK after BID x 5 administration is shown. Figure 8C Quantification of ALK after QD×1 administration is shown. Fig.8D Quantification of ALK after BID x 5 administration is shown. Anti-β2m is a loading control that does not recognize mouse β2m.

[0027] FIG. 9A to FIG. 9G Inhibition of signaling through the MAPK and PI3K / AKT pathways and induction of apoptosis in PDX tumors bearing HIP1-ALK are shown. Abbreviations: β2m = β2-microglobulin; BID = twice daily; HP-β-CD = 2-hydroxypropyl-β-cyclodextrin; PDX = patient-derived xenograft; PO = oral; QD = once daily; SEM = standard error of the mean. Mice bearing PDX tumors bearing HIP1-ALK were treated with a single dose (QD×1) or BID×5 days (BID×5) of oral vehicle (20% HP-β-CD), compound 1, or lorlatinib, and then tumors were collected at the indicated time points (n=2 or 3) and analyzed by Western blotting. Anti-β2m is a loading control that cannot recognize mouse β2m. pERK is a marker for MAPK signaling, pAKT and pS6 are markers for PI3K / AKT signaling, and cleaved PARP is a marker for apoptosis. Fig. 9AShown is the quantification of pERK / ERK after QD x 1 administration. Fig. 9B Quantification of pERK / ERK after BID x 5 administration is shown. Fig. 9C Shown is the quantification of pAKT / AKT after QD x 1 administration. Fig.9D Shown is the quantification of pAKT / AKT after BID administration. Fig.9E Shown is the quantification of pS6 / S6 after QD x 1 administration. Fig.9F Shown is the quantification of pS6 / S6 after BID x 5 administration. Figure 9G Shown is the quantification of cleaved PARP / β2m after QD×1 administration.

[0028] Fig.10 Compound 1 was shown to exhibit potent antitumor activity in a patient-derived cell line (PDC) xenograft mouse model (nude mice subcutaneously implanted with MR448re cells (EML4-ALK_G1202R / T1151M expressing PDC)).

[0029] Fig.11 It was shown that compound 1 can overcome the ALK G1202R compound mutation (BaF3 model).

[0030] Fig.12 An overview of the food effect study design is shown.

[0031] Fig.13 An overview of the design of a drug interaction study is shown.

[0032] Fig.14 is a representative XRPD pattern of Form 2 of Compound 1 free base.

[0033] Fig.15 is a representative DSC thermogram of Form 2 of Compound 1 free base.

[0034] Fig.16 is a representative DVS isotherm of Form 2 of Compound 1 free base.

[0035] Fig.17 is a representative depiction of the unit cell axes from a single crystal X-ray diffraction study of Form 2 of Compound 1 free base.

[0036] Fig.18 The plate layout of the viability assay portion of the combination study with osimertinib is shown.

[0037] Fig.19 Layout of conditions showing the in vitro signaling pathway studies portion of the combination study with osimertinib.

[0038] Fig. 20A Patient treatment history for the YU-1077 cell line is shown. Fig. 20B Sanger sequencing confirmation is shown. E6:A20 indicates that EML4 exon 6 is fused to ALK exon 20. NCBI sequence IDs for EML4 and ALK are provided.

[0039] Fig.21 Dose-response curves are provided showing the activity of various compounds against the YU-1077 cell line in a 3-day viability assay. Mean values ​​± SEM are plotted, n=5. IC 50 Values ​​were calculated using a fixed Emax = 50%.

[0040] Fig. 22 Shown are Western blots showing the effects of ALK TKI on ALK kinase activity (pALK) and downstream signaling (pERK, pAKT, pS6) in the YU-1077 cell line. Cells were treated for 6 hours. p = phosphorylated form of each protein marker.

[0041] Fig.23A Representative MRI images are shown, demonstrating YU-1077 tumor growth in the brain over 2 weeks, which was completely inhibited by Compound 1. Visible tumor masses are indicated by arrows. Fig. 23B 3D modeling of brain MRI scans is shown to determine tumor volume. Visible tumor masses are highlighted with arrows and pattern fills. Images from each mouse are superimposed together. All treatments were administered orally and were well tolerated. The vehicle was 20% HP-β-CD and was used to formulate compound 1. Alectinib was formulated in 20% PEG-400 and 3% Tween 80 in water.

[0042] Fig.24A Compound 1 is shown to inhibit brain YU-1077 tumor growth. Tumor volumes were determined by 3D modeling. Mean ± SEM are plotted. The number of mice per cohort is as indicated, except for the final data point for the alectinib cohort (n=6 instead of n=7). Fig. 24B Survival analysis is shown. DETAILED DESCRIPTION

[0043] definition

[0044] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art in the field of the present disclosure. The following references provide general definitions of many terms used in the present disclosure to technicians: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd edition, 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th edition, R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, unless otherwise indicated, the following terms have the following meanings assigned to them.

[0045] In some embodiments, chemical structures and corresponding chemical names are disclosed. In the event of a conflict, the chemical structure, rather than the name, controls the meaning.

[0046] As used herein, the terms "comprising" and "including" can be used interchangeably. The terms "comprising" and "including" should be interpreted as stipulating the presence of the features or components mentioned, but not excluding the presence or addition of one or more features or components or combinations thereof. In addition, the terms "comprising" and "including" are intended to include examples covered by the term "consisting of". Therefore, the term "consisting of" can be used instead of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0047] The term "consisting of" means that a subject has at least 90%, 95%, 97%, 98% or 99% of the features or components it consists of. In another embodiment, the term "consisting of" excludes any other features or components from the scope of any subsequent description, except those features or components that are not essential to the technical effect to be achieved.

[0048] Unless otherwise specified or obvious from the context, as used herein, the term "or" should be understood as inclusive. Unless otherwise explicitly stated or clearly different from the context, as used herein, the terms "a", "an", and "the" should be understood as singular or plural. For example, when a compound provided herein is administered to a "patient", it includes administering the compound to an individual patient or a patient population.

[0049] As used herein and unless otherwise indicated, "stereoisomer" refers to various stereoisomeric forms of compounds containing one or more asymmetric centers or steric hindrances in the structure. In some embodiments, stereoisomers are enantiomers, mixtures of enantiomers, atropisomers or tautomers thereof. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer or geometric isomer (e.g., atropisomer), or may be in the form of a mixture of stereoisomers, including a racemic mixture and a mixture rich in one or more stereoisomers. In some embodiments, compounds provided herein may be atropisomers. In certain embodiments, atropisomers are stereoisomers produced due to hindered rotation around a single bond, wherein energy differences due to steric strain or other factors produce sufficiently high rotational barriers to allow separation of single conformers. Stereoenantiomers can be separated from a mixture by methods known to those skilled in the art (including the formation and crystallization of chiral high pressure liquid chromatography (HPLC) and chiral salts); or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions, p. 268 (EL Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses compounds in the form of individual isomers that are substantially free of other isomers and alternatively in the form of mixtures of various isomers.

[0050] In certain embodiments, provided herein are compounds that can be racemic. In certain embodiments, provided herein are compounds that may be enriched in one enantiomer. For example, provided herein are compounds that may have greater than about 30%ee, about 40%ee, about 50%ee, about 60%ee, about 70%ee, about 80%ee, about 90%ee or even about 95% or greater ee. In certain embodiments, provided herein are compounds that may have more than one stereocenter. In certain such embodiments, provided herein are compounds that may be enriched in one or more diastereomers. For example, provided herein are compounds that may have greater than about 30%de, about 40%de, about 50%de, about 60%de, about 70%de, about 80%de, about 90%de or even about 95% or greater de.

[0051] In certain embodiments, therapeutic preparations can be enriched to mainly provide a kind of enantiomer of compound.Enantiomer-enriched mixtures can include, for example, at least about 60 mol % of a kind of enantiomer, or more specifically at least about 75 mol %, about 90 mol %, about 95 mol % or even about 99 mol %.In certain embodiments, the compound enriched in a kind of enantiomer is substantially free of another kind of enantiomer, wherein "substantially free of" means that as compared with the amount of another kind of enantiomer in, for example, a composition or a mixture of compounds, the material in question accounts for less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1%.For example, if a composition or a mixture of compounds contains about 98 grams of the first enantiomer and about 2 grams of the second enantiomer, it can be said that it contains about 98 mol % of the first enantiomer and only about 2% of the second enantiomer.

[0052] In certain embodiments, the therapeutic preparation can be enriched to provide primarily one diastereomer of the compound. A diastereoisomer-enriched mixture can contain, for example, at least about 60 mole % of one diastereomer, or more specifically at least about 75 mole %, about 90 mole %, about 95 mole % or even about 99 mole %.

[0053] In some embodiments, a portion of a compound exists as a mixture of tautomers. A "tautomer" is a structural isomer of a portion or compound that is easily interconverted with another structural isomer. For example, a pyrazole ring has two tautomers:

[0054]

[0055] They differ in the positions of pi bonds and hydrogen atoms. Unless expressly stated otherwise, a diagram of one tautomer of a moiety or compound encompasses all possible tautomers.

[0056] The term "subject" contemplated for administration includes, but is not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult of at least 40 years of age. In certain embodiments, the subject is an adult of at least 50 years of age. In certain embodiments, the subject is an adult of at least 60 years of age. In certain embodiments, the subject is an adult of at least 70 years of age. In certain embodiments, the subject is an adult of at least 18 years of age or at least 12 years of age. As used herein and unless otherwise indicated, a human subject to whom a therapeutic agent (e.g., a compound as described herein) is intended to be administered to treat, prevent, or manage a disease, disorder, or condition, or a symptom thereof, is also referred to as a "patient."

[0057] As used herein, the therapeutic agent of "preventing" a disease or illness refers to a compound that, in a statistical sample, reduces the incidence of a disease or illness in a treated sample relative to an untreated control sample, or delays the onset of one or more symptoms of a disease or illness relative to an untreated control sample or reduces its severity. These effects are also referred to as "preventive" effects. Therefore, as used herein and unless otherwise indicated, the term "prevention (prevention / preventing)" refers to a method for obtaining a beneficial or desired result, including but not limited to a preventive benefit. For preventive benefit, a therapeutic agent can be administered to a patient at risk of suffering from a specific disease or to a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease may not yet be made. In one embodiment, a therapeutic agent is administered before the clinical manifestation of an unwanted disease (e.g., a disease or other unwanted state of a subject) to obtain a preventive benefit (e.g., it protects the subject from developing an unwanted disease).

[0058] As used herein and unless otherwise indicated, the term "treatment" refers to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, overall or partial alleviation of symptoms associated with a disease or disorder or patient, reduction in disease extent, a stable (i.e., non-worsening) disease state, a delay or slowing of disease progression, an improvement or alleviation of the disease state, and relief (whether partial or total), whether detectable or undetectable. "Treatment" may also mean prolonged survival, such as compared to expected survival when not receiving treatment. In one embodiment, "treatment" includes administering a therapeutic agent after the occurrence of an unwanted disorder (i.e., intended to alleviate, improve, or stabilize an existing unwanted disorder or its side effects).

[0059] As used herein and unless otherwise indicated, "cancer" refers to any malignant and / or invasive growth or tumor caused by abnormal cell growth, including solid tumors (named after the cell type that forms them), blood cancers, bone marrow cancers, or cancers of the lymphatic system. Examples of solid tumors include, but are not limited to, sarcomas and carcinomas. Examples of blood cancers include, but are not limited to, leukemias, lymphomas, and myelomas. Cancers include, but are not limited to, primary cancers that originate from a specific site in the body, metastatic cancers that spread from the primary site to other parts of the body, recurrences after the initial primary cancer has remitted, and second primary cancers (i.e., new primary cancers of a different type from the previous cancer in people with a history of previous cancer).

[0060] As used herein and unless otherwise indicated, "abnormal cell growth" refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (non-cancerous) or malignant (cancerous). In some embodiments of the methods provided herein, the abnormal cell growth is cancer.

[0061] In some embodiments, the abnormal cell growth is a cancer mediated by anaplastic lymphoma kinase (ALK). In some such embodiments, the ALK is a genetically altered ALK. In other embodiments, the abnormal cell growth is a cancer mediated by ROS1 kinase. In some such embodiments, the ROS1 kinase is a genetically altered ROS1 kinase. In some embodiments, the abnormal cell growth is a cancer, specifically NSCLC. In some such embodiments, the NSCLC is mediated by ALK or ROS1. In specific embodiments, the cancer is NSCLC mediated by a genetically altered ALK or a genetically altered ROS1.

[0062] As used herein and unless otherwise indicated, the term "managing" encompasses preventing recurrence of a particular disease or condition in a patient already suffering from that disease or condition, prolonging the time a patient already suffering from that disease or condition maintains remission, reducing mortality in a patient, and / or maintaining a reduction in the severity of symptoms associated with the disease or condition being managed or avoiding symptoms.

[0063] As used herein, an "effective amount" refers to an amount sufficient to achieve a desired biological effect. As used herein, a "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic effect. For example, a therapeutically effective amount may refer to an amount sufficient to ameliorate at least one sign or symptom of cancer.

[0064] A "response" to a treatment method can include a decrease or improvement in negative symptoms, a slowing of progression of the disease or its symptoms, an increase in beneficial symptoms or clinical outcomes, a reduction in side effects, stabilization of the disease, partial or complete cure of the disease, etc.

[0065] As used herein and unless otherwise indicated, the term "relapse" refers to a condition, disease or disorder that responded to (eg, achieved a complete response) a prior treatment and then progressed. Prior treatment may include one or more lines of therapy.

[0066] As used herein and unless otherwise indicated, the term "refractory" refers to a condition, disease or disorder that has not responded to previous treatment, which may include one or more lines of therapy.

[0067] As used herein and unless otherwise indicated, the terms "about" and "approximately" when used in connection with a dose, amount or weight percentage of a composition or dosage form ingredient means a dose, amount or weight percentage that one of ordinary skill in the art considers to provide a pharmacological effect equivalent to that obtained by a specified dose, amount or weight percentage. In certain embodiments, the terms "about" and "approximately" when used in this context encompass doses, amounts or weight percentages within 30%, within 20%, within 15%, within 10% or within 5% of a specified dose, amount or weight percentage.

[0068] As used herein and unless otherwise specified, the terms "about" and "approximately" when used in conjunction with a numerical value or range of values ​​used to characterize a particular solid form, e.g., a particular temperature or temperature range, such as, for example, describing a melting, dehydration, desolvation, or glass transition temperature; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or moisture content, expressed, for example, in mass or percentage; or a peak position, such as, for example, in an analysis by IR or Raman spectroscopy or XRPD; indicate that the value or range of values ​​may deviate to an extent that is considered reasonable by a person of ordinary skill in the art while still describing the particular solid form. For example, in a particular embodiment, the terms "about" and "approximately" when used in this context indicate that the numerical value or range of values ​​may vary within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the stated value or range of values. For example, in some embodiments, the values ​​of XRPD peak positions can vary up to ±0.2 degrees 2θ while still describing a specific XRPD peak. In one embodiment, the values ​​of XRPD peak positions can vary up to ±0.1 degrees 2θ. In one embodiment, the values ​​of XRPD peak positions can vary up to ±0.05 degrees 2θ.

[0069] The term "between" includes the endpoint numbers on both ends of the range. For example, the range described by "between 3 and 5" includes the numbers "3" and "5".

[0070] As used herein and unless otherwise indicated, the term "pharmaceutically acceptable" refers to salts that are suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1–19. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, L-arginine, benthamine, benzathine, betaine, calcium hydroxide, choline, danol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, salts of Na, Ca, K, Mg, Zn, or other metals.

[0071] Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or incidental presence of such solvents.

[0072] Pharmaceutically acceptable anionic salts include, but are not limited to, acetate, aspartate, benzenesulfonate, benzoate, benzenesulfonate, bicarbonate, bitartrate, bromide, camphorsulfonate, carbonate, chloride, citrate, decanoate, edetate, essulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, methylsulfate, mucate, naphthenate, nitrate, octanoate, oleate, palmitate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, theoclorate, and toluenesulfonate.

[0073] As used herein and unless otherwise indicated, the term "solid form" and related terms refer to a physical form that is not predominantly liquid or gaseous. The solid form may be crystalline, amorphous, or a mixture thereof.

[0074] Compound

[0075] In one embodiment, the compound used in the methods provided herein is a compound of the formula, also referred to as "Compound 1" or a compound of Formula (I):

[0076]

[0077] or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. The chemical name of compound 1 is (19R)-5-chloro-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2 , 6 .0 8 , 12 .0 13 , 18 ] pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decene-22-amine, and described in International Application Publication No. WO 2021 / 226269, the entire contents of which are incorporated herein by reference. As used herein, "Compound 1", "Compound 1 free base", "Compound 1 (free base)" and "free base Compound 1" are used interchangeably.

[0078] It should be understood that when a compound as described herein is provided in the form of its pharmaceutically acceptable salt, the weights thereof refer to the portion excluding the salt portion (ie, as Compound 1 free base), unless otherwise indicated.

[0079] In one embodiment, compound 1 (free base) is used in the methods provided herein. In one embodiment, the tautomers of compound 1 are used in the methods provided herein. In one embodiment, compound 1 substantially free of (S)-enantiomers is used in the methods provided herein. As used herein, "substantially free" means that the presence of (S)-enantiomers is less than about 10% by weight of compound 1 (e.g., less than about 5% by weight, less than about 1% by weight, less than about 0.05% by weight, less than about 0.02% by weight, or less than about 0.01% by weight). In one embodiment, compound 1 is substantially pure, and its enantiomeric purity is at least about 98% (e.g., about 99%, 99.5%, 99.8%, or 99.9%).

[0080] In one embodiment, the (S)-enantiomer of Compound 1 is used in the methods provided herein. In one embodiment, the tautomer of the (S)-enantiomer of Compound 1 is used in the methods provided herein. In one embodiment, a pharmaceutically acceptable salt of the (S)-enantiomer of Compound 1 is used in the methods provided herein.

[0081] In one embodiment, the racemic mixture of Compound 1 is used in the methods provided herein. In one embodiment, a tautomer of the racemic mixture of Compound 1 is used in the methods provided herein. In one embodiment, a pharmaceutically acceptable salt of the racemic mixture of Compound 1 is used in the methods provided herein.

[0082] In one embodiment, a solid form of Compound 1 is used in the methods provided herein. In one embodiment, a solid form of the free base of Compound 1 is used in the methods provided herein. In one embodiment, Form 2 of Compound 1 is used in the methods provided herein. Fig.14 A representative XRPD pattern of Form 2 of Compound 1 is provided in .

[0083] In one embodiment, a solid form comprising a free base of Compound 1 for use in the methods provided herein is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or all XRPD peaks located at about 7.6, 9.4, 11.2, 12.4, 13.2, 14.3, 15.4, 15.6, 16.2, 16.9, 17.9, 18.9, 21.1, 21.6, 21.8, 22.5, 22.7, 23.0, 24.5, 24.9, 27.0, and 28.8 ° 2θ when measured using Cu Ka radiation (e.g., 2θ ± 0.2 degrees). In one embodiment, the solid form is characterized by at least 3 peaks. In one embodiment, the solid form is characterized by at least 5 peaks. In one embodiment, the solid form is characterized by at least 7 peaks. In one embodiment, the solid form is characterized by at least 9 peaks. In one embodiment, the solid form is characterized by at least 11 peaks. In one embodiment, the solid form is characterized by all peaks.

[0084] In one embodiment, a solid form comprising a free base of Compound 1 for use in the methods provided herein is characterized by an XRPD pattern comprising at least three peaks selected from the group consisting of about (e.g., ± 0.2°) 11.2, 12.4, 13.2, 14.3, 18.9, 21.1, 21.6, 21.8, 22.5, 22.7, 23.0, and 27.0 ° 2θ when measured using Cu Ka radiation. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of about (e.g., ± 0.2°) 11.2, 12.4, 13.2, 14.3, 18.9, 21.1, 21.6, 21.8, 22.5, 22.7, 23.0, and 27.0 ° 2θ. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of approximately (e.g., ± 0.2°) 11.2, 12.4, 13.2, 14.3, 18.9, 21.1, 21.6, 21.8, 22.5, 22.7, 23.0, and 27.0° 2θ.

[0085] In one embodiment, the solid form of the free base of compound 1 used in the methods provided herein is characterized by an XRPD pattern comprising peaks at approximately (e.g., ± 0.2°) 12.4, 18.9, and 21.1° 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately (e.g., ± 0.2°) 13.2 and 22.5° 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately (e.g., ± 0.2°) 11.2 and 22.7° 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately (e.g., ± 0.2°) 11.2, 12.4, 13.2, 14.3, 18.9, 21.1, 21.8, 22.5, 22.7, 23.0, and 27.0° 2θ.

[0086] In one embodiment, the solid form is characterized by an XRPD pattern that is Fig.14 The XRPD pattern matches that shown in .

[0087] In one embodiment, the XRPD patterns described herein are obtained using Cu Ka radiation. In one embodiment, the XRPD patterns are measured using Cu Ka radiation, wherein the Cu Ka radiation comprises a wavelength of The Kα1 radiation and wavelength are of Kα2 radiation, with a Kα1:Kα2 ratio of 0.5.

[0088] Fig.15 A representative DSC thermogram of Form 2 is provided. In one embodiment, a solid form comprising the free base of Compound 1 for use in the methods provided herein exhibits (as characterized by DSC) a thermal event (endotherm) with an onset temperature of about 260°C (e.g., ±2°). In one embodiment, the thermal event has a peak temperature of about 261°C (e.g., ±2°). In one embodiment, without being bound by a particular theory, the thermal event corresponds to melting. In one embodiment, the solid form is characterized by a DSC thermogram that is similar to Fig.15 In one embodiment, the DSC thermogram is as measured by DSC using a scan rate of about 10°C / min.

[0089] Fig.16 A representative DVS isotherm of Form 2 is provided. In one embodiment, a solid form comprising a free base of Compound 1 for use in the methods provided herein exhibits a weight gain of about 0.3% (e.g., ±0.05%) when subjected to an increase in relative humidity from about 0% relative humidity to about 90% relative humidity. In one embodiment, the solid form is characterized by a DVS isotherm that is Fig.16In one embodiment, the DVS isotherm is measured at about 25°C.

[0090] In one embodiment, the solid form of the free base of Compound 1 for use in the methods provided herein is characterized by the approximate unit cell dimensions: α = 90°, β = 90°, and γ = 90°. In one embodiment, Form 2 has the following approximate unit cell dimensions: α = 90°, β = 90°, and γ = 90°. In one embodiment, Form 2 has the following approximate unit cell dimensions: α = 90°, β = 90° and γ = 90°. In one embodiment, Form 2 has a unit cell with space group P212121. In one embodiment, the volume of Form 2 is about / unit cell. In one embodiment, the Z value of Form 2 is 4. In one embodiment, the density of Form 2 is about 1.336 g / cm 3 .

[0091] In one embodiment, the solid form containing the free base of compound 1 used in the methods provided herein is anhydrous. In one embodiment, the solid form is a crystalline anhydrous free base of compound 1. In one embodiment, the solid form is substantially free of amorphous compound 1. In one embodiment, the solid form is substantially free of other crystalline forms of compound 1. In one embodiment, the solid form is substantially free of a salt of compound 1. In one embodiment, the solid form is not solvated. In one embodiment, one or more residual solvents may be present in the solid form, but the residual solvent does not form a solvate of compound 1. In one embodiment, the solid form is substantially pure. In one embodiment, the solid form is substantially chemically pure. In one embodiment, the solid form is about 95% by weight or more chemically pure. In one embodiment, the solid form is about 96% by weight or more chemically pure. In one embodiment, the solid form is about 97% by weight or more chemically pure. In one embodiment, the solid form is about 98% by weight or more chemically pure. In one embodiment, the solid form is about 99% by weight or more chemically pure. In one embodiment, the solid form is substantially enantiomerically pure. In one embodiment, the solid form is about at least 98% enantiomerically pure. In one embodiment, the solid form is about at least 99% enantiomerically pure. In one embodiment, the solid form is about at least 99.5% enantiomerically pure. In one embodiment, the solid form is substantially physically pure.

[0092] In one embodiment, the solid form comprising the free base of Compound 1 for use in the methods provided herein is a solid form comprising Form 2 of the free base of Compound 1.

[0093] How to use

[0094] In one embodiment, provided herein is a method of treating cancer comprising administering a heteroaromatic macrocyclic ether compound, such as Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0095] In one embodiment, provided herein is a method of treating, preventing or managing solid tumors using a heteroaromatic macrocyclic ether compound (eg, Compound 1), or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0096] In one embodiment, provided herein is a method of treating a subject having a solid tumor, comprising administering to the subject a therapeutically effective amount of Compound 1:

[0097]

[0098] or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0099] In one embodiment, the cancer is lung cancer, bile duct cancer, colorectal cancer, angiosarcoma, sarcoma, hemangioendothelioma, esophageal cancer, kidney cancer, breast cancer, colon cancer, thyroid cancer, neuroblastoma, blood cancer, anaplastic large cell lymphoma (ALCL), atypical meningioma, breast cancer, cholangiocarcinoma, gastric cancer, glioblastoma, inflammatory myofibroblastic tumor (IMT), inflammatory hepatocellular adenoma (HCA), melanoma, pancreatic cancer, papillary thyroid cancer, salivary gland cancer, serous ovarian cancer, or Spitz-like tumor.

[0100] In one embodiment, the solid tumor is an advanced solid tumor. In one embodiment, the solid tumor is a locally advanced or metastatic solid tumor. In one embodiment, the advanced solid tumor relapses after prior treatment with a tyrosine kinase inhibitor (TKI), is refractory to prior treatment with a tyrosine kinase inhibitor, or is resistant to prior treatment with a tyrosine kinase inhibitor. In one embodiment, the solid tumor is non-small cell lung cancer (NSCLC). In one embodiment, the solid tumor is advanced NSCLC. In one embodiment, the solid tumor is metastatic. In one embodiment, the solid tumor is CNS metastatic. In one embodiment, the solid tumor is metastatic NSCLC. In one embodiment, the solid tumor is CNS metastatic NSCLC. As used herein and unless otherwise indicated, "advanced tumor" refers to a tumor that is incurable or grows beyond the original site of origin, whether locally advanced or metastatic.

[0101] In one embodiment, the solid tumor (or cancer) is ALK positive. In one embodiment, the solid tumor is ALK positive NSCLC. In one embodiment, the solid tumor is an advanced or metastatic ALK positive solid tumor. In one embodiment, the solid tumor is an advanced ALK positive solid tumor. In one embodiment, the solid tumor is an advanced ALK positive NSCLC. In one embodiment, the solid tumor is a metastatic ALK positive solid tumor. In one embodiment, the solid tumor is a locally advanced or metastatic ALK positive solid tumor. In one embodiment, the solid tumor is a locally advanced ALK positive solid tumor. In one embodiment, the solid tumor is a CNS metastatic ALK positive solid tumor. In one embodiment, the solid tumor is a metastatic ALK positive NSCLC. In one embodiment, the solid tumor is a CNS metastatic ALK positive NSCLC. In one embodiment, the solid tumor is a locally advanced or metastatic solid tumor carrying an ALK rearrangement or activating ALK mutation.

[0102] In one embodiment, the ALK positive solid tumor or cancer is anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, diffuse large B-cell lymphoma, esophageal squamous cell carcinoma, renal medullary carcinoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, cholangiocarcinoma, Spitz-like tumor, neuroblastoma or anaplastic thyroid cancer. In certain embodiments, the ALK positive solid tumor is anaplastic thyroid cancer. In one embodiment, the subject has not received previous therapy. In one embodiment, the subject is first used for (ie, has not received) tyrosine kinase inhibitor (TKI) therapy.

[0103] In one embodiment, the subject has been treated with one or more previous therapies. In one embodiment, the subject has been treated with at least one previous TKI therapy. In one embodiment, the subject has been treated with at least two previous TKI therapies. In one embodiment, the subject has been treated with one previous TKI therapy. In one embodiment, the subject has been treated with two previous TKI therapies. In one embodiment, the subject has been treated with three previous TKI therapies. In one embodiment, the TKI is an ALK TKI. In one embodiment, the ALK TKI is crizotinib, ceritinib, alectinib, brigatinib or lorlatinib. In certain embodiments, the subject with ALK-positive NSCLC has previously received at least one ALK TKI. In certain embodiments, one of the previous ALK TKIs is a 2nd or 3rd generation TKI (e.g., ceritinib, alectinib, brigatinib or lorlatinib). In certain embodiments, the subject with a solid tumor has previously received at least one previous systemic anticancer therapy. In certain embodiments, the subject with a solid tumor has no satisfactory standard therapy. In certain embodiments, the subject with locally advanced or metastatic ALK-positive NSCLC has received 1 prior 2nd generation ALK TKI (ceritinib, alectinib, brigatinib, or lorlatinib). In certain embodiments, the subject with locally advanced or metastatic ALK-positive NSCLC has received 2-3 prior 1st or 2nd generation ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib). In certain embodiments, the subject with locally advanced or metastatic ALK-positive NSCLC has received 2-3 prior ALK TKI treatments, with lorlatinib being the 2nd or 3rd line.

[0104] In one embodiment, the subject has not been treated with a prior systemic anticancer therapy. In one embodiment, the subject has been treated with at most one prior systemic anticancer therapy. In one embodiment, the subject has been treated with at least one prior systemic anticancer therapy. In one embodiment, the subject has been treated with at least two prior systemic anticancer therapies. In one embodiment, the subject has been treated with one prior systemic anticancer therapy. In one embodiment, the subject has been treated with two prior systemic anticancer therapies.

[0105] In one embodiment, the subject has not received a prior chemotherapy treatment. In one embodiment, the subject has received a prior chemotherapy treatment. In one embodiment, the subject has received up to two prior chemotherapy treatments. In one embodiment, the subject has received at least one prior chemotherapy treatment. In one embodiment, the subject has received at least two prior chemotherapy treatments. In one embodiment, the subject has received one prior chemotherapy treatment. In one embodiment, the subject has received two prior chemotherapy treatments.

[0106] In one embodiment, the subject has not received a prior immunotherapy treatment. In one embodiment, the subject has received a prior immunotherapy treatment. In one embodiment, the subject has received up to two prior immunotherapy treatments. In one embodiment, the subject has received at least one prior immunotherapy treatment. In one embodiment, the subject has received at least two prior immunotherapy treatments. In one embodiment, the subject has received one prior immunotherapy treatment. In one embodiment, the subject has received two prior immunotherapy treatments.

[0107] As used herein, "immunotherapy" refers to the treatment of diseases by activating or suppressing the immune system. Immunotherapy intended to induce or amplify immune responses is classified as activation immunotherapy, while immunotherapy that reduces or suppresses immune responses is classified as suppression immunotherapy. Immunotherapy can regulate immune effector cells (e.g., lymphocytes, macrophages, dendritic cells, natural killer cells (NK cells), cytotoxic T lymphocytes (CTLs), etc.) by targeting abnormal antigens expressed on the surface of tumor cells to work together to fight cancer. Exemplary immunotherapy includes, but is not limited to, checkpoint inhibitors (e.g., anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1) inhibitors, and programmed death ligand 1 (PD-L1) inhibitors). Exemplary PD-1 inhibitors include, but are not limited to, pembrolizumab (Keytruda), nivolumab (Opdivo), and cemilimab (Libtayo). Exemplary PD-L1 inhibitors include, but are not limited to, atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi). Exemplary CTLA-4 inhibitors include, but are not limited to, ipilimumab (Yervoy).

[0108] In one embodiment, the solid tumor is advanced or metastatic ALK-positive NSCLC, and the subject has been treated with at least one previous ALK TKI therapy. In one embodiment, the at least one previous ALK TKI therapy is ceritinib, alectinib, or brigatinib. In one embodiment, the at least one previous ALK TKI therapy is crizotinib, ceritinib, alectinib, or brigatinib. In one embodiment, the at least one previous ALK TKI therapy is ceritinib, alectinib, brigatinib, or lorlatinib. In one embodiment, the at least one previous ALK TKI therapy is crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib. In one embodiment, the subject has been treated with one or more previous systemic anticancer therapies. In one embodiment, the solid tumor is advanced or metastatic ALK-positive NSCLC, and the subject has progressed in the previous treatment.

[0109] In one embodiment, the solid tumor is advanced or metastatic ALK-positive NSCLC, and the subject has been treated with one prior ALK TKI therapy. In one embodiment, the prior ALK TKI therapy is ceritinib, alectinib, or brigatinib. In one embodiment, the at least one prior ALK TKI therapy is crizotinib, ceritinib, alectinib, or brigatinib. In one embodiment, the at least one prior ALK TKI therapy is ceritinib, alectinib, brigatinib, or lorlatinib. In one embodiment, the at least one prior ALK TKI therapy is crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib. In one embodiment, the subject has been treated with ≤2 prior chemotherapy and / or immunotherapy. In one embodiment, the subject has been treated with two or more prior chemotherapy and / or two or more prior immunotherapy.

[0110] In one embodiment, the solid tumor is advanced or metastatic ALK-positive NSCLC, and the subject has been treated with two or three prior ALK TKI therapies. In one embodiment, the two or three prior ALK TKI therapies are selected from crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In one embodiment, the subject has been treated with ≤2 prior chemotherapy and / or immunotherapy. In one embodiment, the subject has been treated with more than two prior chemotherapy and / or more than two prior immunotherapy.

[0111] In one embodiment, the solid tumor is advanced or metastatic ALK-positive NSCLC, and the subject has been treated with two or three prior ALK TKI therapies. In one embodiment, the solid tumor is advanced or metastatic ALK-positive NSCLC, and the subject has been treated with one prior ALK TKI therapy, and one ALK TKI is a 2nd or 3rd generation TKI (such as ceritinib, alectinib, brigatinib, or lorlatinib). In one embodiment, the second or third prior ALK TKI therapy is lorlatinib. In one embodiment, the subject has been treated with ≤2 prior chemotherapy and / or immunotherapy. In one embodiment, the subject has been treated with more than two prior chemotherapy and / or more than two prior immunotherapy.

[0112] In one embodiment, the subject has normal renal function. In one embodiment, the subject has a creatinine clearance of not less than about 90 mL / min (e.g., according to the Cockcroft-Gault formula). In one embodiment, the subject has a creatinine clearance of not less than about 80 mL / min (e.g., according to the Cockcroft-Gault formula). In one embodiment, the subject has a creatinine clearance of not less than about 60 mL / min (e.g., according to the Cockcroft-Gault formula).

[0113] In one embodiment, the compound used herein (Compound 1 or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof) is administered once daily (QD). In one embodiment, the compound is administered twice daily (BID). In certain embodiments, the compound used herein is Compound 1.

[0114] In one embodiment, the compound used herein (Compound 1 or its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof) is administered in an amount of from about 5 mg to about 400 mg per day (by weight of free base Compound 1). In one embodiment, the compound is administered in an amount of from about 15 mg to about 200 mg per day. In one embodiment, the compound is administered in an amount of from about 20 mg to about 200 mg per day. In one embodiment, the compound is administered in an amount of from about 25 mg to about 200 mg per day. In one embodiment, the compound is administered in an amount of from about 50 mg to about 200 mg per day. In one embodiment, the compound is administered in an amount of from about 5 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of from about 15 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of from about 20 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of from about 25 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of from about 15 mg to about 125 mg per day. In one embodiment, the compound is administered in an amount from about 20 mg to about 125 mg per day. In one embodiment, the compound is administered in an amount from about 25 mg to about 125 mg per day. In one embodiment, the compound is administered in an amount from about 15 mg to about 100 mg per day. In one embodiment, the compound is administered in an amount from about 20 mg to about 100 mg per day. In one embodiment, the compound is administered in an amount from about 25 mg to about 100 mg per day. In one embodiment, the compound is administered in an amount from about 50 mg to about 250 mg per day. In one embodiment, the compound is administered in an amount from about 50 mg to about 200 mg per day. In one embodiment, the compound is administered in an amount from about 50 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount from about 50 mg to about 125 mg per day. In one embodiment, the compound is administered in an amount from about 50 mg to about 100 mg per day. In one embodiment, the compound is administered in an amount from about 10 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount from about 10 mg to about 100 mg per day. In one embodiment, the compound is administered in an amount from about 10 mg to about 50 mg per day. In one embodiment, the compound is administered in an amount from about 10 mg to about 25 mg per day. In one embodiment, the compound is administered in an amount from about 15 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount from about 15 mg to about 100 mg per day. In one embodiment, the compound is administered in an amount from about 15 mg to about 50 mg per day.In one embodiment, the compound is administered in an amount from about 25 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount from about 50 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount from about 100 mg to about 150 mg per day.

[0115] In one embodiment, the compound is administered in an amount of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg per day.

[0116] In one embodiment, the amount is about 5 mg / day. In one embodiment, the amount is about 10 mg / day. In one embodiment, the amount is about 15 mg / day. In one embodiment, the amount is about 20 mg / day. In one embodiment, the amount is about 25 mg / day. In one embodiment, the amount is about 30 mg / day. In one embodiment, the amount is about 35 mg / day. In one embodiment, the amount is about 40 mg / day. In one embodiment, the amount is about 45 mg / day. In one embodiment, the amount is about 50 mg / day. In one embodiment, the amount is about 75 mg / day. In one embodiment, the amount is about 100 mg / day. In one embodiment, the amount is about 125 mg / day. In one embodiment, the amount is about 150 mg / day. In one embodiment, the amount is about 200 mg / day. In one embodiment, the amount is about 250 mg / day. As used herein, the weight refers to the weight of the free base compound 1. In certain embodiments, the compound used herein is compound 1.

[0117] In one embodiment, the compound used herein (Compound 1 or its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof) is administered in an amount from about 5 mg to about 400 mg (by weight of the free base Compound 1) once a day. In one embodiment, the compound is administered in an amount from about 10 mg to about 250 mg once a day. In one embodiment, the compound is administered in an amount from about 15 mg to about 200 mg once a day. In one embodiment, the compound is administered in an amount from about 25 mg to about 200 mg once a day. In one embodiment, the compound is administered in an amount from about 25 mg to about 200 mg once a day. In one embodiment, the compound is administered in an amount from about 50 mg to about 200 mg once a day. In one embodiment, the compound is administered in an amount from about 5 mg to about 150 mg once a day. In one embodiment, the compound is administered in an amount from about 10 mg to about 100 mg once a day. In one embodiment, the compound is administered in an amount from about 10 mg to about 150 mg once a day. In one embodiment, the compound is administered in an amount of about 15 mg to about 150 mg, once a day. In one embodiment, the compound is administered in an amount of about 25 mg to about 150 mg, once a day. In one embodiment, the compound is administered in an amount of about 50 mg to about 150 mg, once a day. In one embodiment, the compound is administered in an amount of about 100 mg to about 150 mg, once a day. In one embodiment, the compound is administered in an amount of about 20 mg to about 150 mg, once a day. In one embodiment, the compound is administered in an amount from about 25 mg to about 150 mg, once a day. In one embodiment, the compound is administered in an amount from about 25 mg to about 100 mg, once a day. In one embodiment, the compound is administered in an amount from about 25 mg to about 50 mg, once a day. In one embodiment, the compound is administered in an amount from about 25 mg to about 125 mg, once a day. In one embodiment, the compound is administered in an amount from about 10 mg to about 100 mg, once a day. In one embodiment, the compound is administered in an amount from about 15 mg to about 100 mg, once a day. In one embodiment, the compound is administered in an amount from about 15 mg to about 50 mg, once a day. In one embodiment, the compound is administered in an amount from about 25 mg to about 100 mg, once a day. In one embodiment, the compound is administered in an amount from about 25 mg to about 100 mg, once a day. In one embodiment, the compound is administered in an amount from about 50 mg to about 100 mg, once a day. In one embodiment, the compound is administered in an amount from about 50 mg to about 125 mg, once a day.In one embodiment, the compound is administered in an amount from about 50 mg to about 100 mg, once a day. In one embodiment, the compound is administered in an amount of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg, once a day. In one embodiment, the amount is about 5 mg, once a day. In one embodiment, the amount is about 10 mg, once a day. In one embodiment, the amount is about 15 mg, once a day. In one embodiment, the amount is about 20 mg, once a day. In one embodiment, the amount is about 25 mg, once a day. In one embodiment, the amount is about 30 mg, once a day. In one embodiment, the amount is about 35 mg, once a day. In one embodiment, the amount is about 40 mg, once a day. In one embodiment, the amount is about 45 mg, once a day. In one embodiment, the amount is about 50 mg, once a day. In one embodiment, the amount is about 75 mg, once a day. In one embodiment, the amount is about 100 mg, once a day. In one embodiment, the amount is about 125 mg, once a day. In one embodiment, the amount is about 150 mg, once a day. In one embodiment, the amount is about 200 mg, once a day. In one embodiment, the amount is about 250 mg, once a day. As used herein, the weight refers to the weight of the free base compound 1. In certain embodiments, the compound used herein is Compound 1.

[0118] In one embodiment, the compound used herein (Compound 1 or its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof) is administered in an amount from about 5 mg to about 400 mg (by weight of the free base Compound 1) twice a day. In one embodiment, the compound is administered in an amount from about 5 mg to about 250 mg twice a day. In one embodiment, the compound is administered in an amount from about 15 mg to about 250 mg twice a day. In one embodiment, the compound is administered in an amount from about 25 mg to about 250 mg twice a day. In one embodiment, the compound is administered in an amount from about 15 mg to about 200 mg twice a day. In one embodiment, the compound is administered in an amount from about 10 mg to about 150 mg twice a day. In one embodiment, the compound is administered in an amount from about 10 mg to about 100 mg twice a day. In one embodiment, the compound is administered in an amount from about 20 mg to about 200 mg twice a day. In one embodiment, the compound is administered in an amount from about 25 mg to about 200 mg twice a day. In one embodiment, the compound is administered in an amount from about 5 mg to about 100 mg, twice a day. In one embodiment, the compound is administered in an amount from about 15 mg to about 100 mg, twice a day. In one embodiment, the compound is administered in an amount from about 10 mg to about 50 mg, twice a day. In one embodiment, the compound is administered in an amount from about 15 mg to about 50 mg, twice a day. In one embodiment, the compound is administered in an amount from about 10 mg to about 100 mg, twice a day. In one embodiment, the compound is administered in an amount from about 25 mg to about 100 mg, twice a day. In one embodiment, the compound is administered in an amount from about 50 mg to about 100 mg, twice a day. In one embodiment, the compound is administered in an amount from about 5 mg to about 150 mg, twice a day. In one embodiment, the compound is administered in an amount from about 10 mg to about 150 mg, twice a day. In one embodiment, the compound is administered in an amount from about 15 mg to about 150 mg, twice a day. In one embodiment, the compound is administered in an amount from about 20 mg to about 150 mg twice a day. In one embodiment, the compound is administered in an amount from about 25 mg to about 150 mg twice a day.In one embodiment, the compound is administered in an amount of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg, twice a day. In one embodiment, the amount is about 5 mg, twice a day. In one embodiment, the amount is about 10 mg, twice a day. In one embodiment, the amount is about 15 mg, twice a day. In one embodiment, the amount is about 20 mg, twice a day. In one embodiment, the amount is about 25 mg, twice a day. In one embodiment, the amount is about 30 mg, twice a day. In one embodiment, the amount is about 35 mg, twice a day. In one embodiment, the amount is about 40 mg, twice a day. In one embodiment, the amount is about 45 mg, twice a day. In one embodiment, the amount is about 50 mg, twice a day. In one embodiment, the amount is about 75 mg, twice a day. In one embodiment, the amount is about 100 mg, twice a day. In one embodiment, the amount is about 125 mg, twice a day. In one embodiment, the amount is about 150 mg, twice a day. In one embodiment, the amount is about 200 mg, twice a day. In one embodiment, the amount is about 250 mg, twice a day. As used herein, the weight refers to the weight of the free base compound 1. In certain embodiments, the compound used herein is compound 1.

[0119] In one embodiment, the compound is administered orally.

[0120] In one embodiment, the compound is administered in the form of one or more tablets. In one embodiment, the unit dose strength of the tablet is about 5 mg, by weight of the free base compound 1. In one embodiment, the unit dose strength of the tablet is about 50 mg, by weight of the free base compound 1. In one embodiment, the unit dose strength of the tablet is about 75 mg, by weight of the free base compound 1. In one embodiment, the unit dose strength of the tablet is about 100 mg, by weight of the free base compound 1. In one embodiment, the unit dose strength of the tablet is about 125 mg, by weight of the free base compound 1. In one embodiment, the unit dose strength of the tablet is about 150 mg, by weight of the free base compound 1.

[0121] In one embodiment, the compound is administered to a fasting subject. In one embodiment, the compound is administered to a subject at least 1 hour before and no earlier than 2 hours after the intake of food and / or beverages other than water. In one embodiment, the compound is administered to a full subject. In one embodiment, the compound is administered together with the intake of food and / or beverages.

[0122] In one embodiment, after administration of Compound 1, the subject experiences an improvement in one or more symptoms selected from the group consisting of cognitive impairment, mood disorders, sleep disorders, dizziness, ataxia, epilepsy, psychotic effects, speech disorders, and weight gain (e.g., compared to previous TKI treatment). In one embodiment, the subject does not experience one or more symptoms selected from the group consisting of cognitive impairment, mood disorders, sleep disorders, dizziness, ataxia, epilepsy, psychotic effects, speech disorders, and weight gain after administration of the compound. In one embodiment, the subject experiences a decrease in the level of one or more of pALK, pERK, pAKT, and phosphorylated S6 after administration of the compound. In one embodiment, the subject experiences a decrease in the level of pALK after administration of the compound. In one embodiment, the subject experiences a decrease in the level of pERK after administration of the compound. In one embodiment, the subject experiences a decrease in the level of pAKT after administration of the compound. In one embodiment, the subject experiences a decrease in the level of phosphorylated-S6 after administration of the compound. In one embodiment, the subject experiences a decrease in the level of cleaved PARP after administration of the compound. In one embodiment, the subject experiences a decrease in the activity of the MAP kinase pathway, the PI3K / AKT pathway, or the JAK / STAT pathway, or any combination thereof in the tumor after administration of the compound. In one embodiment, the subject experiences a decrease in the activity of the MAP kinase pathway, the PI3K / AKT pathway, or the JAK / STAT pathway, or any combination thereof in a solid tumor after administration of the compound. In one embodiment, the subject experiences a decrease in the activity of the MAP kinase pathway in the tumor after administration of the compound. In one embodiment, the subject experiences a decrease in the activity of the MAP kinase pathway in the solid tumor after administration of the compound. In one embodiment, the subject experiences a decrease in the activity of the PI3K / AKT kinase pathway in the tumor after administration of the compound. In one embodiment, the subject experiences a decrease in the activity of the JAK / STAT kinase pathway in the tumor after administration of the compound. In one embodiment, the subject experiences a decrease in the activity of the JAK / STAT kinase pathway in the solid tumor after administration of the compound. In one embodiment, the subject experiences an increase in the expression level of one or more apoptosis markers in the tumor after administration of the compound. In one embodiment, the subject experiences an increase in the expression level of one or more apoptosis markers in a solid tumor after administration of the compound. In one embodiment, the subject experiences a decrease in the level of one or more proliferation markers (e.g., Ki 67) in a tumor after administration of the compound.In one embodiment, a change in the level of one or more markers provided herein is experienced 1 hour after administration of the compound. In one embodiment, a change in the level of one or more markers provided herein is experienced 12 hours after administration of the compound.

[0123] In some embodiments, the cancer is a disease in which cell proliferation is uncontrolled due to certain genetic changes. Some of these changes occur in genes encoding receptor tyrosine kinases (RTKs), which are membrane-bound proteins that transmit signals from outside the cell to promote cell survival, growth and proliferation. Abnormal RTK activation can lead to excessive cell growth, leading to cancer. In general, RTKs contain an N-terminal domain that binds to an extracellular ligand, a transmembrane domain, and a C-terminal kinase domain that catalyzes intracellular signal transduction.

[0124] In some embodiments, Compound 1 is an inhibitor of human anaplastic lymphoma kinase (ALK). ALK, also known as cluster of differentiation 246 (CD246), is an RTK encoded by the ALK gene. ALK and ROS1 are evolutionarily related; both belong to the insulin receptor superfamily, and their kinase domains share approximately 80% sequence similarity. Several ALK ligands in humans have been identified, including pleiotrophin and heparin-binding cytokine growth factor. Although the role of ALK in humans is still undetermined, a large body of evidence from mouse studies suggests that it is essential for the development of the nervous system. Like ROS1, ALK chromosomal rearrangements also result in constitutively active fusion proteins that promote oncogenic transformation through MAPK, JAK / STAT or other signaling pathways. ALK rearrangements account for 3-5% of NSCLC, roughly half of anaplastic large cell lymphoma (ALCL), and a subset of many other cancers, with the most prominent fusions being EML4-ALK in NSCLC and NPM1-ALK in ALCL. Oncogenic point mutations and ALK amplifications have also been observed, although at a much lower frequency than translocations. Crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are FDA-approved TKIs for the treatment of ALK-positive NSCLC and other cancers and can be used as first-line therapy or after previous therapy. For example, crizotinib shows an overall response rate of 60-80% and a median progression-free survival of 8-11 months, which is comparable to its activity in ROS1-positive NSCLC. For the above FDA-approved TKIs, despite initial responses, many resistance mutations have emerged. Some of these mutations, such as a combination of the L1196M gatekeeper mutation and the G1202R solvent front mutation, are resistant to all approved drugs. There is a need in the art for new treatments for ALK-positive cancers carrying resistance mutations.

[0125] In one embodiment, the compounds provided herein selectively inhibit ALK. In one embodiment, the compounds selectively inhibit ALK but not ROS1. By way of non-limiting example, the ratio of selectivity can be greater than a factor of about 1.5, greater than a factor of about 2, greater than a factor of about 3, greater than a factor of about 4, greater than a factor of about 5, or greater than a factor of about 10, wherein selectivity can be measured by a ratio of IC50 values, etc. In one embodiment, the selectivity of ALK for ROS1 is measured by the ratio of the IC50 value for ROS1 to the IC50 value for ALK.

[0126] In one embodiment, the compound selectively inhibits ALK but not TRK (e.g., TRKA, TRKB and / or TRBC). By way of non-limiting example, the ratio of selectivity can be greater than a factor of about 5, greater than a factor of about 10, greater than a factor of about 50, greater than a factor of about 100, greater than a factor of about 200, greater than a factor of about 400, greater than a factor of about 600, greater than a factor of about 800, greater than a factor of about 1000, greater than a factor of about 1500, greater than a factor of about 2000, greater than a factor of about 5000, or greater than a factor of about 10,000, wherein selectivity can be measured by a ratio of IC50 values, etc. In one embodiment, the selectivity of ALK to TRK is measured by the ratio of the IC50 value for TRK to the IC50 value for ALK.

[0127] In one embodiment, provided herein is a method for selectively inhibiting ALK but not ROS1, wherein the inhibition occurs in a cell. In one embodiment, provided herein is a method for selectively inhibiting ALK but not TRK (e.g., TRKA, TRKB and / or TRBC), wherein the inhibition occurs in a cell. In one embodiment, the method includes contacting ALK with an effective amount of a compound provided herein. In one embodiment, such contact occurs in a cell. In one embodiment, such contact occurs in a mammal (such as a human) cell. In one embodiment, such contact occurs in a human subject suffering from a cancer provided herein.

[0128] In one embodiment, provided herein is a method of selectively inhibiting ALK but not ROS1, wherein the inhibition occurs in a subject with cancer, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In certain embodiments, provided herein is a method of treating a subject with a cancer associated with ALK, the method comprising selectively inhibiting ALK but not ROS1 by administering to the subject an amount of a compound or pharmaceutical composition provided herein, wherein the amount is sufficient to selectively inhibit ALK but not ROS1.

[0129] In one embodiment, provided herein is a method of selectively inhibiting ALK but not TRK, wherein the inhibition occurs in a subject with cancer, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In certain embodiments, provided herein is a method of treating a subject with a cancer associated with ALK, the method comprising selectively inhibiting ALK but not TRK (e.g., TRKA, TRKB, and / or TRBC) by administering to the subject an amount of a compound or pharmaceutical composition provided herein, wherein the amount is sufficient to selectively inhibit ALK but not TRK (e.g., TRKA, TRKB, and / or TRBC).

[0130] As used herein and unless otherwise indicated, inhibition of ALK includes inhibition of wild-type ALK or genetically altered ALK (such as mutation, rearrangement, amplification or copy gain thereof) or partially deleted ALK protein.

[0131] Cancers treated by the methods of the present disclosure include, but are not limited to, lung cancer (e.g., non-small cell lung cancer, inflammatory myofibroblastic tumor), ovarian cancer (e.g., serous ovarian cancer), melanoma (e.g., Spitzoid melanoma), glioblastoma, bile duct cancer (e.g., cholangiocarcinoma), gastric cancer, colorectal cancer, angiosarcoma, anaplastic large cell lymphoma, diffuse large B-cell lymphoma, large B-cell lymphoma, esophageal cancer (e.g., esophageal squamous cell carcinoma), kidney cancer (e.g., renal medullary carcinoma or renal cell carcinoma), breast cancer (e.g., triple-negative breast cancer), thyroid cancer (e.g., papillary thyroid carcinoma), neuroblastoma, epithelioid hemangioendothelioma, colon cancer, and Spitzoid tumors.

[0132] In one embodiment, the cancer treated by the methods of the present disclosure includes cancer derived from one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB and TRKC. In certain embodiments, the cancer treated by the methods of the present disclosure includes cancer that is resistant to treatment against one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB and TRKC.

[0133] In one embodiment, the cancer in the method provided herein is anaplastic lymphoma kinase positive (ALK+). As used herein and unless otherwise specified, "ALK positive" (ALK+) cancer, disease or condition refers to an inappropriate (e.g., inappropriately high) expression of the ALK gene and / or a mutation in the ALK gene and / or a partially deleted ALK protein and / or a mutation in the ALK protein, and / or a cancer mediated by ALK and / or responsive to ALK inhibition, disease or condition. In one embodiment, "ALK positive" (ALK+) cancer, disease or condition refers to a cancer, disease or condition characterized by inappropriately high expression of the ALK gene and / or a mutation in the ALK gene, or by mediation of ALK. In one embodiment, "ALK positive" (ALK+) cancer, disease or condition refers to a cancer, disease or condition characterized by the presence of a partially deleted ALK protein (e.g., NB1, AskaSS). In one embodiment, "ALK positive" (ALK+) cancer is mediated by genetically altered ALK. In some embodiments, the cancer, disease or condition carries an ALK wild-type gene or a genetically altered ALK gene. In one embodiment, "ALK positive" (ALK+) cancer is mediated by a fusion protein comprising a fragment of a protein encoded by the ALK gene and a fragment of a protein encoded by a gene selected from the group consisting of NPM, EML4, TPR, TFG, ATIC, CLTC1, TPM4, MSN ALO17 and MYH9. In one embodiment, the fusion protein is one or more of an EML4-ALK fusion protein, an NPM-ALK fusion protein or a TPR-ALK fusion protein. In some embodiments, the genetically altered ALK is an EML4-ALK fusion protein. In some embodiments, the EML4-ALK fusion protein is a wild-type protein. In some embodiments, the EML4-ALK fusion protein comprises at least one resistance mutation. In some embodiments, the EML4-ALK fusion protein comprises at least one mutation selected from the group consisting of L1196M, G1202R, D1203N, L1152P / R, F1174C / L / V, C1156Y, I1171N, G1123S, S1206Y, G1269S / A, and T1151_L1152insT.In some embodiments, the EML4-ALK fusion protein comprises at least one mutation selected from the group consisting of G1202R, G1202K, L1196M, G1269A, G1269V, C1156Y, I1171T, I1171N, I1171S, F1174I, F1174L, F1174S, V1180L, S1206Y, E1129K, E1210K, T1151 M, T1151_L1152insT, F1174C, G1202del, D1203N, S1206C, S1206F, L1152R, L1196Q, L1198P, L1198F, L1198H, R1275Q, L1152P, C1156T, F1245C, T1151K, I1268V, F1174V, L1198Q, S1206A, and F1245V.

[0134] In one embodiment, "ALK-positive" (ALK+) cancer is mediated by a fusion protein comprising a fragment of a protein encoded by the ALK gene and a fragment of a protein encoded by a gene selected from the group consisting of NPM. In some embodiments, the genetically altered ALK is an NPM-ALK fusion protein. In some embodiments, the fusion protein comprises a fragment of a protein encoded by the ALK gene and a fragment of a protein encoded by the TPR gene. In some embodiments, the genetically altered ALK is a TPR-ALK fusion protein. In some embodiments, the TPR-ALK fusion protein contains a wild-type kinase domain. In some embodiments, the TPR-ALK fusion protein comprises at least one resistance mutation. In some embodiments, the TPR-ALK fusion protein comprises an L1196M mutation.

[0135] In one embodiment, the mutation changes the biological activity of the ALK nucleic acid molecule or polypeptide. As used herein and unless otherwise indicated, a "mutation" or "mutant" of ALK includes one or more deletions, substitutions, insertions, inversions, duplications, translocations, amplifications or missense mutations in the amino acid or nucleotide sequence of ALK or a fragment thereof. As used herein and unless otherwise indicated, an ALK "rearrangement" refers to a genetic translocation involving the ALK gene, which may result in an ALK fusion gene and / or an ALK fusion protein. The ALK fusion may also include one or more deletions, substitutions, insertions, inversions, duplications, translocations, amplifications or fragments thereof, as long as the mutant retains kinase phosphorylation activity.

[0136] In some embodiments, provided herein are methods of treating cancer in a subject, comprising identifying genetically altered ALK in the subject and administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0137] In one embodiment, the ALK mutation includes one or more ALK point mutations. In some embodiments, the cancer treated by the methods of the present disclosure includes one or more mutations in the ALK kinase. In one embodiment, the one or more ALK point mutations are selected from point mutations at T1151, L1152, C1156, I1171, F1174, V1180, L1196, L1198, G1202, D1203, S1206, E1129, E1210, F1245, G1269 and R1275. In one embodiment, the one or more ALK point mutations are selected from R1060H, F1174C / I / L / S / V, F1245C / I / L / V, R1275L / Q, T1151M, M1166R, I1171N, I1171S, I1171N, I1183T, L1196M, A1200V, L1204F, L1240V, D1270G, Y1278S, R1192P, G1128A, G1286R and T1343I. In some embodiments, the one or more ALK point mutations are selected from G1202R, G1202K, L1196M, G1269A, G1269V, C1156Y, I1171T, I1171N, I1171S, F1174I, F1174L, F1174S, V1180L, S1206Y, E1129K, E1210K, T1151M, T1151-L1152 insT, F1174C, G1202del, D1203N, S1206Y, S1206C, S1206F, L1152R, L1196Q, L1198P, L1198F, L1198H, R1275Q, L1152P, C1156T, F1245C, T1151K, I1268V, F1174V, L1198Q, S1206A, and F1245V. In one embodiment, the ALK mutation is G1202R. In one embodiment, the ALK mutation is L1196M. In one embodiment, the ALK mutation is G1269A. In one embodiment, the ALK mutation is G1269V. In one embodiment, the ALK mutation is L1198F. In one embodiment, the ALK mutation is L1198H. In one embodiment, the ALK mutation is T1151M. In one embodiment, the ALK mutation is F1174L. In one embodiment, the ALK mutation is F1174I. In one embodiment, the ALK mutation is F1174S. In one embodiment, the ALK mutation is I1171N. In one embodiment, the ALK mutation is I1171S. In one embodiment, the ALK mutation is I1171T.In one embodiment, the ALK mutation is I1171N. In one embodiment, the ALK mutation is E1129K. In one embodiment, the ALK mutation is S1206F. In one embodiment, the ALK mutation is E1210K. In one embodiment, the ALK mutation is D1203N. In one embodiment, the ALK mutation is R1275G. In one embodiment, the ALK mutation is F1245C. In one embodiment, the ALK mutation is T1151K. In one embodiment, the ALK mutation is I1268V. In one embodiment, the ALK mutation is F1174V. In one embodiment, the ALK mutation is L1198Q. In one embodiment, the ALK mutation is S1206A.

[0138] As used herein and unless otherwise indicated, "co-mutation" refers to mutations that occur simultaneously, i.e., when two or more mutations are present at the same time, e.g., in the same cell and on the same allele, in the same cell but on different alleles, or in different cells.

[0139] As used herein and unless otherwise indicated, "compound mutation" refers to two or more mutations located on the same allele. Compound mutations are a subset of co-mutations. If there are two mutations located on the same allele, compound mutations are sometimes also referred to as double mutations.

[0140] In some embodiments, the ALK mutation is a co-mutation of G1202R and one or more mutations selected from L1196M, G1269A, T1151M, F1174S, and L1198F. In one embodiment, the ALK mutation is a G1202R / L1196M compound mutation. In one embodiment, the ALK mutation is a G1202R / G1269A compound mutation. In one embodiment, the ALK mutation is a G1202R / L1198F compound mutation. In one embodiment, the ALK mutation is a G1202R / T1151M compound mutation. In one embodiment, the ALK mutation is a G1202R / F1174S compound mutation. In one embodiment, the ALK mutation is a G1202R / F1174L compound mutation. In one embodiment, the ALK mutation is a co-mutation of C1156Y and one or more mutations selected from L1256F, S1206F, F1174V and F1174I. In one embodiment, the ALK mutation is a C1156Y / L1256F compound mutation. In one embodiment, the ALK mutation is a C1156Y / S1206F compound mutation. In one embodiment, the ALK mutation is a C1156Y / F1174V compound mutation. In one embodiment, the ALK mutation is a C1156Y / F1174I compound mutation. In one embodiment, the ALK mutation is a co-mutation of L1196M and one or more mutations selected from L1198H, I1179V and L1256F. In one embodiment, the ALK mutation is a L1196M / L1198H compound mutation. In one embodiment, the ALK mutation is a L1196M / I1179V compound mutation. In one embodiment, the ALK mutation is a L1196M / L1256F compound mutation.

[0141] In one embodiment, the ALK mutation is a G1202R / L1196M double mutation. In one embodiment, the ALK mutation is a G1202R / G1269A double mutation. In one embodiment, the ALK mutation is a G1202R / L1198F double mutation. In one embodiment, the ALK mutation is a G1202R / T1151M double mutation. In one embodiment, the ALK mutation is a G1202R / F1174S double mutation. In one embodiment, the ALK mutation is a G1202R / F1174L double mutation. In one embodiment, the ALK mutation is a C1156Y / L1256F double mutation. In one embodiment, the ALK mutation is a C1156Y / S1206F double mutation. In one embodiment, the ALK mutation is a C1156Y / F1174V double mutation. In one embodiment, the ALK mutation is a C1156Y / F1174I double mutation. In one embodiment, the ALK mutation is a L1196M / L1198H double mutation. In one embodiment, the ALK mutation is a L1196M / I1179V double mutation. In one embodiment, the ALK mutation is a L1196M / L1256F double mutation.

[0142] In one embodiment, the ALK mutation comprises one or more ALK rearrangements (in one embodiment, one rearrangement). In one embodiment, the ALK mutation comprises one or more ALK fusions (in one embodiment, one fusion). In some embodiments, the cancer treated by the methods of the present disclosure comprises an ALK fusion. In one embodiment, the ALK fusion is with one of the fusion partners described in Ou et al., JTO Clinical and Research Reports, 1(1): 1-10, the entire contents of which are incorporated herein by reference. In one embodiment, the ALK fusion is with one of the fusion partners selected from the group consisting of: EML4, TFG, KIF5B, KLC1, STRN, HIP1, TPR, BIRC6, DCTN1, SQSTM1, SOCS5, SEC31A, CLTC, PRKAR1A, PPM1B, EIF2AK3, CRIM1, CEBPZ, PICALM, CLIP1, BCL11A, GCC2, LMO7, PHACTR1, CMTR1, VIT, DYSF, ITGAV, PLEKHA7, CUX1, VKORC1L1, FBXO36, SPTBN1, EML6, FBXO11, CLIP4, CAMKMT, NCOA1, MYT1L, SRBD1, SRD5A2, NYAP2, MPRIP, ADAM17, ALK, L PIN1, WDPCP, CEP55, ERC1, SLC16A7, TNIP2, ATAD2B, SLMAP, FBN1, SWAP70, TCF12, TRIM66, WNK3 , AKAP8L, SPECC1L, PRKCB, CDK15, LCLAT1, YAP1, PLEKHM2, DCHS1, PPFIBP1, ATP13A4, C12orf75 , EPAS1, FAM179A, FUT8, LIMD1, LINC00327, LOC349160, LYPD1, RBM20, TACR1, TANC1, TTC27, TU BBB, SMPD4, SORCS1, LINC00211, SOS1, C9orf3, CYBRD1, MTA3, THADA, TSPYL6, WDR37 and PLEKHH2.In one embodiment, the ALK fusion is performed with one of the fusion partners selected from the group consisting of EML4, TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, NPM1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, ATIC, MSN, ALO17, MYH9 and KIF5B. In one embodiment, the ALK mutation is EML4-ALK, a fusion between the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK tyrosine kinase domain. EML4-ALK has many variants, which differ in that the breakpoints are connected, of which variant 1 (v1) and variant 3 (v3) are the most common clinically. In one embodiment, the ALK mutation is NPM1-ALK. In one embodiment, the ALK mutation is STRN-ALK.

[0143] In one embodiment, the ALK mutation includes an ALK rearrangement and one or more ALK point mutations. In one embodiment, the ALK mutation is EML4-ALK wt (variant 1). In one embodiment, the ALK mutation is EML4-ALK (variant 2). In one embodiment, the ALK mutation is EML4-ALK (variant 3). In one embodiment, the ALK mutation is EML4-ALK wt (variant 4, 5, 6 or 7). In one embodiment, the ALK mutation is EML4-ALK G1202R. In one embodiment, the ALK mutation is EML4-ALK I1171N. In one embodiment, the ALK mutation is EML4-ALK I1171S. In one embodiment, the ALK mutation is EML4-ALK I1171T. In one embodiment, the ALK mutation is EML4-ALK L1196M. In one embodiment, the ALK mutation is EML4-ALK D1203N. In one embodiment, the ALK mutation is EML4-ALK L1196M / G1202R. In one embodiment, the ALK mutation is EML4-ALK G1202R / G1269A. In one embodiment, the ALK mutation is EML4-ALK G1202R / L1196M. In one embodiment, the ALK mutation is EML4-ALK G1202R / L1198F. In one embodiment, the ALK mutation is EML4-ALK G1202R / T1151M. In one embodiment, the ALK mutation is EML4-ALK G1202R / F1174S. In one embodiment, the ALK mutation is EML4-ALK G1202R / F1174L.

[0144] In one embodiment, the ALK-positive solid tumor is characterized by the presence of a mutation in the ALK gene. In one embodiment, the ALK mutation comprises one or more ALK rearrangements, one or more ALK point mutations, or a combination thereof. In one embodiment, the ALK mutation comprises G1202R, F1174C, F1174L, I1171N, I1171S, I1171T, L1196M, V1180L, C1156Y, G1202del, G1202K, G1269A, F1174S, S1206Y, E1210K, T1151M, T1151_L1152insT, D1203N, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T or F1245V, or a combination thereof. In one embodiment, the ALK mutation comprises G1202R. In one embodiment, the ALK mutation comprises F1174S or F1174L. In one embodiment, the ALK mutation comprises I1171S. In one embodiment, the ALK mutation comprises I1171T. In one embodiment, the ALK mutation comprises I1171N. In one embodiment, the ALK mutation comprises F1171M. In one embodiment, the ALK mutation comprises D1203N and one selected from I1171S, I1171T, I1171N, and I1171M. In one embodiment, the ALK mutation comprises C1156Y and one selected from I1171S, I1171T, I1171N, and I1171M. In one embodiment, the ALK mutation comprises R1275Q. In one embodiment, the ALK mutation comprises T1151M. In one embodiment, the ALK mutation comprises one or more compound mutations. In one embodiment, the compound mutation is G1202R / L1196M, G1202R / G1269A, G1202R / L1198F or G1202R / F1174S. In one embodiment, the compound mutation is G1202R / L1196M. In one embodiment, the compound mutation is G1202R / G1269A. In one embodiment, the compound mutation is G1202R / L1198F. In one embodiment, the compound mutation is G1202R / F1174S. In one embodiment, the ALK-positive solid tumor is characterized by the presence of a partially deleted ALK protein. In one embodiment, the ALK mutation is Ex2-3del. In one embodiment, the ALK mutation is Ex2-17del.

[0145] In one embodiment, the partially deleted ALK protein affects the proliferation and metastatic properties of cancer cells. The ALK protein can be partially deleted by a variety of mechanisms. The first mechanism is shedding, in which the 80kDa extracellular domain of the ALK protein is post-translationally cleaved near residue Asn654, leaving a 140kDa C-terminal transmembrane and intracellular domain on the cell. Shedding has been observed in many cell lines expressing ALK, most notably cell lines from neuroblastoma disease backgrounds. In preclinical models of cancer in vitro and in vivo, shedding increases the migration and proliferation of cancer cells (Moog-Lutz, JBC (2005), Huang, Cell Reports (2021)). The second mechanism is alternative transcription initiation (ATI), in which transcription of the ALK gene starts from an alternative start site downstream of the original site, resulting in the deletion of exons 1-18 and part of exon 19. ALK ATI has been identified in 11% of melanomas and a small number of lung cancers and anaplastic thyroid cancers. Expression of ALK ATI transforms Ba / F3 and NIH3T3 cells, giving them oncogenic potential. One ALK ATI patient showed clinical response to ALK inhibitor therapy, suggesting that ALK ATI may be a targetable driver mutation (Wiesner, Nature (2015)). The third mechanism is partial deletion of the ALK gene, such as through a chromosomal rearrangement event. A variety of deletion variants have been identified, including deletions of exons 2-3, exons 1-5, exons 4-11, and exons 2-17, some of which have been shown to activate ALK signaling and transform Ba / F3 or NIH3T3 cells. Partial deletions of ALK have been detected in neuroblastomas, sarcomas, and lymphomas. (Okubo, Oncogene (2012); Cazes, Can Res (2013); Fransson, Genes Chromosomes & Cancer (2014); Fleuren, Can Res (2017); Fukuhara, Hematol Oncol (2017)).

[0146] In one embodiment, the ALK+ cancer is determined by an FDA-approved test or other test known in the art. Tests that may be used include, but are not limited to, FoundationOne CDx TM(F1CDx) (a sequencing-based in vitro diagnostic device for the detection of substitutions, insertion and deletion alterations (indels), copy number alterations (CNAs), and selected gene rearrangements, as well as genomic features, including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens); VENTANA ALK (D5F3) CDx assay (qualitative detection of anaplastic lymphoma kinase (ALK) protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue stained with the BenchMark XT or BenchMark ULTRA automated stainers); and the Vysis ALKBreak Apart FISH Probe Kit test (qualitative test for the detection of rearrangements involving the ALK gene in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens by fluorescence in situ hybridization (FISH). In one embodiment, the test is a fluorescent in situ hybridization (FISH) test, e.g., the Vysis ALK Break Apart FISH Probe Kit test. For more information about FDA-approved tests, visit, e.g., https: / / www.fda.gov / MedicalDevices / ProductsandMedicalProceedures / InVitroDiagnostics / ucm303030.htm; for more information about the Vysis ALKBreak Apart FISH Probe Kit, visit, e.g., https: / / www.molecular.abbott / us / en / products / oncology / vysis-alk-break-apart-fish-probe-kit; all of which are incorporated herein by reference.

[0147] In one embodiment of any of the methods described herein, the presence of an ALK mutation in the sample indicates that the subject has an ALK-positive disease or an increased risk of suffering from an ALK-positive (e.g., ALK-driven) cancer. In other embodiments, the presence of a mutation in the sample indicates that the subject has an ALK-positive (e.g., ALK-driven) cancer that is refractory to TKI treatment or an increased risk of suffering from an ALK-positive (e.g., ALK-driven) cancer that is refractory to TKI treatment. In a specific embodiment, the presence of a mutation in the sample indicates that the subject has an ALK-positive (e.g., ALK-driven) cancer that is refractory to treatment with one or more of crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, and ASP3026 or an increased risk of suffering from an ALK-positive (e.g., ALK-driven) cancer that is refractory to treatment with one or more of crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, and ASP3026. In certain embodiments, the presence of a mutation in the sample indicates that the subject has an ALK-positive (e.g., ALK-driven) cancer that is refractory to one or more of crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib or is at increased risk of developing an ALK-positive (e.g., ALK-driven) cancer that is refractory to one or more of crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In some embodiments, the ALK protein or ALK fusion protein comprises a contiguous sequence of between 30 and 1620 amino acids that is at least 95% identical to the amino acid sequence of ALK [Homo sapiens] (NCBI Reference Sequence: NP_004295.2 or UniProt Sequence No.: Q9UM73 sequence). In another non-limiting embodiment, the ALK protein or ALK fusion protein comprises a continuous sequence between 30 and 1620 amino acids, which is at least 85% identical to the amino acid sequence of ALK [Homo sapiens] (NCBI Reference Sequence: NP_004295.2 or UniProt Sequence No.: Q9UM73 sequence). In another non-limiting embodiment, wherein the ALK protein or ALK fusion protein comprises a continuous sequence between 30 and 1620 amino acids, which is at least 90% identical to the amino acid sequence of ALK [Homo sapiens] (NCBI Reference Sequence: NP_004295.2 or UniProt Sequence No.: Q9UM73 sequence). In another non-limiting embodiment, wherein the ALK protein or ALK fusion protein comprises a continuous sequence between 30 and 1620 amino acids, which is at least 95% identical to the amino acid sequence of ALK [Homo sapiens] (NCBI Reference Sequence: NP_004295.2 or UniProt Sequence No.: Q9UM73 sequence).In another non-limiting embodiment, the ALK protein or ALK fusion protein comprises a contiguous sequence of between 30 and 1620 amino acids that is at least about 85-90%, 91-93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of ALK [Homo sapiens] (NCBI Reference Sequence: NP_004295.2 or UniProt Sequence No.: Q9UM73 sequence).

[0148] Also provided is a method for treating a subject having cancer (e.g., an ALK-positive cancer), comprising: determining whether cancer cells in a sample obtained from a subject having cancer and previously administered a first ALK inhibitor have one or more ALK inhibitor resistance mutations; and administering compound 1 (e.g., Form 2) or a pharmaceutically acceptable salt thereof to the subject as a monotherapy or in combination with another anticancer agent if the subject's cancer cells have one or more ALK inhibitor resistance mutations. In some embodiments, the one or more ALK inhibitor resistance mutations confer increased resistance to cancer cells or tumors to treatment with a first ALK inhibitor. In some embodiments, the one or more ALK inhibitor resistance mutations include one or more ALK inhibitor resistance mutations. For example, the one or more ALK inhibitor resistance mutations may include one or more point mutations at one or more of amino acid positions 1202, 1196, 1269, 1156, 1171, 1174, 1180, 1206, 1210, 1151, 1203, 1152, 1198, 1275, and 1245, such as G1202R, L1196M, G1269A, C1156Y, I1171T, I1174, 171N, I1171S, F1174L, F1174S, V1180L, S1206Y, E1210K, T1151M, T1151_L1152insT, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T and F1245V. In some embodiments, another anticancer agent is any anticancer agent known in the art. For example, another anticancer agent can be another ALK inhibitor (e.g., a second ALK inhibitor).

[0149] In one embodiment, provided herein are compounds that are CNS penetrant compounds. In one embodiment, after administering an effective amount of a compound provided herein (e.g., orally or intravenously), the compound is able to penetrate the CNS (e.g., the blood-brain barrier) and reach a concentration in the CNS (e.g., the brain) that is still sufficient to inhibit (e.g., selectively inhibit) ALK.

[0150] In one embodiment, provided herein is a method for treating CNS metastasis of cancer, comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof. In one embodiment, the CNS metastasis is a brain metastasis. In one embodiment, the cancer is an ALK+ cancer.

[0151] In one embodiment, the solid tumor (or cancer) is leukocyte receptor tyrosine kinase (LTK) positive. In one embodiment, the solid tumor is LTK positive breast invasive ductal carcinoma, prostate adenocarcinoma, pancreatic adenocarcinoma, adenocarcinoma of unknown primary or bladder urothelial carcinoma. In one embodiment, the cancer is LTK positive leukemia. In one embodiment, the solid tumor is LTK positive lung cancer. In one embodiment, the solid tumor is LTK positive NSCLC. In one embodiment, the solid tumor (or cancer) has LTK mutation. In one embodiment, the LTK mutation is G269A, F218I, N257T, A13fs or A214fs. In one embodiment, the solid tumor (or cancer) has LTK fusion. In one embodiment, the LTK fusion is CLIP1-LTK. See Cooper AJ, Sequist LV, Johnson TW, Lin JJ. LTK fusions: A new target emerges in non-smallcell lung cancer. Cancer Cell. 2022 Jan 10;40(1):23-25; and Izumi, H., Matsumoto, S., Liu, J., et al. The CLIP1–LTK fusion is an oncogenic driver in non-small-cell lung cancer. Nature 600, 319–323 (2021), each of which is incorporated herein by reference in its entirety.

[0152] In one embodiment, the compound is an inhibitor of human tropomyosin receptor kinase A, B or C. In certain embodiments, the compound inhibits mutant or non-mutated ALK with an IC50 that is no more than one-fifth of the compound's IC50 for inhibiting wild-type tropomyosin receptor kinase A, B or C. TRK inhibition, particularly in the central nervous system (CNS), is associated with adverse effects including dizziness / ataxia / gait disturbance, paresthesias, weight gain, and cognitive changes.

[0153] In some embodiments, a method of minimizing adverse events in a subject in need of treatment of cancer (e.g., ALK positive cancer) is provided, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, and wherein the method minimizes adverse events associated with TRK inhibitors. In some embodiments, the cancer is ALK-related (or ALK+) cancer. In some embodiments, the adverse event is a TRK-related CNS adverse event.

[0154] As used herein, "minimizing" adverse events refers to the incidence of adverse events in subjects or patient populations treated with TRK inhibitors (e.g., entrectinib, ripretinib or lorlatinib) compared to the typical incidence of adverse events in subjects or patient populations. In some embodiments, the incidence of adverse events refers to the frequency or percentage of specific adverse events occurring in subjects or patient populations. In some embodiments, the incidence of adverse events refers to the total number of adverse events experienced by individual subjects. In some embodiments, minimizing adverse events refers to minimizing TRK-related CNS adverse events. In some embodiments, minimizing TRK-related CNS adverse events means that less than 40% of patient populations have TRK-related CNS adverse events. In some embodiments, minimizing TRK-related CNS adverse events means less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10% or less than 5% of patient populations have TRK-related CNS adverse events. In some embodiments, minimizing TRK-related CNS adverse events means that less than 12% of patient populations have more than one TRK-related CNS adverse event. In some embodiments, minimizing TRK-related CNS adverse events means less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% of the patient population has more than one TRK-related CNS adverse event.

[0155] In some embodiments, a TRK-related CNS adverse event refers to one or more of: dizziness, ataxia, gait disturbance, paresthesia, weight gain, increased appetite, paresthesia, movement abnormalities, cognitive changes, speech effects (e.g., dysarthria, slow speech, or speech disorders), mood disorders (e.g., irritability, anxiety, depression, mood swings, personality changes, mood swings, affective disorders, aggression, agitation, mood changes, depressed mood, euphoria, or mania), and cognitive disorders (e.g., memory impairment, cognitive impairment, amnesia, confusion, attention disorder, delirium, mental disorder, attention-deficit / hyperactivity disorder, dementia, sleep disorder, or reading disorder).

[0156] In one embodiment, provided herein is a method for preventing or limiting TRK-related CNS side effects or adverse events in cancer treatment, comprising administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof to a subject in need. In one embodiment, the method prevents the occurrence of TRK-related CNS adverse events. In one embodiment, the method limits the frequency of occurrence of TRK-related CNS adverse events. In one embodiment, the method limits the severity of TRK-related side effects. In one embodiment, provided herein is a method for treating CNS metastasis of cancer and reducing TRK-related side effects, comprising administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof to a patient in need. In one embodiment, compared with standard care treatment (e.g., approved ALK inhibitors for ALK+ cancer (e.g., crizotinib, entrectinib, lorlatinib or ripretinib)), the reduction / limitation / prevention of CNS side effects or adverse events is determined in a statistical sample. In one embodiment, the TRK-related side effects are TRKB-related CNS side effects. In one embodiment, the TRK-related CNS side effect or adverse event is dizziness, ataxia, gait disturbance, paresthesia, weight gain, cognitive impairment, mood disorders, or sleep disturbances.

[0157] In one embodiment, provided herein is a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., Compound 1 (e.g., Form 2) or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is a cancer mediated by ALK. In one embodiment, the cancer is an ALK-related cancer. In one embodiment, the cancer is an ALK+ cancer. In one embodiment, the cancer is identified as ALK+.

[0158] In one embodiment, provided herein is a method for treating ALK+ cancer comprising administering a therapeutically effective amount of Compound 1 (eg, Form 2) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0159] In one embodiment, provided herein is a method for treating cancer in a subject comprising: (i) identifying the subject's cancer as ALK+, and (ii) administering to the subject a therapeutically effective amount of Compound 1 (e.g., Form 2) or a pharmaceutically acceptable salt thereof.

[0160] In one embodiment, the cancer (or ALK+ cancer) is a solid tumor. In one embodiment, the cancer (or ALK+ cancer) is lung cancer (e.g., non-small cell lung cancer (NSCLC)), glioblastoma, inflammatory myofibroblastic tumor (IMT), bile duct cancer (e.g., cholangiocarcinoma), ovarian cancer (e.g., serous ovarian cancer), gastric cancer, colorectal cancer, angiosarcoma, melanoma (e.g., Spitz-like melanoma), epithelioid hemangioendothelioma, esophageal cancer (e.g., esophageal squamous cell carcinoma (ESCC)), kidney cancer (e.g., renal medullary carcinoma or renal cell carcinoma), breast cancer (e.g., triple-negative breast cancer), colon cancer, thyroid cancer (e.g., papillary thyroid carcinoma), Spitz-like tumor, pancreatic cancer, inflammatory hepatocellular adenoma or neuroblastoma. In one embodiment, the cancer (or ALK+ cancer) is ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, childhood renal cell carcinoma, breast cancer, ER + Breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, bile duct epithelial carcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic bile duct epithelial carcinoma, papillary thyroid carcinoma, Spitzoid tumor, sarcoma, astrocytoma, brain low-grade glioma, secretory breast cancer, breast analog carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, skin melanoma, head and neck squamous cell carcinoma, childhood glioma CML, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, skin melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, and serous and clear cell endometrial carcinoma.

[0161] In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is advanced or metastatic non-small cell lung cancer. In one embodiment, the cancer is ALK+ non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory ALK+ non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed ALK+ non-small cell lung cancer.

[0162] In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is recurrent or refractory glioblastoma. In one embodiment, the cancer is recurrent or refractory ALK+ glioblastoma. In one embodiment, the cancer is newly diagnosed glioblastoma. In one embodiment, the cancer is newly diagnosed ALK+ glioblastoma.

[0163] In one embodiment, the cancer is IMT. In one embodiment, the cancer is ALK+IMT. In one embodiment, the cancer is relapsed or refractory IMT. In one embodiment, the cancer is relapsed or refractory ALK+IMT. In one embodiment, the cancer is newly diagnosed IMT. In one embodiment, the cancer is newly diagnosed ALK+IMT.

[0164] In one embodiment, the cancer is cholangiocarcinoma. In one embodiment, the cancer is cholangiocarcinoma. In one embodiment, the cancer is ALK+ cholangiocarcinoma. In one embodiment, the cancer is recurrent or refractory cholangiocarcinoma. In one embodiment, the cancer is recurrent or refractory ALK+ cholangiocarcinoma. In one embodiment, the cancer is newly diagnosed cholangiocarcinoma. In one embodiment, the cancer is newly diagnosed ALK+ cholangiocarcinoma. In one embodiment, the cholangiocarcinoma patient has a STRN-ALK fusion mutation. In one embodiment, the cholangiocarcinoma patient progresses after alectinib treatment. In one embodiment, the cholangiocarcinoma patient has an acquired G1202R resistance mutation.

[0165] In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is ALK+ ovarian cancer. In one embodiment, the cancer is recurrent or refractory ovarian cancer. In one embodiment, the cancer is recurrent or refractory ALK+ ovarian cancer. In one embodiment, the cancer is newly diagnosed ovarian cancer. In one embodiment, the cancer is newly diagnosed ALK+ ovarian cancer. In one embodiment, the ovarian cancer is serous ovarian cancer. In one embodiment, the ovarian cancer is high-grade serous ovarian cancer.

[0166] In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is ALK+ gastric cancer. In one embodiment, the cancer is recurrent or refractory gastric cancer. In one embodiment, the cancer is recurrent or refractory ALK+ gastric cancer. In one embodiment, the cancer is newly diagnosed gastric cancer. In one embodiment, the cancer is newly diagnosed ALK+ gastric cancer.

[0167] In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is ALK+ colorectal cancer. In one embodiment, the cancer is recurrent or refractory colorectal cancer. In one embodiment, the cancer is recurrent or refractory ALK+ colorectal cancer. In one embodiment, the cancer is newly diagnosed colorectal cancer. In one embodiment, the cancer is newly diagnosed ALK+ colorectal cancer.

[0168] In one embodiment, the cancer is angiosarcoma. In one embodiment, the cancer is ALK+ angiosarcoma. In one embodiment, the cancer is recurrent or refractory angiosarcoma. In one embodiment, the cancer is recurrent or refractory ALK+ angiosarcoma. In one embodiment, the cancer is a newly diagnosed angiosarcoma. In one embodiment, the cancer is a newly diagnosed ALK+ angiosarcoma.

[0169] In one embodiment, the cancer is a sarcoma. In one embodiment, the cancer is a soft tissue sarcoma. In one embodiment, the cancer is a synovial sarcoma. In one embodiment, the cancer is one or more selected from the group consisting of inflammatory myofibroblastic tumor, leiomyosarcoma, and neurofibroma. In one embodiment, the cancer is one or more selected from the group consisting of Ewing's sarcoma, fibrosarcoma, osteosarcoma, pulmonary sarcoma, uterine carcinosarcoma, and uterine leiomyosarcoma.

[0170] In one embodiment, the cancer is melanoma. In one embodiment, the cancer is a Spitz-like tumor. In one embodiment, the cancer is a Spitz-like melanoma. In one embodiment, the cancer is an ALK+ Spitz-like melanoma. In one embodiment, the cancer is a recurrent or refractory Spitz-like melanoma. In one embodiment, the cancer is a recurrent or refractory ALK+ Spitz-like melanoma. In one embodiment, the cancer is a newly diagnosed Spitz-like melanoma. In one embodiment, the cancer is a newly diagnosed ALK+ Spitz-like melanoma.

[0171] In one embodiment, the cancer is epithelioid hemangioendothelioma. In one embodiment, the cancer is ALK+ epithelioid hemangioendothelioma. In one embodiment, the cancer is relapsed or refractory epithelioid hemangioendothelioma. In one embodiment, the cancer is relapsed or refractory ALK+ epithelioid hemangioendothelioma. In one embodiment, the cancer is newly diagnosed epithelioid hemangioendothelioma. In one embodiment, the cancer is newly diagnosed ALK+ epithelioid hemangioendothelioma.

[0172] In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is ESCC. In one embodiment, the cancer is ALK+ESCC. In one embodiment, the cancer is recurrent or refractory ESCC. In one embodiment, the cancer is recurrent or refractory ALK+ESCC. In one embodiment, the cancer is newly diagnosed ESCC. In one embodiment, the cancer is newly diagnosed ALK+ESCC.

[0173] In one embodiment, the cancer is kidney cancer. In one embodiment, the cancer is renal medullary carcinoma. In one embodiment, the cancer is ALK+ renal medullary carcinoma. In one embodiment, the cancer is recurrent or refractory renal medullary carcinoma. In one embodiment, the cancer is recurrent or refractory ALK+ renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed ALK+ renal medullary carcinoma. In one embodiment, the cancer is renal cell carcinoma. In one embodiment, the cancer is ALK+ renal cell carcinoma. In one embodiment, the cancer is recurrent or refractory renal cell carcinoma. In one embodiment, the cancer is recurrent or refractory ALK+ renal cell carcinoma. In one embodiment, the cancer is newly diagnosed renal cell carcinoma. In one embodiment, the cancer is newly diagnosed ALK+ renal cell carcinoma.

[0174] In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is ALK+ breast cancer. In one embodiment, the cancer is relapsed or refractory breast cancer. In one embodiment, the cancer is relapsed or refractory ALK+ breast cancer. In one embodiment, the cancer is newly diagnosed breast cancer. In one embodiment, the cancer is newly diagnosed ALK+ breast cancer. In one embodiment, the breast cancer is triple negative breast cancer.

[0175] In one embodiment, the cancer is colon cancer. In one embodiment, the cancer is ALK+ colon cancer. In one embodiment, the cancer is recurrent or refractory colon cancer. In one embodiment, the cancer is recurrent or refractory ALK+ colon cancer. In one embodiment, the cancer is newly diagnosed colon cancer. In one embodiment, the cancer is newly diagnosed ALK+ colon cancer.

[0176] In one embodiment, the cancer is thyroid cancer. In one embodiment, the cancer is papillary thyroid cancer. In one embodiment, the cancer is ALK+ papillary thyroid cancer. In one embodiment, the cancer is recurrent or refractory papillary thyroid cancer. In one embodiment, the cancer is recurrent or refractory ALK+ papillary thyroid cancer. In one embodiment, the cancer is newly diagnosed papillary thyroid cancer. In one embodiment, the cancer is newly diagnosed ALK+ papillary thyroid cancer.

[0177] In one embodiment, the cancer is an ALK+ glioma (e.g., Grade 1, Grade 2, Grade 3, or Grade 4). In one embodiment, the cancer is a recurrent or refractory glioma. In one embodiment, the cancer is a recurrent or refractory ALK+ glioma. In one embodiment, the cancer is a newly diagnosed ALK+ glioma. In one embodiment, the cancer is an ALK+ glioblastoma. In one embodiment, the cancer is a newly diagnosed ALK+ glioblastoma. In one embodiment, the cancer is a recurrent or refractory glioblastoma. In one embodiment, the cancer is a recurrent or refractory ALK+ glioblastoma. In one embodiment, the cancer is a neuroblastoma. In one embodiment, the cancer is an ALK+ neuroblastoma. In one embodiment, the cancer is a recurrent or refractory neuroblastoma. In one embodiment, the cancer is a recurrent or refractory ALK+ neuroblastoma. In one embodiment, the cancer is a newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ALK+ neuroblastoma.

[0178] In one embodiment, the cancer is ALK+ pancreatic cancer. In one embodiment, the cancer is recurrent or refractory pancreatic cancer. In one embodiment, the cancer is recurrent or refractory ALK+ pancreatic cancer. In one embodiment, the cancer is newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ALK+ pancreatic cancer.

[0179] In one embodiment, the cancer is ALK+ inflammatory hepatocellular adenoma. In one embodiment, the cancer is recurrent or refractory inflammatory hepatocellular adenoma. In one embodiment, the cancer is recurrent or refractory ALK+ inflammatory hepatocellular adenoma. In one embodiment, the cancer is newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ALK+ inflammatory hepatocellular adenoma.

[0180] In one embodiment, the cancer is a blood cancer. In one embodiment, the cancer is an ALK+ blood cancer.

[0181] In one embodiment, the cancer is an ALK+ lymphoma. In one embodiment, the lymphoma is a non-Hodgkin lymphoma. In one embodiment, the lymphoma is an ALK+ non-Hodgkin lymphoma. In one embodiment, the lymphoma is an ALK+ anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-cell lymphoma.

[0182] In one embodiment, the cancer is ALCL. In one embodiment, the cancer is ALK+ALCL. In one embodiment, the cancer is relapsed or refractory ALCL. In one embodiment, the cancer is relapsed or refractory ALK+ALCL. In one embodiment, the cancer is relapsed or refractory ALK+ALCL. In one embodiment, the cancer is newly diagnosed ALCL. In one embodiment, the cancer is newly diagnosed ALK+ALCL.

[0183] In one embodiment, the cancer is DLBCL. In one embodiment, the cancer is ALK+DLBCL. In one embodiment, the cancer is relapsed or refractory DLBCL. In one embodiment, the cancer is relapsed or refractory ALK+DLBCL. In one embodiment, the cancer is newly diagnosed DLBCL. In one embodiment, the cancer is newly diagnosed ALK+DLBCL.

[0184] In one embodiment, the cancer is a large B-cell lymphoma. In one embodiment, the cancer is an ALK+ large B-cell lymphoma. In one embodiment, the cancer is a relapsed or refractory large B-cell lymphoma. In one embodiment, the cancer is a relapsed or refractory ALK+ large B-cell lymphoma. In one embodiment, the cancer is a newly diagnosed large B-cell lymphoma. In one embodiment, the cancer is a newly diagnosed ALK+ large B-cell lymphoma. In one embodiment, the cancer (or ALK+ cancer) is newly diagnosed. In one embodiment, the cancer (or ALK+ cancer) is previously untreated.

[0185] In one embodiment, the cancer is one or more selected from the group consisting of acinar adenocarcinoma, adrenocortical carcinoma, anaplastic astrocytoma, anaplastic large cell lymphoma, B-cell acute lymphoblastic leukemia, B-cell lymphoma, breast cancer, cervical squamous cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, colorectal adenocarcinoma, cutaneous melanoma, diffuse large B-cell lymphoma, diffuse gastric cancer, endocervical adenocarcinoma, endometrial adenocarcinoma, epithelial ovarian cancer, esophageal cancer, Ewing's sarcoma, fallopian tube serous carcinoma, fibrosarcoma. Gallbladder cancer, ganglioglioma, gastroesophageal junction adenocarcinoma, glioblastoma, head and neck cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, high-grade serous carcinoma, inflammatory myofibroblastic tumor, leiomyosarcoma, neurofibroma, soft tissue sarcoma, infiltrating ductal carcinoma, low-grade serous carcinoma, lung adenocarcinoma, medulloblastoma, melanoma, mucinous cystadenocarcinoma, mucoepidermoid carcinoma, mucoepidermoid carcinoma, multiple myeloma, neuroblastoma, non-Hodgkin lymphoma, bone and flesh tumors, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, papillary cell renal cell carcinoma, papillary thyroid carcinoma, pericardial mesothelioma, peritoneal mesothelioma, prostate adenocarcinoma, pulmonary sarcoma, renal cell carcinoma, salivary gland carcinoma, small cell lung cancer, small intestine cancer, smooth muscle tumor of uncertain malignant potential, squamous cell carcinoma, gastric cancer, thyroid cancer, urothelial carcinoma, uterine carcinosarcoma, uterine corpus endometrial carcinoma, uterine leiomyosarcoma, uterine papillary serous carcinoma, and uterine sarcoma.

[0186] In one embodiment, the cancer (or ALK+ cancer) is newly diagnosed. In one embodiment, the cancer (or ALK+ cancer) is previously untreated.

[0187] In one embodiment, the cancer is recurrent or refractory. In one embodiment, the cancer is recurrent. In one embodiment, the cancer (or ALK+ cancer) is recurrent. In one embodiment, the cancer (or ALK+ cancer) is refractory to wild-type ALK inhibitors. In one embodiment, the cancer (or ALK+ cancer) is refractory to genetically altered ALK inhibitors. In one embodiment, the cancer (or ALK+ cancer) is refractory to one or more of crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In one embodiment, the cancer (or ALK+ cancer) is refractory to one or more of crizotinib, ceritinib, alectinib, and brigatinib. In one embodiment, the cancer (or ALK+ cancer) is refractory to one or more of crizotinib, ceritinib, alectinib, brigatinib, ASP3026, and lorlatinib.

[0188] In one embodiment, the cancer (or ALK+ cancer) is intolerant to one or more of crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In one embodiment, the cancer (or ALK+ cancer) is intolerant to one or more of crizotinib, ceritinib, alectinib, and brigatinib. In one embodiment, the cancer (or ALK+ cancer) is intolerant to one or more of crizotinib, ceritinib, alectinib, brigatinib, ASP3026, and lorlatinib. As used herein, the term "intolerant to a drug" refers to a subject (e.g., a patient) whose drug treatment must be stopped or suspended due to unacceptable side effects. The subject (e.g., patient) may be intolerant to treatment when the treatment is initially given, or may become intolerant to treatment over time.

[0189] In one embodiment, the subject is previously untreated. In one embodiment, the subject has not received treatment with a tyrosine kinase inhibitor (TKI) therapy. In one embodiment, the subject has received a previous first-line or multi-line therapy. In one embodiment, the subject has received a previous two-line or more-line therapy. In one embodiment, the subject has developed resistance to one or more previous lines of therapy. In one embodiment, the subject has progressed in a previous first-line or multi-line therapy. In one embodiment, the previous therapy includes a tyrosine kinase inhibitor (TKI). In one embodiment, the previous TKI therapy includes treatment with one or more of crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, ripretinib, cabozantinib, foretinib, taletrectinib, merestinib, masitinib and ensartinib. In one embodiment, the subject has progressed in a previous treatment with crizotinib, alectinib, ceritinib, brigatinib or lorlatinib. In one embodiment, the subject has progressed in a previous treatment with crizotinib, alectinib, ceritinib, brigatinib or lorlatinib and at least one other TKI. In one embodiment, the subject has progressed in a previous treatment with crizotinib. In one embodiment, the subject has progressed in a previous treatment with alectinib. In one embodiment, the subject has progressed in a previous treatment with ceritinib. In one embodiment, the subject has progressed in a previous treatment with brigatinib. In one embodiment, the subject has progressed in a previous treatment with lorlatinib. In one embodiment, the previous therapy includes one or more chemotherapy. In one embodiment, the subject has progressed in a previous TKI therapy (e.g., one or more of crizotinib, alectinib, ceritinib, brigatinib and lorlatinib) and one or more chemotherapy. In one embodiment, the previous therapy includes two or more chemotherapy. In one embodiment, the prior therapy includes one or more immunotherapies. In one embodiment, the subject has made progress in a prior TKI treatment (e.g., one or more of crizotinib, alectinib, ceritinib, brigatinib, and lorlatinib) and one or more immunotherapies. In one embodiment, the prior therapy includes two or more immunotherapies. In one embodiment, the one or more chemotherapy and / or one or more immunotherapies are therapies other than TKI therapy.

[0190] In one embodiment, the cancer is an advanced cancer, e.g., relapsed after prior TKI therapy, refractory to prior TKI therapy, progressed during prior TKI therapy, or is resistant to prior TKI therapy. In some embodiments, the cancer is locally advanced.

[0191] In one embodiment, the cancer (or ALK+ cancer) is resistant to a tyrosine kinase inhibitor (TKI). In one embodiment, the cancer (or ALK+ cancer) is resistant to a previous tyrosine kinase inhibitor (TKI).

[0192] In one embodiment, the cancer is resistant lung cancer. In one embodiment, the cancer is resistant non-small cell lung cancer. In one embodiment, the cancer is non-small cell lung cancer that is resistant to TKI. In one embodiment, the cancer is ALK+ non-small cell lung cancer that is resistant to TKI.

[0193] In one embodiment, the cancer is lung cancer (e.g., NSCLC). In one embodiment, the cancer is advanced lung cancer, e.g., relapsed after prior TKI treatment, refractory to prior TKI treatment, progressed during prior TKI treatment, or resistant to prior TKI treatment.

[0194] In one embodiment, the compounds provided herein are administered as first-line treatment. In one embodiment, the compounds provided herein are administered as second-line treatment. In one embodiment, the compounds provided herein are administered as third-line or fourth-line treatment.

[0195] In one embodiment, the cancer (or ALK cancer) is metastatic. In one embodiment, the cancer has CNS metastases. In one embodiment, the cancer has brain metastases. In one embodiment, the cancer is metastatic non-small cell lung cancer (NSCLC). In one embodiment, the cancer is metastatic ALK+NSCLC.

[0196] In one embodiment, provided herein is a method for treating a subject having metastatic ALK+ non-small cell lung cancer (NSCLC), comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., Compound 1 (e.g., Form 2), or a pharmaceutically acceptable salt thereof.

[0197] In one embodiment, the subject is an adult subject over 18 years of age. In one embodiment, the subject is a pediatric subject no older than 18 years of age. In one embodiment, the subject is a pediatric subject at least 12 years of age but no older than 18 years of age. In one embodiment, the subject is a patient.

[0198] In one embodiment, provided herein are methods for treating an adult subject with metastatic ALK+ NSCLC comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., Compound 1 (e.g., Form 2), or a pharmaceutically acceptable salt thereof.

[0199] In one embodiment, provided herein is a method for treating an adult subject with metastatic ALK+ NSCLC, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the subject has progressed on or is intolerant to at least 1 prior TKI therapy.

[0200] In one embodiment, provided herein is a method for treating ALK-related (or ALK+) cancer in a subject in need thereof, wherein the cancer has become resistant to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., Compound 1 (e.g., Form 2), or a pharmaceutically acceptable salt thereof.

[0201] In one embodiment, provided herein is a method for treating an ALK-related (or ALK+) cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), and wherein the cancer has been identified as having one or more ALK inhibitor resistance mutations, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, such as compound 1 (e.g., Form 2), or a pharmaceutically acceptable salt thereof. In one embodiment, the one or more ALK inhibitor resistance mutations include one or more amino acid substitutions at amino acid positions selected from 1151, 1196, 1198, 1202, and 1269. In one embodiment, the one or more ALK inhibitor resistance mutations include one or more amino acid substitutions selected from T1151M, L1196M, L1198F, G1202R, and G1269A. In one embodiment, the one or more ALK inhibitor resistance mutations are G1202R. In one embodiment, the one or more ALK inhibitor resistance mutations include G1202R and one or more of L1196M, L1198F, G1269A, and T1151M.

[0202] In one embodiment, provided herein is a method for treating an adult subject having metastatic NSCLC that is ALK+ and has the mutation G1202R, comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., Compound 1 (e.g., Form 2), or a pharmaceutically acceptable salt thereof, wherein the subject has progressed on or is intolerant to at least 1 prior TKI therapy.

[0203] In one embodiment, provided herein is a method for treating ALK-related (e.g., ALK+) cancer in a subject in need thereof, wherein the cancer has become resistant to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., Compound 1 (e.g., Form 2), or a pharmaceutically acceptable salt thereof.

[0204] In one embodiment, the cancer or disease occurs in a pediatric subject (including an infant subject). In one embodiment, the cancer is systemic anaplastic large cell lymphoma (ALCL) that is ALK+ in pediatric subjects and young adults 1 year of age or older. In another embodiment, the cancer is relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) that is ALK+ in pediatric subjects and young adults 1 year of age or older.

[0205] In one embodiment, the TKI is an ALK inhibitor. In one embodiment, the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, ripretinib, cabozantinib, foretinib, mesartinib, taretinib, masitinib or ensartinib. In one embodiment, the TKI is crizotinib. In one embodiment, the TKI is ceritinib. In one embodiment, the TKI is alectinib. In one embodiment, the TKI is brigatinib. In one embodiment, the TKI is lorlatinib. In one embodiment, the TKI is a first-generation ALK TKI (e.g., crizotinib). In one embodiment, the TKI is a second-generation ALK TKI (e.g., ceritinib, alectinib or brigatinib). In one embodiment, the TKI is a third-generation ALK TKI (e.g., lorlatinib).

[0206] In certain embodiments, the subject relapses after receiving first-line treatment for cancer. In certain embodiments, the subject relapses after receiving first-line treatment for cancer with an ALK TKI selected from crizotinib, ceritinib, alectinib, and brigatinib. In certain embodiments, the subject relapses after receiving cancer treatment with at least one ALK TKI selected from crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In other embodiments, the subject relapses after receiving second-line treatment for cancer. In other embodiments, the subject relapses after receiving second-line treatment for cancer with one or more ALK TKIs selected from crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In other embodiments, the subject relapses after receiving third-line treatment for cancer. In other embodiments, the subject relapses after second-line or third-line treatment for cancer, wherein lorlatinib is in the second or third line.

[0207] In certain embodiments, the subject develops resistance after receiving first-line treatment for cancer. In certain embodiments, the subject develops resistance after receiving first-line treatment for cancer with an ALK TKI selected from crizotinib, ceritinib, alectinib, and brigatinib. In certain embodiments, the subject develops resistance after receiving cancer treatment with at least one ALK TKI selected from crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In other embodiments, the subject develops resistance after receiving second-line treatment for cancer. In other embodiments, the subject develops resistance after receiving second-line treatment for cancer with one or more ALK TKIs selected from crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In other embodiments, the subject develops resistance after receiving third-line treatment for cancer. In other embodiments, the subject develops resistance after second-line or third-line treatment for cancer, wherein lorlatinib is in second-line or third-line treatment.

[0208] In one embodiment, compound 1 is administered to a subject for one or more days, once a day (QD). In one embodiment, compound 1 is administered to a subject for one or more days, twice a day (BID). In one embodiment, compound 1 is administered to a subject for at least one treatment cycle, once a day (QD). In one embodiment, compound 1 is administered to a subject for at least one treatment cycle, twice a day (BID). In one embodiment, a treatment cycle is at least 7 days. In one embodiment, a treatment cycle is at least 14 days. In one embodiment, a treatment cycle is at least 15 days. In one embodiment, a treatment cycle is at least 21 days. In one embodiment, a treatment cycle is at least 28 days. In one embodiment, compound 1 is administered to a subject for at least one treatment cycle (e.g., 21 days). In one embodiment, compound 1 is administered to a subject for at least two treatment cycles (e.g., 42 days). In one embodiment, compound 1 is administered to a subject for at least three treatment cycles (e.g., 63 days).

[0209] In one embodiment, the patient did not experience grade 4 adverse events after administration of compound 1. In one embodiment, the patient did not experience grade 3 adverse events after administration of compound 1. In one embodiment, the patient did not experience grade 2 adverse events after administration of compound 1. In one embodiment, the patient did not experience grade 1 adverse events after administration of compound 1. As used herein and unless otherwise indicated, the level of the adverse event follows the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) level, which is incorporated herein by reference. In some embodiments, the adverse event is TEAE. In some embodiments, the adverse event is TRAE.

[0210] In one embodiment, the patient does not experience neurological adverse events after administration of Compound 1. In one embodiment, the patient does not experience psychiatric events (e.g., insomnia) after administration of Compound 1. In one embodiment, the patient does not experience one or more CNS adverse events selected from the group consisting of dizziness, ataxia, gait disturbance, paresthesia, weight gain, hyperphagia, paresthesia, movement abnormalities, cognitive changes, seizures, hallucinations, speech disorders (e.g., aphasia, dysarthria, slow speech or speech disorders), mood disorders (e.g., irritability, anxiety, depression, affective disorders, mood swings, personality changes, mood swings, affective disorders, aggression, stress, agitation, mood changes, depressed mood, euphoria, suicidal ideation or mania), mental state, sleep disorders and cognitive disorders (e.g., memory disorders, cognitive disorders, amnesia, confusion, attention disorders, delirium, mental disorders, attention deficit / hyperactivity disorder, dementia, sleep disorders, disorientation or reading disorders). In one embodiment, the neurological adverse event is one or more selected from the group consisting of: cognitive impairment, mood disorders, sleep disorders, dizziness and ataxia. In one embodiment, the patient does not experience adverse events of weight gain and / or glucose metabolism disorders. In one embodiment, the glucose metabolism disorder is hyperglycemia (e.g., diabetes). In one embodiment, the glucose metabolism disorder is hypoglycemia. In one embodiment, the patient experiences a grade 1 treatment-related adverse event (TRAE) after administering compound 1. In one embodiment, the patient experiences a maximum of grade 1 TRAE after administering compound 1. In one embodiment, the patient experiences a maximum of grade 2 TRAE after administering compound 1. In one embodiment, the patient experiences a maximum of grade 2 TRAE after administering compound 1. In one embodiment, the patient experiences grade 3 TRAE after administering compound 1. In one embodiment, the patient experiences a maximum of grade 3 TRAE after administering compound 1. In one embodiment, the patient experiences a grade 1 treatment-emergent adverse event (TEAE) after administering compound 1. In one embodiment, the patient experiences a maximum of grade 1 TEAE after administering compound 1. In one embodiment, the patient experiences a maximum of grade 2 TEAE after administering compound 1. In one embodiment, the patient experiences a maximum of Grade 2 TEAEs following administration of Compound 1. In one embodiment, the patient experiences a maximum of Grade 3 TEAEs following administration of Compound 1. In one embodiment, the patient experiences a maximum of Grade 3 TEAEs following administration of Compound 1.

[0211] In one embodiment, the patient does not experience significant hepatotoxicity after administration of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the patient does not experience a significant increase in aminotransferase after administration of compound 1 or a pharmaceutically acceptable salt. In some embodiments, the patient does not experience a significant increase in alanine aminotransferase (ALT) after administration of compound 1 or a pharmaceutically acceptable salt. In some embodiments, the patient experiences a maximum of 3 levels of ALT elevation as a treatment-emergent adverse event (TEAE) or treatment-related adverse event (TRAE) after administration of compound 1 or a pharmaceutically acceptable salt. In some embodiments, the patient experiences a maximum of 2 levels of ALT elevation as a TEAE or TRAE after administration of compound 1 or a pharmaceutically acceptable salt. In some embodiments, the patient experiences a maximum of 1 level of ALT elevation as a TEAE or TRAE after administration of compound 1 or a pharmaceutically acceptable salt. In some embodiments, the patient does not experience a significant increase in aspartate aminotransferase (AST) after administration of compound 1 or a pharmaceutically acceptable salt. In some embodiments, the patient experiences up to Grade 3 AST elevations as TEAEs or TRAEs after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences up to Grade 2 AST elevations as TEAEs or TRAEs after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences up to Grade 1 AST elevation as TEAEs or TRAEs after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the ALT or AST elevation occurs within about two months after administration of Compound 1 or a pharmaceutically acceptable salt thereof, and subsequently returns to normal limits or baseline. In some embodiments, the ALT or AST elevation occurs within about two months after administration of Compound 1 or a pharmaceutically acceptable salt thereof, and returns to normal limits or baseline within about 3 months after the ALT or AST elevation occurs. In some embodiments, the ALT or AST elevation occurs within about two months after administration of Compound 1 or a pharmaceutically acceptable salt thereof, and returns to normal limits or baseline within about 2 months after the ALT or AST elevation occurs. In some embodiments, the ALT or AST increase occurs within about two months after administration of Compound 1 or a pharmaceutically acceptable salt thereof, and returns to normal limits or baseline within about one month after the ALT or AST increase occurs. In some embodiments, the ALT or AST increase occurs within about two months after administration of Compound 1 or a pharmaceutically acceptable salt thereof, and returns to normal limits or baseline within about three weeks after the ALT or AST increase occurs.In some embodiments, the ALT or AST increase occurs within about two months after administration of Compound 1 or a pharmaceutically acceptable salt thereof, and returns to normal limits or baseline within about two weeks after the ALT or AST increase occurs. In one embodiment, the patient does not experience a significant increase in ALT or AST after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the administration is once a day. In some embodiments, the administration is twice a day. In some embodiments, the administration is once a day and is performed continuously during the dosing period. In some embodiments, the administration is twice a day and is performed continuously during the dosing period.

[0212] In some embodiments, after administering compound 1 or a pharmaceutically acceptable salt thereof to a patient at a certain dose level, the patient experiences a grade 1 increase in ALT or AST as a TEAE or TRAE, and the administration continues at the same dose level. In some embodiments, after administering compound 1 or a pharmaceutically acceptable salt thereof to a patient at a certain dose level, the patient experiences a grade 2 increase in ALT or AST as a TEAE or TRAE, and the administration continues at the same dose level (in further embodiments, under weekly monitoring (e.g., until the increase in ALT or AST returns to grade 1 or lower)). In some embodiments, after administering compound 1 or a pharmaceutically acceptable salt thereof to a patient at a certain dose level, the patient experiences a grade 3 increase in ALT or AST as a TEAE or TRAE, and the administration undergoes a dose interruption (i.e., the administration is stopped / suspended for a period of time). In some embodiments, after administering compound 1 or a pharmaceutically acceptable salt thereof to a patient at a certain dose level, the patient experiences a grade 3 increase in ALT or AST as a TEAE or TRAE, and the administration is subject to dose modification (e.g., reduction). In some embodiments, when ALT or AST increases and returns to grade 1 or lower, or when ALT or AST returns to baseline, the patient resumes the same dose level after dose interruption. In some embodiments, the patient resumes the same dose level (first dose level) after dose interruption and experiences the same grade of ALT or AST increase (in one embodiment, it subsides within 30 days (e.g., the severity returns to grade 1 or lower, or ALT or AST returns to baseline)), and then the patient receives a lower dose level (second dose level, for example, according to Table A). In one embodiment, the first dose level is 50 mg QD, and the second dose level is 25 mg QD. In one embodiment, the first dose level is 100 mg QD, and the second dose level is 50 mg QD. In one embodiment, the first dose level is 150 mg QD, and the second dose level is 100 mg QD. In one embodiment, the first dose level is 200 mg QD, and the second dose level is 150 mg QD. In one embodiment, the dose level is reduced for the second time.

[0213] In some embodiments, after administration of Compound 1 or a pharmaceutically acceptable salt thereof, less than 40% of the patient population has adverse events (e.g., TEAEs or TRAEs) with elevated ALT or AST. In some embodiments, after administration of Compound 1 or a pharmaceutically acceptable salt thereof, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5% of the patient population has adverse events (e.g., TEAEs or TRAEs) with elevated ALT or AST. In some embodiments, less than about 15% of the patient population has adverse events with elevated ALT or AST. In some embodiments, less than about 14% of the patient population has adverse events with elevated ALT or AST. In some embodiments, less than about 13% of the patient population has adverse events with elevated ALT or AST. In some embodiments, less than about 12% of the patient population has adverse events with elevated ALT or AST. In some embodiments, less than about 11% of the patient population has adverse events with elevated ALT or AST. In some embodiments, less than about 10% of the patient population has adverse events with elevated ALT or AST. In some embodiments, less than about 9% of the patient population has adverse events of increased ALT or AST. In some embodiments, less than about 8% of the patient population has adverse events of increased ALT or AST. In some embodiments, less than about 7% of the patient population has adverse events of increased ALT or AST. In some embodiments, less than about 6% of the patient population has adverse events of increased ALT or AST. In some embodiments, less than about 5% of the patient population has adverse events of increased ALT or AST. In certain embodiments, the adverse event of increased ALT or AST is Grade 1. In certain embodiments, the adverse event of increased ALT or AST is Grade 2 (or lower). In certain embodiments, the increased adverse event of ALT or AST is Grade 3 (or lower).

[0214] In one embodiment, the patient does not experience significant hyperlipidemia after administration of Compound 1 or a pharmaceutically acceptable salt. In one embodiment, the patient does not experience a significant increase in blood triglycerides after administration of Compound 1 or a pharmaceutically acceptable salt. In one embodiment, the patient experiences a maximum of a Grade 3 increase in blood triglycerides as a TEAE or TRAE after administration of Compound 1 or a pharmaceutically acceptable salt. In one embodiment, the patient experiences a maximum of a Grade 2 increase in blood triglycerides as a TEAE or TRAE after administration of Compound 1 or a pharmaceutically acceptable salt. In one embodiment, the patient experiences a maximum of a Grade 1 increase in blood triglycerides as a TEAE or TRAE after administration of Compound 1 or a pharmaceutically acceptable salt. In one embodiment, the patient does not experience a significant increase in total cholesterol after administration of Compound 1 or a pharmaceutically acceptable salt. In one embodiment, the patient experiences a maximum of a Grade 3 increase in total cholesterol as a TEAE or TRAE after administration of Compound 1 or a pharmaceutically acceptable salt. In one embodiment, the patient experiences a maximum of a Grade 2 increase in total cholesterol as a TEAE or TRAE after administration of Compound 1 or a pharmaceutically acceptable salt. In one embodiment, the patient experiences at most a 1-grade increase in total cholesterol as a TEAE or TRAE after administration of compound 1 or a pharmaceutically acceptable salt. In certain embodiments, the patient is also administered a lipid-lowering agent. In some embodiments, after administering compound 1 or a pharmaceutically acceptable salt thereof to a patient at a certain dose level, the patient experiences a 1-grade increase in total cholesterol or triglycerides as a TEAE or TRAE, and the administration continues at the same dose level. In some embodiments, after administering compound 1 or a pharmaceutically acceptable salt thereof to a patient at a certain dose level, the patient experiences a 1-grade increase in total cholesterol or triglycerides as a TEAE or TRAE, and the administration continues at the same dose level and further administers a lipid-lowering agent. In some embodiments, after administering compound 1 or a pharmaceutically acceptable salt thereof to a patient at a certain dose level, the patient experiences a 2-grade increase in total cholesterol or triglycerides as a TEAE or TRAE, and the administration continues at the same dose level. In some embodiments, after administering Compound 1 or a pharmaceutically acceptable salt thereof to a patient at a certain dose level, the patient experiences a Grade 2 increase in total cholesterol or triglycerides as a TEAE or TRAE, and the administration continues at the same dose level and a lipid-lowering agent is further administered. In some embodiments, after administering Compound 1 or a pharmaceutically acceptable salt thereof to a patient at a certain dose level, the patient experiences a Grade 3 increase in total cholesterol or triglycerides as a TEAE or TRAE, and the administration continues at the same dose level.In some embodiments, after compound 1 or its pharmaceutically acceptable salt is administered to a patient at a certain dose level, the patient experiences a 3-grade increase in total cholesterol or triglycerides as a TEAE or TRAE, and the administration undergoes a dose interruption (ie, the administration stops / pauses for a period of time) or changes (eg, reduction). In some embodiments, when the increase in total cholesterol or triglycerides is restored to grade 2 or below, or when total cholesterol or triglycerides are restored to baseline, the patient resumes the same dose level after dose interruption or modification. In some embodiments, the patient experiences a 3-grade increase in total cholesterol or triglycerides as a TEAE or TRAE, and the administration continues at the same dose level and further administers a lipid-lowering agent. In some embodiments, the patient experiences a 3-grade increase in total cholesterol or triglycerides as a TEAE or TRAE, and the administration undergoes a dose interruption or modification (eg, reduction) and further administers a lipid-lowering agent. In some embodiments, the lipid-lowering agent is selected from statins, fibrates, niacin, lecithin, bile acid sequestrants, ezetimibe, lomitapide, plant sterols, omega-3, PCSK9 inhibitors, choline, L-arginine, flaxseed oil, and pycnogenol. In one embodiment, the dose reduction is performed according to Table A.

[0215] In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered once a day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered twice a day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered once a day, continuously during the administration period. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered twice a day, continuously during the administration period.

[0216] In one embodiment, the patient does not experience a significant increase in total bilirubin as a TEAE or TRAE following administration of Compound 1. In one embodiment, the patient does not experience a significant increase in alkaline phosphatase following administration of Compound 1.

[0217] As used herein in conjunction with adverse events and unless otherwise specified, "significant" refers to about at least about 10% compared to baseline. In some embodiments, "significant" refers to about at least about 20% compared to baseline. In some embodiments, "significant" refers to about at least about 30% compared to baseline. In some embodiments, "significant" refers to about at least about 40% compared to baseline. In some embodiments, "significant" refers to about at least about 50% compared to baseline. In some embodiments, "significant" refers to about at least about 60% compared to baseline. In some embodiments, "significant" refers to about at least about 70% compared to baseline. In some embodiments, "significant" refers to about at least about 80% compared to baseline. In some embodiments, "significant" refers to about at least about 90% compared to baseline. In some embodiments, the administration is once a day. In some embodiments, the administration is twice a day. In some embodiments, the administration is once a day, continuously during the administration period. In some embodiments, the administration is twice a day, continuously during the administration period.

[0218] In one embodiment, the patient does not experience gastrointestinal disorders (e.g., constipation, diarrhea, oral hypoesthesia, nausea or vomiting) after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the patient experiences up to grade 3 gastrointestinal disorders (e.g., constipation, diarrhea, oral hypoesthesia, nausea or vomiting) as adverse events (TEAEs) or treatment-related adverse events (TRAEs) during treatment. In one embodiment, the patient experiences up to grade 2 gastrointestinal disorders (e.g., constipation, diarrhea, oral hypoesthesia, nausea or vomiting) TEAEs or TRAEs. In one embodiment, the patient experiences up to grade 1 gastrointestinal disorders (e.g., constipation, diarrhea, oral hypoesthesia, nausea or vomiting) TEAEs or TRAEs. In certain embodiments, the patient does not experience significant nausea, constipation or diarrhea. In certain embodiments, the patient experiences up to grade 3 nausea, constipation or diarrhea as TEAEs or TRAEs. In certain embodiments, the patient experiences up to grade 2 nausea, constipation or diarrhea as TEAEs or TRAEs. In certain embodiments, the patient experiences up to grade 1 nausea, constipation or diarrhea as TEAEs or TRAEs. In some embodiments, after compound 1 or its pharmaceutically acceptable salt is administered to a patient at a certain dose level, the patient experiences a grade 1 gastrointestinal disorder as a TEAE or TRAE, and the administration continues at the same dose level. In some embodiments, after compound 1 or its pharmaceutically acceptable salt is administered to a patient at a certain dose level, the patient experiences a grade 2 gastrointestinal disorder as a TEAE or TRAE, and the administration continues at the same dose level. In some embodiments, after compound 1 or its pharmaceutically acceptable salt is administered to a patient at a certain dose level, the patient experiences a grade 2 gastrointestinal disorder as a TEAE or TRAE, and the administration is interrupted (i.e., the administration is stopped / suspended for a period of time) or modified (e.g., reduced). In some embodiments, after compound 1 or its pharmaceutically acceptable salt is administered to a patient at a certain dose level, the patient experiences a grade 3 gastrointestinal disorder as a TEAE or TRAE, and the administration is subject to dose interruption or modification (e.g., reduction). In some embodiments, when the level of gastrointestinal disease adverse events returns to grade 2 or lower, the patient resumes the same dose level after dose interruption or modification. In some embodiments, when the level of gastrointestinal disease adverse events returns to grade 1 or lower, the patient resumes the same dose level after dose interruption or modification. In certain embodiments, the patient is also administered an antiemetic (e.g., bismuth subsalicylate, antihistamines, metoclopramide, etc.) to manage nausea. In certain embodiments, the patient is also administered a laxative (e.g., an oral osmotic agent such as MiraLAX, an oral stool softener such as Colace, an oral stimulant such as Dulcolax, or a rectal suppository such as Dulcolax) to manage constipation.In certain embodiments, the patient is also administered an antidiarrheal agent (e.g., loperamide, bismuth subsalicylate, etc.) to manage diarrhea. In one embodiment, the dose reduction is performed according to Table A.

[0219] In one embodiment, the patient did not experience musculoskeletal and connective tissue disorders (e.g., back pain, musculoskeletal chest pain, musculoskeletal pain, or pain in the extremities) after administration of compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the patient did not experience musculoskeletal and connective tissue disorders (e.g., back pain, musculoskeletal chest pain, musculoskeletal pain, or pain in the extremities) as TEAEs or TRAEs after administration of compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the patient experienced up to grade 3 musculoskeletal and connective tissue disorders (e.g., back pain, musculoskeletal chest pain, musculoskeletal pain, or pain in the extremities) as TEAEs or TRAEs after administration of compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the patient experienced up to grade 2 musculoskeletal and connective tissue disorders (e.g., back pain, musculoskeletal chest pain, musculoskeletal pain, or pain in the extremities) as TEAEs or TRAEs after administration of compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the patient experiences up to grade 1 musculoskeletal and connective tissue disorders (e.g., back pain, musculoskeletal chest pain, musculoskeletal pain, or pain in the extremities) as TEAEs or TRAEs after administration of compound 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the patient does not experience significant pain after administration of compound 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the patient experiences grade 1 pain as a TEAE or TRAE after administration of compound 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the patient experiences grade 2 pain as a TEAE or TRAE after administration of compound 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the patient experiences grade 3 pain as a TEAE or TRAE after administration of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the patient experiences grade 2 musculoskeletal and connective tissue disorders and undergoes dose interruption or modification (e.g., reduction). In some embodiments, after compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient at a certain dose level, the patient experiences grade 3 musculoskeletal and connective tissue disorders as TEAEs or TRAEs, and the administration is interrupted in dose (i.e., the administration is stopped / suspended for a period of time) or modified (e.g., reduced). In some embodiments, when the level of adverse events of musculoskeletal and connective tissue disorders is restored to grade 2 or lower, the patient recovers the same dose level after dose interruption or modification. In some embodiments, when the level of adverse events of musculoskeletal and connective tissue disorders is restored to grade 1 or lower, the patient recovers the same dose level after dose interruption or modification. In one embodiment, the patient is also administered analgesics (e.g., acetaminophen, NSAID, COX-2 inhibitors such as etoricoxib). In one embodiment, the dose reduction is performed according to Table A.

[0220] In one embodiment, the patient does not experience respiratory, chest and mediastinal disorders (e.g., cough, dyspnea, exertional dyspnea, or increased bronchial secretions). In one embodiment, the patient does not experience respiratory, chest and mediastinal disorders (e.g., cough, dyspnea, exertional dyspnea, or increased bronchial secretions) as TRAEs or TEAEs. In one embodiment, the patient experiences up to grade 3 respiratory, chest and mediastinal diseases (e.g., cough, dyspnea, exertional dyspnea, or increased bronchial secretions) as TAREs or TEAEs. In one embodiment, the patient experiences up to grade 2 respiratory, chest and mediastinal disorders (e.g., cough, dyspnea, exertional dyspnea, or increased bronchial secretions) as TRAEs or TEAEs. In one embodiment, the patient experiences up to grade 1 respiratory, chest and mediastinal disorders (e.g., cough, dyspnea, exertional dyspnea, or increased bronchial secretions) as TRAEs or TEAEs. In one embodiment, the patient experiences up to grade 1 respiratory, chest and mediastinal disorders (e.g., cough, dyspnea, exertional dyspnea or increased bronchial secretions) as TRAE or TEAE. In one embodiment, the patient experiences up to grade 1 cough as TRAE or TEAE. In one embodiment, the patient experiences up to grade 2 cough as TRAE or TEAE. In one embodiment, the patient experiences up to grade 3 cough as TRAE or TEAE. In one embodiment, the patient is also administered cough suppressants (e.g., dextromethorphan, guaifenesin, menthol, antihistamines (e.g., chlorpheniramine and clemastine), decongestants (e.g., pseudoephedrine or phenylephrine), benzonatate, salbutamol, promethazine, steroids (e.g., prednisone, prednisolone, dexamethasone, fluticasone propionate, budesonide, salbutamol + ipratropium bromide, montelukast, nociception-opioid-1-receptor agonists, codeine and gelatin, etc.)). In one embodiment, the patient is also administered prednisone (e.g., not more than 10 mg / day) as a cough suppressant. In some embodiments, after administering Compound 1 or a pharmaceutically acceptable salt thereof to a patient at a certain dose level, the patient experiences Grade 1 respiratory, thoracic, and mediastinal disorders (e.g., cough, dyspnea, dyspnea on exertion, or increased bronchial secretions), and the administration continues at the same dose level. In some embodiments, after administering Compound 1 or a pharmaceutically acceptable salt thereof to a patient at a certain dose level, the patient experiences Grade 2 respiratory, thoracic, and mediastinal disorders (e.g., cough, dyspnea, dyspnea on exertion, or increased bronchial secretions) as TEAEs or TRAEs, and the administration continues at the same dose level.In some embodiments, after administering Compound 1 or a pharmaceutically acceptable salt thereof to a patient at a certain dose level, the patient experiences Grade 2 respiratory, chest and mediastinal disorders (e.g., cough, dyspnea, dyspnea on exertion, or increased bronchial secretions) as TEAEs or TRAEs, and the administration is subject to dose interruption (i.e., the administration is stopped / suspended for a period of time) or modification (e.g., reduction). In some embodiments, after administering Compound 1 or a pharmaceutically acceptable salt thereof to a patient at a certain dose level, the patient experiences Grade 2 respiratory, chest and mediastinal disorders (e.g., cough, dyspnea, dyspnea on exertion, or increased bronchial secretions) as TEAEs or TRAEs, and the administration is subject to dose interruption until the severity of the adverse event is Grade 1 or lower. In some embodiments, after administering Compound 1 or a pharmaceutically acceptable salt thereof to a patient at a certain dose level, the patient experiences Grade 3 respiratory, chest and mediastinal disorders (e.g., cough, dyspnea, dyspnea on exertion, or increased bronchial secretions) as TEAEs or TRAEs, and the administration is subject to dose interruption or modification (e.g., reduction). In some embodiments, when the adverse events of respiratory system, chest and mediastinal disorders return to grade 2 or lower, the patient resumes the same dose level after dose interruption or modification. In some embodiments, when the adverse events of respiratory system, chest and mediastinal disorders return to grade 1 or lower, the patient resumes the same dose level after dose interruption or modification. In certain embodiments, the respiratory system, chest and mediastinal disorders are cough. In one embodiment, the dose reduction is performed according to Table A.

[0221] In one embodiment, the patient does not experience significant weight gain after administration of compound 1 or a pharmaceutically acceptable salt. In one embodiment, after administration of compound 1 or a pharmaceutically acceptable salt, the patient population does not experience statistically significant (e.g., ≥ baseline about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%) weight gain. In one embodiment, after about one month of once-daily administration of compound 1 or a pharmaceutically acceptable salt, the patient population does not experience statistically significant weight gain. In one embodiment, after about two months of once-daily administration of compound 1 or its pharmaceutically acceptable salt, the patient population does not experience statistically significant weight gain. In one embodiment, after about three months of once-daily administration of compound 1 or its pharmaceutically acceptable salt, the patient population does not experience statistically significant weight gain. In one embodiment, after about four months of once-daily administration of compound 1 or its pharmaceutically acceptable salt, the patient population does not experience statistically significant weight gain. In one embodiment, after about five months of once daily administration of compound 1 or a pharmaceutically acceptable salt thereof, the patient population does not experience statistically significant weight gain. In one embodiment, after about six months of once daily administration of compound 1 or a pharmaceutically acceptable salt thereof, the patient population does not experience statistically significant weight gain. In one embodiment, after about 8 months of once daily administration of compound 1 or a pharmaceutically acceptable salt thereof, the patient population does not experience statistically significant weight gain. In one embodiment, after about 10 months of once daily administration of compound 1 or a pharmaceutically acceptable salt thereof, the patient population does not experience statistically significant weight gain. In one embodiment, after about 12 months of once daily administration of compound 1 or a pharmaceutically acceptable salt thereof, the patient population does not experience statistically significant weight gain. In some embodiments, the weight gain is abdominal obesity. In some embodiments, the weight gain is an increase in waist circumference. In some embodiments, the weight gain of the patient population is an average increase in waist circumference. In some embodiments, the patient does not experience obesity-related complications (e.g., diabetes (e.g., type 2), cardiovascular comorbidities, depression or osteoarthritis, thrombosis, and an increased risk of severe infectious processes).

[0222] In one embodiment, the patient does not experience treatment-related serious adverse events (SAEs). In one embodiment, the patient does not experience treatment-related CNS adverse events. In one embodiment, the patient does not experience treatment-related dizziness.

[0223] In one embodiment, the patient has a complete response after one or more treatment cycles. In one embodiment, the patient has a partial response after one or more treatment cycles. In one embodiment, the patient has achieved stable disease after one or more treatment cycles. In one embodiment, the patient does not experience disease progression after one or more treatment cycles.

[0224] In one embodiment, the patient is a patient population. In one embodiment, the patient population does not experience statistically significant (e.g., ≥ about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40% baseline) adverse events as described herein (e.g., TEAE or TRAE). In one embodiment, the patient population does not experience statistically significant ≥ about 7% of baseline adverse events as described herein (e.g., TEAE or TRAE). In one embodiment, the patient population does not experience statistically significant ≥ about 8% of baseline adverse events as described herein (e.g., TEAE or TRAE). In one embodiment, the patient population does not experience statistically significant ≥ about 9% of baseline adverse events as described herein (e.g., TEAE or TRAE). In one embodiment, the patient population does not experience statistically significant ≥ about 10% of baseline adverse events as described herein (e.g., TEAE or TRAE). In one embodiment, the patient population does not experience statistically significant ≥ about 15% of baseline adverse events as described herein (e.g., TEAEs or TRAEs). In one embodiment, the patient population does not experience statistically significant ≥ about 20% of baseline adverse events as described herein (e.g., TEAEs or TRAEs). In one embodiment, the patient population does not experience statistically significant ≥ about 25% of baseline adverse events as described herein (e.g., TEAEs or TRAEs). In one embodiment, the patient population does not experience statistically significant ≥ about 30% of baseline adverse events as described herein (e.g., TEAEs or TRAEs). In one embodiment, the patient population does not experience statistically significant ≥ about 35% of baseline adverse events as described herein (e.g., TEAEs or TRAEs). In one embodiment, the patient population does not experience statistically significant ≥ about 40% of baseline adverse events as described herein (e.g., TEAEs or TRAEs). In one embodiment, the patient population does not experience statistically significant ≥ about 45% of baseline adverse events as described herein (e.g., TEAEs or TRAEs). In one embodiment, the adverse event is hepatotoxicity. In one embodiment, the adverse event is a substantial increase in transaminases. In one embodiment, the adverse event is a substantial increase in ALT or AST. In one embodiment, the adverse event is hyperlipidemia. In one embodiment, the adverse event is a substantial increase in blood triglycerides. In one embodiment, the adverse event is a substantial increase in total cholesterol. In one embodiment, the adverse event is a substantial increase in total bilirubin. In one embodiment, the adverse event is a gastrointestinal disorder (e.g., constipation, diarrhea, oral hypoesthesia, nausea, or vomiting).In one embodiment, the adverse event is a musculoskeletal and connective tissue disorder (e.g., back pain, musculoskeletal chest pain, musculoskeletal pain, or pain in the extremities). In one embodiment, the adverse event is a respiratory, chest, and mediastinal disorder (e.g., cough, dyspnea, exertional dyspnea, or increased bronchial secretions). In one embodiment, the adverse event is substantial weight gain. In one embodiment, the adverse event is a TEAE. In one embodiment, the adverse event is a TRAE. In one embodiment, the adverse event is grade 1. In one embodiment, the adverse event is grade 2. In one embodiment, the adverse event is grade 3. In one embodiment, the adverse event is at most grade 1. In one embodiment, the adverse event is at most grade 2. In one embodiment, the adverse event is at most grade 3.

[0225] As used herein and unless otherwise specified, complete response (CR) refers to the disappearance of all one or more target lesions. In some embodiments of CR, the short axis of any pathological lymph node (whether target or non-target) must be reduced to <10mm. Partial response (PR) refers to a reduction of at least 30% in the sum of the diameters of one or more target lesions. Progressive disease (PD) refers to an increase of at least 20% in the sum of the diameters of one or more target lesions. In some embodiments of PD, in addition to a relative increase of 20%, the sum also shows an increase of at least 5mm. In some embodiments, the appearance of one or more new lesions is also considered to be progress. Stable disease (SD) refers to neither sufficient contraction to meet the conditions of PR nor sufficient enlargement to meet the conditions of PD, with the minimum total diameter during the study as a reference. More descriptions of these terms according to RECIST 1.1 can be found in European Journal of Cancer 45 (2009) 228–247.

[0226] In one embodiment, provided herein is a method for reducing lesions in a subject having an ALK-positive solid tumor (e.g., NSCLC), comprising

[0227] (i) obtaining a first radiographic measurement of lesion size;

[0228] (ii) administering a pharmaceutically effective amount of Compound 1 once a day for one or more days; and

[0229] (iii) obtaining a second radiographic measurement of lesion size;

[0230] Wherein, the lesion size determined by the second measurement is at most 100% of the lesion size determined by the first measurement. In some embodiments, the measurement of the lesion size is defined in RECIST 1.1 response criteria. In one embodiment, the lesion is a target lesion, for example, as described in Example 1 or Example 15.

[0231] In one embodiment, the size of the lesions is characterized as the sum of the diameters of the lesions. In one embodiment, the sum of the diameters of the lesions determined from the second measurement is at most about 90% of the sum of the diameters of the lesions determined from the first measurement. In one embodiment, the sum of the diameters of the lesions determined by the second measurement is at most about 80% of the diameters of the lesions determined by the first measurement. In one embodiment, the sum of the diameters of the lesions determined by the second measurement is at most about 70% of the diameters of the lesions determined by the first measurement. In one embodiment, the sum of the diameters of the lesions determined by the second measurement is at most about 60% of the diameters of the lesions determined by the first measurement. In one embodiment, the sum of the diameters of the lesions determined by the second measurement is at most about 50% of the diameters of the lesions determined by the first measurement. In one embodiment, the sum of the diameters of the lesions determined by the second measurement is at most about 0.01% to about 90% of the sum of the diameters of the lesions determined by the first measurement. In one embodiment, the second measurement shows no detectable lesions.

[0232] In one embodiment, the patient has brain metastases. In one embodiment, the patient has brain metastases and has not experienced intracranial progression after at least one treatment cycle. In one embodiment, the patient has brain metastases and has not experienced intracranial progression after at least two treatment cycles.

[0233] In one embodiment, the patient has one or more ALK variant alleles in circulating tumor DNA reduced by at least about 5% to about 100% after at least one treatment cycle. In one embodiment, the patient has one or more ALK variant alleles in circulating tumor DNA reduced by at least about 5% to about 100% after at least 15 days of treatment. In one embodiment, the patient has one or more ALK variant alleles in circulating tumor DNA reduced by at least about 30% after at least one treatment cycle. In one embodiment, the patient has one or more ALK variant alleles in circulating tumor DNA reduced by at least about 40% after at least one treatment cycle. In one embodiment, the patient has one or more ALK variant alleles in circulating tumor DNA reduced by at least about 50% after at least one treatment cycle. In one embodiment, the patient has one or more ALK variant alleles in circulating tumor DNA reduced by at least about 60% after at least one treatment cycle. In one embodiment, the patient has one or more ALK variant alleles in circulating tumor DNA reduced by at least about 70% after at least one treatment cycle. In one embodiment, the patient has one or more ALK variant alleles in circulating tumor DNA reduced by at least about 80% after at least one treatment cycle. In one embodiment, the patient has one or more ALK variant alleles in circulating tumor DNA reduced by at least about 90% after at least one treatment cycle. In one embodiment, the patient has one or more ALK variant alleles in circulating tumor DNA reduced by about 100% after at least one treatment cycle. In one embodiment, the patient has one or more ALK variant alleles in circulating tumor DNA that are undetectable after at least one treatment cycle. In one embodiment, the patient has one or more ALK variant alleles in circulating tumor DNA that are undetectable after at least one treatment cycle. In one embodiment, the ALK variant allele is selected from one or more of G1202R, F1174L, F1174I, E1129K, S1206F, E1210K, G1269A, D1203N and G1269V. In one embodiment, the ALK variant allele is G1202R. In one embodiment, the ALK variant allele is D1203N. In one embodiment, the ALK variant allele is F1174L and / or F1174I.

[0234] In one embodiment, the prior therapy is a prior ALK TKI therapy. In one embodiment, the ALK TKI is selected from one or more of lorlatinib, crizotinib, ceritinib, alectinib and brigatinib. In one embodiment, the prior therapy is ALK TKI therapy and systemic therapy. In one embodiment, the ALKTKI is selected from one or more of lorlatinib, crizotinib, ceritinib, alectinib, brigatinib and systemic therapy, and the systemic therapy is selected from pemetrexed, cisplatin, carboplatin, bevacizumab, datopotamab deruxtecan, trastuzumab deruxtecan (T-DXd, DS-8201a) and checkpoint inhibitors (e.g., pembrolizumab, nivolumab, atezolizumab) One or more. In certain embodiments, the checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor, a cytotoxic T lymphocyte-related regulator (e.g., a CTLA-4 inhibitor), a LAG-3 inhibitor, or a TIM-3 inhibitor. In certain embodiments, the PD-1 inhibitor or PD-L1 inhibitor is selected from pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, simimumab, and dotalimumab. In certain embodiments, the PD-1 inhibitor is selected from pembrolizumab, nivolumab, atezolizumab, simimumab, and dotalimumab. sintilimab, spartalizumab (PDR001), pidilizumab (CureTech), MEDI0680 (Medimmune), dotalimab (TSR-042), PF-06801591 (Pfizer), sintilimab, toripalimab, tislelizumab (BGB-A317), camrelizumab (INCSHR1210, SHR-1210), AMP-224 (Amplimmune), CBT-501 (CBT Pharmaceuticals), CBT-502 (CBT Pharmaceuticals), JS001 (Junshi Biosciences), IBI308 (Innovent Biologics), INCSHR1210 (Incyte) (also known as SHR-1210 (Hengrui Medicine)), BGBA317 (BeiGene), BGB-108 (BeiGene), BAT-I306 (Bio-Thera Solutions), GLS-010 (Yuheng Pharmaceuticals; WuXi Biologics), AK103, AK104, AK105 (CanSino Biologics; Hangzhou Hans Bio; Hanzhong Bio), LZM009 (Livzon), HLX-10 (Fuhong Hanlin), MEDI0680 (Medimmune), PDF001 (Novartis), PF-06801591 (Pfizer), pidilizumab (CureTech), REGN2810 (Regeneron), and TSR-042 (Tesaro), CS1003 (CStone Pharmaceuticals), or MEDI0680 (Medimmune). In certain embodiments, the PD-L1 inhibitor is selected from atezolizumab, FAZ053 (Novartis) and BMS-936559 (Bristol-Myers Squibb), KN035 (Alphamab; 3DMed; Ascletis Pharma), Envafolimab (TRACON Pharmaceuticals), BMS936559 (Bristol-Myers Squibb), CS1001 (CStone Pharmaceuticals, Ligand Pharmaceuticals), CX-072 (CytomX Therapeutics), FAZ053 (Novartis), SHR-1316 (Hengrui Medicine), TQB2450 (Zhengda Tianqing), STI-A1014 (Zhaoke Pharmaceuticals;Lee's Pharm, Lonza, Sorrento Therapeutics, NantWorks), LYN00102 (Lynkcell), A167 (Harbour BioMed, Kelun Group), BGB-A333 (BeiGene), MSB2311 (Mabspace Biosciences), HLX-20 (Fuhong Hanlin), cosibelimab (Fortress Biotech), LY3300054 or iodapolimab (Eli Lilly), GS-4224 (Gilead Sciences), STI-A1015 (Yuhan, Sorrento Therapeutics), BCD-135 (BIOCAD), cosibelimab (Dana-Farber Cancer Institute, TG Therapeutics), APL-502 (Apollomics), AK106 (Akeso Biopharma), MSB2311 (Transcenta Holding), TG-1501 (TG Therapeutics) or FAZ053 (Novartis), MT-6035 (Molecular Templates), icariin or ZKAB001 (Lonza, Lee's Pharmaceutical Holdings, Sorrento Therapeutics, Shenogen Pharma Group), TRIDENT antibody (MacroGenics, Zai Lab), YBL-007 (Anh-Gook Pharmaceutical, Y-Biologics), HTI-1316 (Hengrui Therapeutics), PD-L1 oncology program (Weizmann Institute of Sciences), JS003 (Shanghai Junshi Biosciences), ND021 (Numab Therapeutics, CStone Pharmaceuticals), Toca 521 (Tocagen) or STT01 (STCube), DB004 (DotBio), MT-5050 (Molecular Templates), and KD036 (Kadmon). ;

[0235] In certain embodiments, methods for treating or preventing cancer can be demonstrated by one or more responses such as increasing apoptosis, inhibiting tumor growth, reducing tumor metastasis, inhibiting tumor metastasis, reducing microvessel density, reducing neovascularization, inhibiting tumor migration, tumor regression, and increasing the survival of the subject.

[0236] In one embodiment, administration of Compound 1 provides a compound area under the curve (AUC) from 0 to 24 hours. 0-24 ) is in the range of (80% to 125% of 100 ng*h / mL) to (80% to 125% of 20000 ng*h / mL). In one embodiment, administration of Compound 1 provides an area under the curve (AUC 0-24 ) is in the range of about 100 ng*h / mL to about 10000 ng*h / mL. In one embodiment, after treatment for at least about 15 days (e.g., once a day for at least about 15 days), the area under the curve (AUC) of the compound from 0 to 24 hours is 0-24 ) is in the range of about 200 ng*h / mL to about 15000 ng*h / mL. In one embodiment, after about 15 days of treatment (e.g., once a day for about 15 days), the area under the curve (AUC) of the compound from 0 to 24 hours is 0-24 ) is in the range of about 300 ng*h / mL to about 10000 ng*h / mL. In one embodiment, after about 15 days of treatment (e.g., once a day for about 15 days), the area under the curve (AUC) of the compound from 0 to 24 hours is 0-24 ) is in the range of about 1000 ng*h / mL to about 9000 ng*h / mL.

[0237] In one embodiment, such administration provides an area under the curve (AUC) from 0 to 24 hours after administration of the compound for each mg of Compound 1 administered. 0-24 ) is in the range of (80% to 125% of 10 ng*h / mL) to (80% to 125% of 300 ng*h / mL). In one embodiment, for each mg of Compound 1 administered, such administration provides an area under the curve (AUC 0-24 ) is in the range of from about 15 ng*h / mL to about 200 ng*h / mL. In one embodiment, after treatment for at least about 15 days (e.g., once a day for at least about 15 days), such administration provides an area under the curve (AUC) of the compound from 0 to 24 hours. 0-24) is in the range of from about 20 ng*h / mL to about 200 ng*h / mL. In one embodiment, after about 15 days of treatment (e.g., once a day for 15 days), such administration provides a compound with an area under the curve (AUC) from 0 to 24 hours. 0-24 ) is in the range of from about 20 ng*h / mL to about 150 ng*h / mL.

[0238] In one embodiment, such administration provides a maximum plasma concentration (C max ) is in the range of (80% to 125% of 20 ng / mL) to (80% to 125% of 2000 ng / mL). In one embodiment, such administration provides a maximum plasma concentration (C max ) is in the range of about 40 to about 1500 ng / mL. In one embodiment, such administration provides a maximum plasma concentration (C max ) is in the range of about 40 to about 1000 ng / mL. In one embodiment, after treatment for at least about 15 days (e.g., once a day for at least about 15 days), the C of the compound provided by Compound 1 is administered. max In the range of about 50 to about 2000 ng*h / mL. In one embodiment, after about 15 days of treatment (e.g., once a day for about 15 days), the C of the compound provided by Compound 1 is administered. max In the range of about 70 to about 1500 ng*h / mL. In one embodiment, after about 15 days of treatment (e.g., once a day for about 15 days), the C of the compound provided by Compound 1 is administered. max In the range of about 100 to about 1100 ng*h / mL.

[0239] In one embodiment, for each mg of Compound 1 administered, such administration provides a maximum plasma concentration (C max ) is in the range of about 2 to about 70 ng / mL. In one embodiment, for each mg of Compound 1 administered, such administration provides a maximum plasma concentration (C max ) is in the range of about 2 to about 50 ng / mL. In one embodiment, after treatment for at least about 15 days (e.g., once a day for at least about 15 days), for each mg of Compound 1 administered, the C of the compound provided by administration of Compound 1 is max In the range of about 3 to about 40 ng / mL. In one embodiment, after about 15 days of treatment (e.g., once a day for about 15 days), for each mg of Compound 1 administered, the C of the compound provided by the administration of Compound 1 is maxIn the range of about 3 to about 30 ng / mL. In one embodiment, after about 15 days of treatment (e.g., once a day for about 15 days), for each mg of Compound 1 administered, the C of the compound provided by the administration of Compound 1 is max In the range of about 3 to about 20 ng / mL.

[0240] In one embodiment, such administration provides a T of the compound after administration. max In the range of about 0.25h to about 5h. In one embodiment, such administration provides a T of the compound after administration of max In the range of about 0.25h to about 4h. In one embodiment, after at least about 15 days of treatment (e.g., once a day for at least about 15 days), such administration provides a T of the compound after administration of max In the range of about 0.5h to about 5h. In one embodiment, after about 15 days of treatment (e.g., once a day for about 15 days), such administration provides a T of the compound after administration of max In the range of about 0.5h to about 4h. In one embodiment, after about 15 days of treatment (e.g., once a day for about 15 days), such administration provides a T of the compound after administration of max In the range of about 0.5h to about 3.0h.

[0241] In one embodiment, such administration provides a t of the compound after administration. 1 / 2 In the range of about 3 hours to about 100 hours. In one embodiment, such administration provides a t of the compound after administration of 1 / 2 In the range of about 8h to about 50h. In one embodiment, after about 15 days of treatment, such administration provides a t of the compound after administration of 1 / 2 In the range of about 10h to about 50h.

[0242] In one embodiment, such administration provides an unbound plasma concentration after administration of greater than about 1.4 ng / mL. In one embodiment, such administration provides an unbound plasma concentration after administration of greater than about 4.2 ng / mL. In one embodiment, such administration provides an unbound plasma concentration after administration of greater than about 12.5 ng / mL.

[0243] In one embodiment, the pharmacokinetic parameters provided herein (e.g., AUC 0-24 , C max , T max and half-life) refer to the arithmetic mean of the patient population. In one embodiment, the pharmacokinetic parameters provided herein (e.g., AUC 0-24 , C max ) refers to the geometric mean of a patient population. In certain embodiments, t1 / 2 Refers to the arithmetic mean of the patient population. In certain embodiments, T max Refers to the median range of a patient population. In certain embodiments, AUC 0-24 , AUC 最终，未结合 , AUC tau , AUC tau_DN , AUC inf , AUC inf_DN , C max , C max_DN , C max_未结合 and C min Each of the refers to the geometric mean for the patient population.

[0244] In some embodiments, the subject or subject population is administered compound 1 or its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof QD. In some embodiments, the subject or subject population is administered compound 1 or its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof BID.

[0245] In certain embodiments, the measurement is performed after administering one compound 1 or its stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. In certain embodiments, the measurement is performed after administering one cycle (e.g., 21 days) of compound 1 or its stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. In certain embodiments, the measurement is performed after administering about 15 days of compound 1 or its stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. In certain embodiments, the measurement is performed after administering two cycles (e.g., 42 days) of compound 1 or its stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. In certain embodiments, the measurement is performed after administering three cycles (e.g., 63 days) of compound 1 or its stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. In certain embodiments, the measurement is performed after administering four cycles (e.g., 84 days) of compound 1 or its stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0246] Combination therapy

[0247] In some embodiments, methods of treating or preventing cancer may include administering Compound 1 in combination with one or more other chemotherapeutic agents.

[0248] As used herein and unless otherwise specified, "in conjunction with" or "in combination with" does not mean that the other agent and Compound 1 must be administered at the same time and / or formulated for delivery together, although such methods of delivery are within the scope of the present disclosure. Compounds provided herein can be administered simultaneously with one or more other agents (e.g., one or more other additional agents), before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks), or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks). In general, each therapeutic agent is administered according to the dosage and / or schedule determined for that particular agent. The other therapeutic agent can be administered with the compounds provided herein in a single composition or separately in different compositions.Triple combination therapy is also contemplated herein.

[0249] Chemotherapeutic agents that can be administered in combination with the compounds of the present disclosure include: 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (Acid Blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate. -[2-Anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, afatinib maleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, bacillus Calmette-Guérin (bcg), bicalutamide, bleomycin, bortezomib, β-methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, camptothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, dapoxetine Carbazine, actinomycin D, daunorubicin, demethoxychlorobenzene, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, nitrogen mustard, medroxyprogesterone, megestrol, melphalan, Mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N-(4-sulfamoylphenylaminomethsulfonyl) pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemetrexed, pentostatin, perifosine, PF-04691502, primycin, pomalidomide, porfimer, PPADS, procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolophylline, romidepsin, rucaparib, selumetinib, sirolimus, 2,4-dinitrobenzenesulfonate sodium, sorafenib, streptozotocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, dichlorocyclopentadiene titanium, tonafolium (tonapofylline), topotecan, trametinib, trastuzumab, retinoic acid, veliparib, vinblastine, vincristine, vindesine, vinorelbine and vorinostat (SAHA). In other embodiments, the chemotherapeutic agents that can be administered in combination with the compounds of the present disclosure include: ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that can be administered in combination with the compounds of the present disclosure include: 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (Acid Blue 25), 1-amino-4-[4-hydroxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-hydroxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate. 4-Fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthrylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylaminomethylthioyl) pivalamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolophylline sodium 2,4-dinitrobenzenesulfonate, sumarin and tonaphylline. ,

[0250] Many combination therapies have been developed for the treatment of cancer. In certain embodiments, the compounds or pharmaceutical compositions provided herein (e.g., Compound 1) can be administered in combination with one or more combination therapies. Table 1 lists examples of combination therapies that can be administered in combination with the compounds provided herein.

[0251] Table 1: Exemplary combination therapies for treating cancer

[0252]

[0253]

[0254]

[0255]

[0256]

[0257] In certain embodiments, the combination therapy of the present disclosure includes co-administration with other types of therapeutic agents, such as immuno-oncology agents. Cancer cells typically have specific cell surface antigens that can be recognized by the immune system. Therefore, immuno-oncology agents, such as monoclonal antibodies, can selectively bind to tumor antigens and cause cell death. Other immuno-oncology agents can inhibit tumor-mediated natural immune responses, inhibit or otherwise activate immune responses, thereby promoting the immune system to recognize tumors. Exemplary antibody immuno-oncology agents include, but are not limited to, abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox), apolizumab, belintoumab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, okiatumomab, intelumumab, ipilimumab, isatuximab, lamblizumab (lambrolizumab), MED14736, MPDL3280A, nivolumab, obotuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab and tremelimumab. In some embodiments, the antibody immuno-oncology agent is selected from anti-CD73 monoclonal antibody (mAb), anti-CD39 mAb, anti-PD-1 mAb, anti-PD-L1 mAb and anti-CTLA4 mAb. Therefore, in some embodiments, the method of the present disclosure includes the combined administration of one or more immuno-oncology agents, such as the above-mentioned agents.

[0258] In some embodiments, the combination therapy comprises administering a compound of the present disclosure such as Compound 1 (e.g., Form 2 of Compound 1) in combination with an SH2 inhibitor such as CGP78850, CPG85793, C90, C126, G7-18NATE, G7-B1, and NSC642056.

[0259] Acquired ALK fusions lead to EGFR inhibitor resistance. See von Buttlar, X. et al. JTO Clin Res Rep. June 2021; 2(6): 100179; Schrock, AB et al. J Thorac Oncol. September 2018; 13(9): 1312-1323. In some embodiments, the combination therapy includes administering a compound of the present disclosure such as Compound 1 (e.g., Form 2 of Compound 1) in combination with an EGFR inhibitor such as erlotinib, osimertinib, cetuximab, gefitinib, necitumumab, lapatinib, neratinib, panitumumab, vandetanib, and necitumumab. In one embodiment, the EGFR inhibitor is erlotinib. In one embodiment, the EGFR inhibitor is osimertinib. In one embodiment, the EGFR inhibitor is gefitinib.

[0260] In some embodiments, provided herein is a method for treating epidermal growth factor receptor (EGFR) related cancers, comprising administering to a subject in need thereof a combination of a second agent comprising a therapeutically effective amount of compound 1 (e.g., form 2 of compound 1) or a pharmaceutically acceptable salt or stereoisomer thereof and a therapeutically effective amount, wherein the second agent is an EGFR inhibitor. In some embodiments, the EGFR inhibitor is selected from the group consisting of erlotinib, osimertinib, cetuximab, gefitinib, nacitozumab, lapatinib, neratinib, panitumumab, vandetanib and nacitozumab. In one embodiment, the EGFR inhibitor is erlotinib. In one embodiment, the EGFR inhibitor is osimertinib. In one embodiment, the EGFR inhibitor is gefitinib. In some embodiments, the subject has at least one EGFR mutation. In some embodiments, the at least one EGFR mutation is located in one or more exons of 18, 19, 20 and 21 and / or TM. In some embodiments, the subject has at least one receptor tyrosine kinase (RTK) mutation. In some embodiments, the RTK mutation is an ALK mutation. In some embodiments, the EGFR-related cancer is NSCLC, pancreatic cancer, breast cancer, or colon cancer. In some embodiments, the EGFR-related cancer is mediated by EGFR.

[0261] In some embodiments, the combination therapy includes a compound of the present disclosure such as Compound 1 (e.g., Form 2 of Compound 1) administered in combination with a Raf (e.g., A-Raf, B-Raf, or C-Raf, also known as Raf-1) inhibitor. In certain embodiments, the Raf inhibitor inhibits Raf mutants. In certain embodiments, the Raf inhibitor is a B-Raf inhibitor. In certain embodiments, the B-Raf inhibitor inhibits B-Raf mutants. In certain embodiments, the B-Raf mutant is a V600 mutant. In certain embodiments, the B-Raf mutant is a V600E mutant. In certain embodiments, the Raf inhibitor is dabrafenib, Y3009120, MLN2480 / TAK-580 (tovorafenib), CCT196969, CCT241161, BGB659, PLX7904, naporafenib, PLX-8394, or lifirafenib.

[0262] In some embodiments, the combination therapy comprises combining a compound of the present disclosure such as Compound 1 (e.g., Form 2 of Compound 1) with a PIK3CA inhibitor such as 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine, inavolisib, gedatolisib, buparlisib, zandelisib, miransertib mesylate, izorlisib, or panulisib. In some embodiments, the PIK3CA inhibitor is a PI3K inhibitor such as dactolisib, apitolisib, gedatolisib, SF1126, omipalisib, samotolisib, bimiralisib, paxalisib, voxtalisib buparlisib, CH5132799, pilaralisib, ZSTK474, sonolisib, pictilisib, copanlisib, B591, TG-100-115, RIDR-PI-103alpelisib (α) or serabelisib (α).

[0263] ALK tyrosine kinase inhibitors are used to treat cancers (e.g., solid tumors) driven by constitutive ALK activity. In some embodiments, the combination therapy comprises administering a compound of the present disclosure, such as Compound 1 (e.g., Form 2 of Compound 1), in combination with a CDK4 inhibitor or a CDK6 inhibitor, such as ribociclib, palboclib, tremaciclib, abemaciclib, or dalpiciclib.

[0264] Signal transducer and activator of transcription 3 (STAT3) is activated in many cancers, including cancers with constitutively active tyrosine kinases such as ALK. See Taniguchi, K et al. Sci. Rep. Mar 23, 2021; 11(1):6685, which is incorporated herein by reference in its entirety. In some embodiments, the combination therapy comprises administering a compound of the present disclosure such as Compound 1 (e.g., Form 2 of Compound 1) in combination with a STAT3 inhibitor such as HL-237, OPB-111077, danvatirsen, C-188-9, KT-333, DUET-01, ENMD-1198, or WP-1066.

[0265] T-LAK cell-directed protein kinase (TOPK, also known as PDZ-binding kinase, gene symbol PBK) has been identified as a substrate of ALK. Treatment of ALK fusion-driven human cancer cells with ALK inhibitors and TOPK inhibitors has shown anti-tumor activity. See Xiao, J. et al. Cell Death Dis. 2022 Sep 27; 13(9):828, which is incorporated herein by reference in its entirety. In some embodiments, the combination therapy comprises administering a compound of the present disclosure such as Compound 1 (e.g., Form 2 of Compound 1) in combination with a STAT3 inhibitor such as SKLB-C05, ADA-07, OTS-964, or HI-032 (HITOPK-032).

[0266] In ALK fusion-driven NSCLC, EML4 is the main fusion partner. Wild-type EML4 is a microtubule-associated protein that is reported to promote interphase microtubule stabilization. More than 10 different EML4-ALK variants have been found, of which variants 1 and 3 (V1 and V3) are the most common. EML4-ALK V3 is localized to interphase microtubules and mitotic spindles. Therefore, treatment of EML3-ALK V3-expressing cells with a combination of ALK inhibitors and microtubule regulators (e.g., stabilizers or destabilizers) results in synergistic antiproliferative activity in vitro. See Lucken, K. et al. Mol. Cancer Res. June 3, 2022; 20(6): 854, which is incorporated herein by reference in its entirety. In some embodiments, the combination therapy comprises a compound of the present disclosure, such as Compound 1 (e.g., Form 2 of Compound 1), and a taxane (e.g., paclitaxel, nab-paclitaxel, docetaxel, and cabazitaxel), an epothilone (e.g., epothilone A, epothilone D, ixabepilone, and sagopilone), tirbanibulin, eribulin mesylate, vinflunine, vinorelbine, narcotine, vincristine sulfate or vinblastine sulfate, colchicine.

[0267] HER2 targeted therapy combined with ALK inhibitor therapy may be beneficial for patients with HER2 amplification and ALK fusion. See Tsui, DCC et al. Clin. Lung Cancer 2022 March; 23(2): e99. In some embodiments, the combination therapy includes a compound of the present disclosure such as Compound 1 (e.g., Form 2 of Compound 1) with a HER2 targeted therapy such as trastuzumab, pertuzumab, magituximab, ado-enmet trastuzumab (T-DM1), de trastuzumab (fam-de trastuzumab), tucatinib, neratinib, lapatinib, vedicizumab, mobocertinib, trastuzumab hyaluronidase, pyrotinib maleate, dacomitinib or afatinib.

[0268] The combination of ALK TKI and anti-angiogenic agents may provide benefits to patients, such as slowing the progression of ALK fusion-positive cancers (such as NSCLC). See Lin, JJ et al. ESMO Open 2022 Feb;7(1):100342. In some embodiments, the combination therapy comprises a compound of the present disclosure such as Compound 1 (e.g., Form 2 of Compound 1) and an anti-angiogenic agent such as axitinib, bevacizumab, cabozantinib, everolimus, lenalidomide, or the like. lenvatinib mesylate, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, thalidomide, vandetanib, ziv-aflibercept, sulfatinib, aplidine, anlotinib hydrochloride, fruquintinib, tivozanib, conbercept, apatinib mesylate, ponatinib, cabozantinib malate, aflibercept, sunitinib malate, or anecortave acetate.

[0269] In vitro experiments have shown that the JNK pathway is active after long-term high-dose treatment of ALK fusion-driven cells with ALK tyrosine kinase inhibitors (TKIs), and may lead to resistance to ALK TKIs (Cancer Lett, December 1, 2021; 522: 119-128). Therefore, JNK inhibition may sensitize ALK fusion-driven cells to ALK TKIs in vitro and increase the persistence of anti-tumor activity. In some embodiments, the combination therapy includes administering a compound of the present disclosure such as compound 1 (e.g., form 2 of compound 1) in combination with a JNK inhibitor such as SP600125, BMS-986360, or JNK-401.

[0270] Patients with NSCLC who are ALK fusion-positive and TP53 mutant may have worse progression-free survival than patients with ALK fusion-positive and wild-type TP53 NSCLC. In preclinical studies, ALK fusion-positive cells with p53 mutations were resistant to apoptosis induced by ALK tyrosine kinase inhibition, but combination treatment with proteasome inhibitors appeared to induce apoptosis and provide higher antitumor activity in ALK / TP53 co-mutated NSCLC tumors compared to single-agent activity. See Tanimoto, A. et al. Clin. Cancer Res. 2021 Mar 1; 27(5): 1410. In some embodiments, the combination therapy comprises administering a compound of the present disclosure, such as compound 1 (e.g., form 2 of compound 1), in combination with a proteasome inhibitor such as izazomib, carfilzomib, or bortezomib.

[0271] In ALK fusion-driven cells, ALK signaling may include activation of mammalian target of rapamycin (mTOR). The combination of ALK inhibitors and mTOR inhibitors may induce increased cell cycle arrest in ALK fusion-positive anaplastic large cell lymphoma (ALCL) cells. See Kim, D. et al. Anticancer Res. 2020 March; 40(3): 1395. In some embodiments, the combination therapy includes administering a compound of the present disclosure such as Compound 1 (e.g., Form 2 of Compound 1) in combination with an mTOR inhibitor such as everolimus, ABI-009, temserolimus, zotarolimus, rapamycin, or umirolimus.

[0272] After treating ALK+ cells with ALK inhibitors, the transcriptional regulator YAP1 may be activated. This effect can be attenuated by combined inhibition of ALK and YAP1. See Tsuji, T. et al. Nat. Commun. 2020; 11: 74. In some embodiments, the combination therapy comprises combining a compound of the present disclosure such as Compound 1 (e.g., Form 2 of Compound 1) with a YAP1 inhibitor such as narciclasine, MYF-03–69, verteporfin, IAG-933, ION-537, IK-930, or VT-3989.

[0273] In some embodiments, the combination therapy includes administering a compound of the present disclosure such as Compound 1 (e.g., Form 2 of Compound 1) in combination with a MEK inhibitor such as trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CI-1040, and TAK-733. See "A Phase IB / II Study of Alectinib Combined With Cobimetinib in Advanced ALK-Rearranged (ALK+) NSCLC", Clinical Trial Identifier: NCT03202940, last updated on March 9, 2021, which is incorporated herein by reference in its entirety.

[0274] In some embodiments, the combination therapy comprises a compound of the present disclosure, such as Compound 1 (e.g., Form 2 of Compound 1) and a MET inhibitor selected from JNJ-38877605, PF-04217903, foretinib, AMG 458, tivantinib, cabozantinib, crizotinib, capmatinib hydrochloride, tepotinib hydrochloride, and savotinib. See Tanizaki J. et al. Br J Cancer, Feb 14, 2012; 106(4):763-7, which is incorporated herein by reference in its entirety.

[0275] In some embodiments, the combination therapy comprises administering a compound of the present disclosure, such as Compound 1 (e.g., Form 2 of Compound 1), in combination with a SHP2 inhibitor, such as TNO-155, RMC-4630, JAB-3068, or RLY-1971.

[0276] In some embodiments, the combination therapy comprises administering a compound of the present disclosure, such as Compound 1 (e.g., Form 2 of Compound 1), in combination with a RAS inhibitor, such as adagrasib and sotorasib.

[0277] In some embodiments, the combination therapy includes administering a compound of the present disclosure such as Compound 1 (e.g., Form 2 of Compound 1) in combination with a trophoblast cell surface antigen 2 (TROP2) antibody-drug conjugate (ADC). TROP2 is a cell surface transmembrane protein that is highly expressed in >50% of non-small cell lung cancers, including lung adenocarcinomas with ALK rearrangements (Inamura, K. et al. Oncotarget. 2017; 8(17): 28725-28735). The combination of Compound 1 and TROP2-ADC can provide additional therapeutic benefits compared to monotherapy, especially for patients with ALK-independent resistance mechanisms. In some embodiments, the TROP2 ADC is DS-1062.

[0278] In some embodiments, the combination therapy comprises administering a compound of the present disclosure, such as Compound 1 (e.g., Form 2 of Compound 1), in combination with an AXL ADC (e.g., enapotamab vedotin). AXL is a receptor tyrosine kinase whose increased expression is associated with acquired ALK TKI resistance and epithelial-mesenchymal transition (reference: Debruyne et al., Oncogene 2016). The combination of Compound 1 and AXL-ADC may provide additional therapeutic benefits compared to each monotherapy, especially for ALK TKI-resistant patients with increased AXL expression.

[0279] In some embodiments, the combination therapy includes administering a compound provided herein, such as Compound 1 (e.g., Form 2 of Compound 1), in combination with a TKI. In one embodiment, the TKI is an ALK inhibitor. In one embodiment, the ALK TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, ripretinib, cabozantinib, foretinib, mesartinib, taretinib, masitinib, or ensartinib. In one embodiment, the ALK TKI is crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib. In one embodiment, the ALK TKI is crizotinib. In one embodiment, the ALK TKI is ceritinib. In one embodiment, the ALK TKI is entrectinib. In one embodiment, the ALK TKI is alectinib. In one embodiment, the ALK TKI is brigatinib. In one embodiment, the ALK TKI is lorlatinib.

[0280] In some embodiments, the combination therapy comprises administering a compound of the present disclosure, such as Compound 1 (e.g., Form 2 of Compound 1), in combination with an anti-PD-1 therapy. In certain embodiments, the combination therapy comprises administering a compound of the present disclosure, such as Compound 1, in combination with oxaliplatin. In other embodiments, the combination therapy comprises administering a compound of the present disclosure, such as Compound 1, in combination with doxorubicin.

[0281] In certain embodiments, the concomitant use (within 12 days after enrollment) of drugs known to be strong CYP3A4 inducers (such as phenobarbital, rifampicin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's wort) is prohibited. In certain embodiments, the concomitant use (within 12 days after enrollment) of drugs known to be strong CYP3A4 inducers (such as phenobarbital, rifampicin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's wort) is allowed. In certain embodiments, the concomitant use (within 12 days after enrollment) of drugs known to be strong CYP3A4 inducers (such as phenobarbital, rifampicin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's wort) is cautious. In certain embodiments, the subject is not using any of a strong CYP3A4 inducer, a strong CYP3A4 inhibitor, a CYP3A4 and / or CYP2C8 sensitive substrate, a P-gp / multidrug resistance protein (MDR1) substrate, a BCRP / breast cancer resistance protein (ABCG2) substrate, an OATP1B1 substrate, an OATP1B3 substrate, a MATE1 substrate, or a gastric acid reducing agent.

[0282] In certain embodiments, drugs that are strong inhibitors of CYP3A4, sensitive substrates of CYP3A4 and / or CYP2C8, substrates of P-glycoprotein (P-gp) / multidrug resistance protein 1 (MDR1), substrates of BCRP / breast cancer resistance protein (ABCG2), substrates of OATP1B1, substrates of OATP1B3, or substrates of MATE1 are used with caution at the same time (within 12 days after enrollment). In certain embodiments, the simultaneous use (within 12 days after enrollment) or co-administration of Compound 1 and any one or more drugs that are strong inhibitors of CYP3A4, sensitive substrates of CYP3A4 and / or CYP2C8, substrates of P-glycoprotein (P-gp) / multidrug resistance protein 1 (MDR1), substrates of BCRP / breast cancer resistance protein (ABCG2), substrates of OATP1B1, substrates of OATP1B3, or substrates of MATE1 are allowed. In certain embodiments, the concomitant use (within 12 days after enrollment) or co-administration of drugs that are strong CYP3A4 inhibitors, CYP3A4 and / or CYP2C8 sensitive substrates, P-glycoprotein (P-gp) / multidrug resistance protein 1 (MDR1) substrates, BCRP / breast cancer resistance protein (ABCG2) substrates, OATP1B1 substrates, OATP1B3 substrates, or MATE1 substrates is prohibited. In certain embodiments, the subject uses any of a strong CYP3A4 inducer, a strong CYP3A4 inhibitor, a CYP3A4 and / or CYP2C8 sensitive substrate, a P-gp / multidrug resistance protein (MDR1) substrate, a BCRP / breast cancer resistance protein (ABCG2) substrate, an OATP1B1 substrate, an OATP1B3 substrate, a MATE1 substrate, or a gastric acid reducing agent. In certain embodiments, the subject is taking any of a strong CYP3A4 inducer or a strong CYP3A4 inhibitor.

[0283] In certain embodiments, simultaneous use (within 12 days after enrollment) or co-administration of gastric acid reducing agents and Compound 1 should be avoided. In certain embodiments, simultaneous use (within 12 days after enrollment) or co-administration of gastric acid reducing agents and Compound 1 should be used with caution. In certain embodiments, simultaneous use (within 12 days after enrollment) or co-administration of gastric acid reducing agents and Compound 1 should be allowed.

[0284] In certain embodiments, the compounds of the present disclosure may be administered in combination with non-chemical methods of cancer treatment. In certain embodiments, the compounds of the present disclosure may be administered in combination with radiotherapy. In certain embodiments, the compounds of the present disclosure may be administered in combination with surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination of these therapies.

[0285] In certain embodiments, the compounds of the present disclosure can be co-administered with one or more other compounds of the present disclosure. In addition, such combinations can be co-administered with other therapeutic agents, such as other agents suitable for treating cancer, immunology or neurological diseases, such as the above-mentioned agents. In certain embodiments, one or more additional chemotherapeutic agents are co-administered with the compounds of the present disclosure to provide a synergistic effect. In certain embodiments, co-administration of one or more additional chemotherapeutic agents provides an additional effect. In certain embodiments, the chemotherapeutic agent is an alkylating agent, an antimetabolite, an antitumor antibiotic, a topoisomerase inhibitor, a platinum drug, a mitotic inhibitor, a hormone therapy or a corticosteroid. In some embodiments, compound 1 (e.g., form 2) can be co-administered with pain therapy. In some embodiments, pain therapy is an anti-inflammatory drug, such as a non-steroidal anti-inflammatory drug (NSAID). In some embodiments, the NSAID is ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, indomethacin, aspirin.

[0286] Pharmaceutical composition

[0287] In certain embodiments, provided herein are pharmaceutical formulations suitable for use in human subjects, comprising a compound provided herein (e.g., Compound 1, and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical formulations can be used to treat or prevent a condition or disease as described herein. The compounds provided herein can be used to manufacture a medicament for treating any disease or condition disclosed herein.

[0288] The compositions and methods provided herein can be used to treat subjects in need. In certain embodiments, the subject is a mammal (such as a human) or a non-human mammal. When applied to a subject (such as a human), the composition or the compound is preferably administered as a pharmaceutical composition, and the pharmaceutical composition includes, for example, a compound provided herein and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art, and include, for example, aqueous solutions (such as water) or physiologically buffered saline or other solvents or vehicles (such as ethylene glycol, glycerol), oils (such as olive oil) or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are used for human administration, particularly invasive administration routes (i.e., avoiding transport or diffusion through epithelial barriers, such as injection or implantation), aqueous solutions are pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to achieve delayed release of a medicament or selectively target one or more cells, tissues or organs. Pharmaceutical compositions can be in dosage unit form, such as tablets, capsules (including spray capsules and gelatin capsules), granules, lyophilized agents for reconstruction, powders, solutions, syrups, suppositories, injections, etc. The composition may also be present in a transdermal delivery system, such as a skin patch. The composition may also be present in a solution suitable for topical administration, such as eye drops.

[0289] Pharmaceutically acceptable carriers can contain physiologically acceptable agents, such as stabilizing, increasing the solubility of compounds (such as compounds provided herein) or increasing the absorption of compounds. Such physiologically acceptable agents include, for example, carbohydrates (such as glucose, sucrose or dextran), antioxidants (such as ascorbic acid or glutathione), chelating agents, low molecular weight proteins or other stabilizers or excipients. The selection of pharmaceutically acceptable carriers (including physiologically acceptable agents) depends on, for example, the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, in which a compound such as provided herein can be incorporated. For example, a liposome comprising phospholipids or other lipids is a relatively simple non-toxic, physiologically acceptable and metabolizable carrier to prepare and administer.

[0290] In one embodiment, provided herein is a pharmaceutical composition comprising Compound 1:

[0291]

[0292] or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, a glidant, a binder and a lubricant.

[0293] In one embodiment, Compound 1 or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, is a free base of Compound 1. In one embodiment, the free base of Compound 1 is amorphous. In one embodiment, the free base of Compound 1 is a crystalline free base of Compound 1. In one embodiment, the free base of Compound 1 is one of the solid forms of the free base of Compound 1 provided herein. In one embodiment, the free base of Compound 1 is Form 2 of the free base of Compound 1. In one embodiment, the free base of Compound 1 is characterized by an XRPD pattern comprising peaks at approximately 12.4, 18.9, and 21.1° 2θ (± 0.2°).

[0294] In one embodiment, Compound 1 or its stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is a pharmaceutically acceptable salt of Compound 1. In one embodiment, the salt is amorphous.

[0295] In one embodiment, the diluent is microcrystalline cellulose. In one embodiment, the disintegrant is cross-linked carboxymethyl cellulose sodium. In one embodiment, the glidant is colloidal silicon dioxide. In one embodiment, the binder is hydroxypropyl cellulose (HPC). In one embodiment, the lubricant is magnesium stearate.

[0296] The pharmaceutical composition can be conveniently presented in unit dosage form. In one embodiment, the pharmaceutical composition is an oral dosage form. In one embodiment, the oral dosage form is a tablet. In certain embodiments, the unit dosage form is a tablet with a dosage specification of 5 mg (based on the weight of free base compound 1). In certain embodiments, the unit dosage form is a tablet with a dosage specification of 25 mg (based on the weight of free base compound 1). In certain embodiments, the unit dosage form is a tablet with a dosage specification of 50 mg (based on the weight of free base compound 1). In certain embodiments, the unit dosage form is a tablet with a dosage specification of 75 mg (based on the weight of free base compound 1). In certain embodiments, the unit dosage form is a tablet with a dosage specification of 100 mg (based on the weight of free base compound 1). In certain embodiments, the unit dosage form is a tablet with a dosage specification of 125 mg (based on the weight of free base compound 1). In certain embodiments, the unit dosage form is a tablet with a dosage specification of 150 mg (based on the weight of free base compound 1). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host being treated, the particular mode of administration. In one embodiment, the oral dosage form is a direct release tablet. In one embodiment, the pharmaceutical composition is film coated.

[0297] In certain embodiments, the present disclosure provides pharmaceutical formulations suitable for use in human patients, comprising any of the compounds described above (e.g., a compound of the present disclosure, such as Compound 1, and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical formulations can be used to treat or prevent a condition or disease as described herein. Any compound of the present disclosure can be used to manufacture a medicament for treating any disease or condition disclosed herein.

[0298] In certain embodiments, pharmaceutical compositions comprising Form 2 and a pharmaceutically acceptable carrier are provided. In certain embodiments, pharmaceutical compositions comprising Form 2 that are substantially free (e.g., less than about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or about 0.01%) of impurities are provided. In certain embodiments, the pharmaceutical compositions comprising Form 2 are substantially free of other crystalline forms of Compound 1.

[0299] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0300] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable", i.e., compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn starch, etc. oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0301] The pharmaceutical composition (preparation) can be administered to a subject by any of a variety of routes of administration, including, for example, oral (e.g., in the form of an aqueous or non-aqueous solution or suspension, tablet, capsule (including spray capsule and gelatin capsule), bolus, powder, granule, paste for applying to the tongue); absorption through the oral mucosa (e.g., sublingual); anal, rectal or vaginal (e.g., as a vaginal suppository, cream or foam); parenteral (including intramuscular, intravenous, subcutaneous or intrathecal, e.g., as a sterile solution or suspension); intranasal; intraperitoneal; subcutaneous; transdermal (e.g., as a patch applied to the skin); and topical (e.g., as a cream, ointment or spray applied to the skin, or as eye drops). The compound can also be formulated as an inhalant. In certain embodiments, the compound can simply be dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for such routes can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896 and patents cited therein.

[0302] The preparation can be conveniently present in unit dosage form and can be prepared by any method known in the pharmaceutical field. In certain embodiments, the unit dosage form is a tablet. In certain embodiments, the unit dosage form is a tablet with a dosage specification of 5 mg (based on the weight of free base compound 1). In certain embodiments, the unit dosage form is a tablet with a dosage specification of 50 mg (based on the weight of free base compound 1). The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary according to the host being treated and the specific mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound producing a therapeutic effect. In general, in percent, the range of this amount will be from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

[0303] The method for preparing these preparations or compositions includes the step of combining active compound (such as compound provided herein) with carrier and optionally one or more auxiliary components. In general, the preparation is prepared by uniformly and intimately combining compound provided herein with liquid carrier or finely divided solid carrier or both, and then shaping the product as required.

[0304] Formulations suitable for oral administration provided herein can be in the form of capsules (including spray capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and gum arabic or tragacanth), lyophilized agents, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a lozenge (using an inert base, such as gelatin and glycerin, or sucrose and gum arabic) and / or as a mouthwash, etc., each containing a predetermined amount of a compound provided herein as an active ingredient. The composition or compound can also be administered as a bolus, ointment or paste.

[0305] To prepare solid dosage forms for oral administration (capsules (including spray capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or two pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate) and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; (3) wetting agents, Such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution delay agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including spray capsules and gelatin capsules), tablets and pills, the composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols.

[0306] Tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant or a dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0307] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including spray capsules and gelatin capsules), pills and granules, may optionally be scored or prepared into coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may also be formulated to provide slow or controlled release of the active ingredient therein, for example using hydroxypropylmethylcellulose in different proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be carried out, for example, by filtering through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain an opacifier and may be such a composition that they release one or more active ingredients only in a certain part of the gastrointestinal tract or preferably in a certain part of the gastrointestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, containing one or more of the above-mentioned excipients, where appropriate.

[0308] Liquid dosage forms that can be used for oral administration include pharmaceutically acceptable emulsions, lyophilized agents for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain an inert diluent commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol, and fatty acid esters of sorbitan and mixtures thereof.

[0309] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, perfuming and emulsifying agents.

[0310] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0311] Formulations for rectal, vaginal or urethral administration may be presented as suppositories which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, and which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0312] Formulations of pharmaceutical compositions for oral administration may be presented as a mouthwash or oral spray or oral ointment.

[0313] Alternatively or additionally, the composition can be formulated for delivery via a catheter, stent, guidewire or other intraluminal device. Delivery via such a device may be particularly suitable for delivery to the bladder, urethra, ureter, rectum or intestine.

[0314] Formulations suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art.

[0315] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be necessary.

[0316] In addition to the active compounds, the ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0317] In addition to the active compound, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane or propane).

[0318] Transdermal patches have additional advantages and can provide controlled delivery of compounds provided herein to the body. Such dosage forms can also be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate of such flux can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0319] Ophthalmic preparations, ophthalmic ointments, powders and solutions etc. are also encompassed within the scope of the present disclosure. Exemplary ophthalmic preparations are described in U.S. Publications No. 2005 / 0080056, No. 2005 / 0059744, No. 2005 / 0031697 and No. 2005 / 004074 and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic preparations have characteristics similar to tears, aqueous humor or vitreous humor or are compatible with these liquids. Preferred routes of administration are topical administration (e.g., topical administration, such as eye drops, or administration by implant).

[0320] As used herein, the phrases "parenteral administration" and "parenteral administration" mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0321] Pharmaceutical compositions suitable for parenteral administration include one or more active compounds in combination with one or more of the following: pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, sterile powders to be reconstituted into sterile injectable solutions or dispersions prior to use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0322] Examples of suitable aqueous and nonaqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). For example, appropriate fluidity can be maintained by using coating materials (such as lecithin), by maintaining the desired particle size (in the case of dispersions), and by using surfactants.

[0323] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It is also desirable to include isotonic agents, such as sugars, sodium chloride, and the like, into the composition. In addition, prolonged absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0324] In some cases, to prolong the effect of the drug, it is necessary to slow down the absorption of the drug injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the drug depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be accomplished by dissolving or suspending the drug in an oil vehicle.

[0325] Injectable reservoir forms are prepared by forming a microcapsule matrix of the subject compound in a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled according to the ratio of the drug to the polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Reservoir injectable formulations are also prepared by embedding the drug in a liposome or microemulsion compatible with body tissues.

[0326] For use in the methods provided herein, the active compound can be provided per se, or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) active ingredient with a pharmaceutically acceptable carrier.

[0327] The method of introduction can also be provided by a rechargeable or biodegradable device. In recent years, various slow-release polymer devices have been developed and tested in vivo for controlled delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), both biodegradable and non-degradable, can be used to form implants to continuously release compounds at specific target sites.

[0328] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject.

[0329] The selected dosage level will depend upon a variety of factors including the activity of the specific compound or combination of compounds employed, or the esters, salts or amides thereof, the route of administration, the time of administration, the rate of excretion of the compound or compounds employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the specific compound or compounds employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts.

[0330] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe the therapeutically effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the pharmaceutical composition or compound at a level lower than the level required to achieve the therapeutic effect, and gradually increase the dosage until the desired effect is achieved. "Therapeutically effective amount" means a concentration of the compound sufficient to cause the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the subject's weight, sex, age and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the subject's illness, the condition being treated, the stability of the compound, and, if necessary, another type of therapeutic agent administered with the compound provided herein. A larger total dose can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13th edition, 1814-1882, incorporated herein by reference).

[0331] If desired, the effective daily dose of the active compound can be administered as one, two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain embodiments provided herein, the active compound can be administered twice or three times daily. In a preferred embodiment, the active compound will be administered once a day.

[0332] In certain embodiments, provided herein is a compound that can be used alone or in combination with another type of therapeutic agent. As used herein, the phrase "combined administration" refers to any form of administration of two or more different therapeutic compounds, so that the previously administered therapeutic compound is still effective in vivo and a second compound is administered (for example, the two compounds are effective in the subject at the same time, which may include the synergistic effect of the two compounds). For example, the different therapeutic compounds can be administered simultaneously or sequentially in the form of the same preparation or a separate preparation. In certain embodiments, the different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours or a week of each other. Therefore, the subject receiving such treatment may benefit from the combined effect of different therapeutic compounds.

[0333] In certain embodiments, provided herein is a compound and one or more additional therapeutic agents (e.g., one or more additional chemotherapeutic agents) co-administered with improved efficacy relative to each separate administration of the compound provided herein or the one or more additional therapeutic agents. In certain such embodiments, the co-administration provides an additional effect, wherein the additional effect refers to the sum of the individual effects of the separate administration of the compound provided herein and one or more additional therapeutic agents.

[0334] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0335] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0336] Now that the disclosure is generally described, it will be more readily understood by reference to the following examples, which are provided merely to illustrate certain aspects and embodiments of the disclosure and are not intended to limit the disclosure.

[0337] Example

[0338] Example 1: Phase 1 / 2 Clinical Study

[0339] An FIH, Phase 1 / 2, multicenter, open-label, dose-escalation and expansion study was conducted to evaluate the safety and tolerability of Compound 1, to determine the RP2D and (if applicable) MTD, and to evaluate antitumor activity in patients with advanced ALK-positive NSCLC and other advanced ALK-positive solid tumors.

[0340] Phase 1 Purpose:

[0341] Primary objective: To determine the RP2D and / or maximum tolerated dose (MTD) of compound 1 in patients with advanced ALK-positive solid tumors.

[0342] Secondary objectives: To evaluate the overall safety and tolerability of compound 1; to characterize the PK characteristics of compound 1; and to evaluate the preliminary antitumor activity of compound 1 in patients with advanced ALK-positive solid tumors.

[0343] Exploratory objectives: Evaluate additional tumor and blood-based molecular markers of response and resistance to Compound 1; evaluate the metabolite profile of Compound 1; evaluate extracranial activity.

[0344] Phase 2 Objectives:

[0345] Primary objective: To evaluate the efficacy of compound 1 at RP2D in patients with advanced ALK-positive NSCLC (including patients with ALK resistance mutations) and other solid tumors.

[0346] Secondary objectives: To evaluate additional clinical efficacy indicators in patients with ALK-positive NSCLC (including patients with ALK resistance mutations) and other solid tumors; to evaluate the intracranial antitumor activity of compound 1 in patients with advanced ALK-positive NSCLC and other solid tumors at RP2D; to characterize the safety and tolerability of compound 1 at RP2D; and to confirm the PK characteristics of compound 1 at RP2D.

[0347] Exploratory objectives: Evaluate additional tumor and blood-based molecular markers of response and resistance to compound 1; assess progression-free survival with subsequent therapy; evaluate extracranial activity.

[0348] End point of phase 1:

[0349] Primary endpoints: RP2D and (if applicable) MTD as determined by the incidence of dose-limiting toxicity (DLT) within cycle 1, overall safety, PK, PD, and preliminary efficacy

[0350] Secondary endpoints:

[0351] The incidence and severity of treatment-emergent adverse events (TEAEs) and changes in clinically relevant laboratory parameters

[0352] · Pharmacokinetic parameters of compound 1: Maximum plasma concentration (C max );C max -Dose normalized, plasma concentration at the end of the dosing interval (C tau ); mean plasma concentration (C avg ); Maximum concentration time (T max ); the area under the curve at the end of the dosing interval (AUC tau ); AUC tau -Dose normalized, area under the curve (AUC) from time 0 to 24 0-24 ); AUC 0-24 -Dose normalized, area under the curve (AUC) from time 0 to infinity inf ); AUC inf -Dose standardization; oral clearance (CL / F); volume of distribution (V z / F); and half-life (t 1 / 2 )

[0353] Objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) - percentage of patients with complete response (CR) or partial response (PR) as defined by RECIST 1.1

[0354] Duration of response (DOR) according to RECIST 1.1 - in responders, defined as the time from first response according to RECIST 1.1 to radiographic disease progression or death

[0355] Intracranial ORR per RECIST 1.1 (IC-ORR) - In patients with measurable metastatic CNS disease, up to five intracranial target lesions were accessible for response per RECIST 1.1

[0356] Intracranial DOR according to RECIST 1.1 (IC-DOR) - In responders with metastatic CNS disease, defined as the time from first IC response according to RECIST 1.1 to radiographic IC disease progression or death

[0357] Clinical benefit rate (CBR) according to RECIST 1.1 - defined as the percentage of patients with a confirmed CR or PR or stable disease (SD) according to RECIST 1.1 for at least 24 weeks duration

[0358] Time to response according to RECIST 1.1 - defined as the time from the first dose to the first confirmed radiological response according to RECIST 1.1

[0359] Progression-free survival (PFS) according to RECIST 1.1 - defined as the time from the first dose to radiographic disease progression or death according to RECIST 1.1

[0360] Exploratory endpoints:

[0361] Baseline levels and / or post-treatment changes in tumor and blood biomarker levels, including but not limited to expression of proteins, phosphorylated proteins, genes, variant allele frequencies, and genetic variants

[0362] Identification and quantification of metabolites of compound 1 in blood samples after treatment

[0363] Extracranial ORR: Among patients with extracranial metastatic disease, defined as the percentage of patients with an extracranial response according to RECIST 1.1 as assessed by the investigator

[0364] Phase 2 endpoints:

[0365] Primary endpoint: ORR according to RECIST 1.1 - defined as the proportion of patients with a confirmed CR or PR according to RECIST 1.1 according to blinded independent central review (BICR) among patients with measurable disease at baseline.

[0366] Secondary End Points

[0367] DOR according to RECIST 1.1 - in responders, defined as the time from confirmed response at first BICR assessment according to RECIST 1.1 to radiographic disease progression or death

[0368] CBR according to RECIST 1.1 - defined as the percentage of patients with a confirmed CR or PR or SD according to RECIST 1.1 for at least 24 weeks duration according to BICR

[0369] Time to response according to RECIST 1.1 - defined as the time from first dose to first confirmed radiological response according to RECIST 1.1 according to BICR

[0370] PFS according to RECIST 1.1 - defined as the time from the first dose to radiographic disease progression according to RECIST 1.1 or death based on BICR assessment

[0371] Overall survival (OS) - defined as the time from first dose to death from any cause

[0372] IC-ORR per RECIST 1.1 - In patients with measurable metastatic CNS disease, response per RECIST 1.1 in up to 5 intracranial target lesions was evaluated by BICR in patients with measurable intracranial disease at baseline

[0373] IC-DOR according to RECIST 1.1 - in responders with metastatic CNS disease, defined as the time from confirmed response at first BICR assessment according to RECIST 1.1 to radiographic disease progression or death

[0374] Time to IC-response per RECIST 1.1 - In patients with metastatic CNS disease, defined as the time from first dose to first confirmed radiographic IC-response per RECIST 1.1

[0375] Intracranial PFS according to RECIST 1.1 (IC-PFS) - In patients with metastatic CNS disease, defined as the time from first dose to radiographic disease progression according to RECIST 1.1 or death based on BICR assessment

[0376] The incidence and severity of TEAEs and changes in clinically relevant laboratory parameters

[0377] Pharmacokinetic parameters of compound 1-C max , C max -Dose standardization, C tau , C avg , T max , AUC tau , AUC tau -Dose normalization, AUC 0-24 , AUC 0-24 -Dose normalization, AUC inf , AUC inf -Dose normalization, CL / F, V z / F,t 1 / 2

[0378] Exploratory endpoints:

[0379] Baseline levels and / or post-treatment changes in tumor and blood biomarker levels, including but not limited to expression of proteins, phosphorylated proteins, genes, variant allele frequencies, and genetic variants

[0380] PFS2: defined as the time from the start of treatment with Compound 1 until disease progression on subsequent therapy (based on local assessment or medical record report of progression on subsequent therapy) or death from any cause

[0381] EC-ORR: Among patients with extracranial metastatic disease, defined as the percentage of patients with extracranial response according to RECIST 1.1 as assessed by the investigator

[0382] Research design: This study was conducted in 2 phases ( Figure 1 ).

[0383] The Phase 1 dose escalation included patients with locally advanced or metastatic solid tumors harboring ALK rearrangements or activating ALK mutations. Patients with ALK fusion-positive NSCLC must have previously received ≥1 ALK TKI, one of which must be a 2nd or 3rd generation TKI (ceretinib, alectinib, brigatinib, or lorlatinib), while patients with other solid tumors must have previously received ≥1 systemic anticancer therapy or have no satisfactory standard of care. The Phase 1 portion of this study was designed to determine the RP2D and, if applicable, the MTD, and to assess the safety of Compound 1.

[0384] The Phase 1 portion of this study adopts a BOIN design, and dose escalation is evaluated through a 3+3 lead-in phase. The DLT observation period is defined as the period from the first dose of C1D1 to the end of the first cycle (21-day cycle). After each group of patients has been treated at a given dose level and monitored for 21 days, the available data (including but not limited to the incidence of DLT / other AEs and preliminary PK) will be reviewed. The initiation of the next dosing group depends on the occurrence of DLT, the results of the BOIN analysis, and the recommendation considering the overall safety profile. The BOIN dose escalation is declared complete when the number of evaluable patients treated with the current dose reaches 12 and it is decided to maintain the current dose or the maximum sample size is reached. However, if the optimal biological dose or the maximum feasible dose is reached before the completion of the BOIN dose escalation, the RP2D can be announced. Patients who develop DLT will not be replaced. Patients who cannot be evaluated for DLT (failed to receive ≥16 days of intended dosing and / or did not complete the 21-day observation period in the first cycle due to reasons other than DLT) may be replaced.

[0385] Following the occurrence of a DLT, if it is determined that continued treatment with Compound 1 is in the patient's interest, treatment with Compound 1 may be resumed at a reduced dose. If the AE leading to dose interruption meets the definition of a DLT, study drug is resumed at the previous safe dose level or at a reduced dose level (see Table A for recommended reduced dose levels). Following resolution of the AE and dose interruption, patients may resume therapy at a dose level reduced by 1. Study treatment may be continued without dose reduction if determined to be in the patient's interest. If the AE recurs with the same or worsening intensity, treatment should be interrupted and the dose reduced if study treatment is continued. A maximum of 3 dose reductions are allowed for any patient.

[0386] Table A: Recommended dose reduction levels (after DLT observation period)

[0387] Initial dose level Dose Level-1 Dose Level - 2** 15mg QD 10mg QD NA 25mg QD 15mg QD 10mg QD 50mg QD 25mg QD 15mg QD 100mg QD 50mg QD 25mg QD 150mg QD 100mg QD 50mg QD 200 mg QD* 150mg QD 100mg QD

[0388] Abbreviations: NA, not applicable; QD: once daily.

[0389] *If a dose reduction is necessary, the dose should be reduced to a lower dose level.

[0390] **If treatment is not tolerated after 2 dose reductions, a third dose reduction may be implemented (if this is in the best interest of the patient and agreed upon by the investigator and sponsor) or treatment may be discontinued.

[0391] During dose escalation, when available data support the safety, PK, and clinical activity of a given dose level, additional patients may be enrolled at that dose level (up to a total of 12 patients, including those already enrolled in BOIN dose escalation). These patients are monitored for DLTs and included in the evaluation to proceed to BOIN dose escalation. A total of up to approximately 54 patients may be treated in Phase 1 dose escalation.

[0392] Once a sufficient number of patients have been enrolled and the first imaging / efficacy assessments have been completed and the data have been reviewed, an RP2D can be selected. The RP2D is expected to be the MTD or the lower optimal biologic dose, or the maximum feasible dose, and is the dose level that is considered appropriate for testing in the Phase 2 portion of the study. The selection of the RP2D is made using all data obtained from the Phase 1 trial and includes evaluations of clinical PK, pharmacodynamics, safety, and antitumor activity.

[0393] Phase 2 includes 4 cohorts:

[0394] Cohort 2a: patients with locally advanced or metastatic NSCLC harboring ALK rearrangements who have received prior 1 second-generation ALK TKI (ceritinib, alectinib, or brigatinib).

[0395] Cohort 2b: patients with locally advanced or metastatic NSCLC harboring ALK rearrangements who have received 2-3 first-generation or second-generation ALK TKIs (crizotinib, ceritinib, alectinib, or brigatinib).

[0396] Cohort 2c: patients with locally advanced or metastatic NSCLC harboring ALK rearrangements who have received 2-3 first-generation or second-generation ALK TKIs (crizotinib, ceritinib, alectinib, or brigatinib).

[0397] Cohort 2d: Patients with other solid tumors harboring ALK rearrangements or activating ALK mutations, including NSCLC patients who are not eligible for 2a-c and have received ≥1 prior systemic anticancer therapy or for whom satisfactory standard therapy is not available.

[0398] The phase 2 portion of this study was designed to estimate the ORR and corresponding 95% CI for the following patient populations: all patients with treated ALK-positive NSCLC in cohorts 2a, 2b, and 2c combined; each of the individual cohorts 2a, 2b, and 2c; and patients in cohorts 2a, 2b, and 2c combined who had an ALK resistance mutation of interest (i.e., any ALK resistance mutation; ALK G1202R mutation, whether or not occurring with other ALK mutations).

[0399] Phase 1 Dose Levels: Phase 1 evaluates escalating doses of Compound 1 monotherapy administered orally once daily (QD) until disease progression, unacceptable toxicity, or voluntary withdrawal of consent. Based on the BOIN design, up to approximately 54 patients will be enrolled and treated at the dose levels shown in the table below.

[0400] Dosage Levels Compound 1 Dosage frequency* DL1 15mg QD DL2 25mg QD DL3 50mg QD DL4 100mg QD DL5 150mg QD DL6** 200mg QD

[0401] *BID dosing may be explored at any dose level ("DL").

[0402] **Higher DL can be explored.

[0403] Intermediate dose levels can be explored during dose escalation; lower dose levels (eg, 10 mg QD) can be explored based on the results of BOIN.

[0404] Recommended Phase 2 Dose: The recommended Phase 2 dose (RP2D) is expected to be the MTD or the lower optimal biological dose, or the maximum feasible dose, and is the dose level considered appropriate for testing in the Phase 2 portion of the study. The selection of the RP2D is made using all data obtained from the Phase 1 trial and includes evaluations of clinical PK, pharmacodynamics, safety, and antitumor activity.

[0405] Duration of treatment: In both phases, patients continued to receive study drug from the first dose until independent radiological confirmation of disease progression, unacceptable toxicity, patient withdrawal, study termination, or commercial availability. Patients could continue to receive Compound 1 when progression occurred in the body or brain that was amenable to local ablation.

[0406] Study End Definition: Study end is defined as the date of the last visit of the last patient in the study or the date the study was terminated.

[0407] Inclusion Criteria: Patients must meet all of the following criteria to be eligible for inclusion in the study:

[0408] 1. Age ≥ 18 years. (Only for Phase 2 cohort 2d: age ≥ 12 years and weight > 40 kg.)

[0409] 2. Disease criteria

[0410] a. Stage 1: locally advanced or metastatic solid tumors confirmed by histology or cytology with documented ALK rearrangement or activating ALK mutation detected by a certified assay (i.e. CLIA in the United States).

[0411] b. Cohorts 2a, 2b, and 2c: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with documented ALK rearrangement detected by a validated assay (i.e., CLIA in the United States).

[0412] c. Cohort 2d: Any other histologically or cytologically confirmed locally advanced or metastatic solid tumor with documented ALK rearrangement or activating ALK mutation detected by a certified assay (i.e., US CLIA), including but not limited to anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, diffuse large B-cell lymphoma, esophageal squamous cell carcinoma, renal medullary carcinoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, cholangiocarcinoma, Spitzoid tumor, neuroblastoma, anaplastic thyroid cancer, and NSCLC patients who are not eligible for Cohort 2a-c.

[0413] 3. Previous anticancer treatment

[0414] a. Stage 1: Patients with ALK fusion-positive NSCLC must have previously received ≥1 ALK TKI, one of which must be a second-generation or third-generation TKI (ceretinib, alectinib, brigatinib, or lorlatinib). Patients with other solid tumors must have previously received ≥1 systemic anticancer therapy or have no satisfactory standard therapy.

[0415] b. Cohort 2a: 1 prior 2nd generation ALK TKI (ceritinib, alectinib, or brigatinib).

[0416] c. Cohort 2b: 2-3 prior 1st or 2nd generation ALK TKIs (crizotinib, ceritinib, alectinib, or brigatinib).

[0417] d. Cohort 2c: 2-3 ALK TKIs, with lorlatinib received as 2nd or 3rd line therapy.

[0418] e. All patients except Phase 2 Cohort 2d: Received ≤2 lines of prior chemotherapy and / or immunotherapy in the locally advanced or metastatic setting. Patients who received >2 lines of prior chemotherapy and / or immunotherapy in the locally advanced or metastatic setting may be enrolled in Phase 2 Cohort 2d.

[0419] f. Phase 2 Cohorts 2a, 2b, and 2c: No prior investigational agents targeting ALK. Patients who have previously received an investigational agent targeting ALK may be enrolled in Phase 1 and Phase 2 Cohort 2d.

[0420] Stage 4.1: Must have evaluable disease (target or non-target) according to RECIST 1.1. Stage 2: Must have measurable disease according to RECIST 1.1, defined as ≥1 radiologically measurable target lesion (Oken et al., Am. J. Clin. Oncol. 1982, 5(6):649-655).

[0421] 5. Submit pre-treatment tumor tissue (archive (if available) or fresh biopsy) for central analysis. The best submitted tumor tissue is obtained during or after the most recent disease progression. If no appropriate tissue is available and if the investigator believes that a biopsy is unsafe and medically infeasible, the patient may be admitted after consultation with the sponsor's medical monitor.

[0422] 6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2 (Eisenhauer et al., Eur. J. Cancer 2009, 45(2):228-247).

[0423] 7. Adequate organ function and bone marrow reserve, as demonstrated by the following laboratory assessments performed prior to the first dose of study drug:

[0424] a. Bone marrow function: absolute neutrophil count (ANC) ≥1500 / μL; platelet count >75,000 / μL; hemoglobin ≥8g / dL.

[0425] b. Renal function: estimated creatinine clearance ≥ 60 mL / min Liver function: bilirubin < 1.5 × ULN, unless there is evidence of Gilbert syndrome, in which case total bilirubin must be < 3.0 mg / dL; aspartate aminotransferase and alanine aminotransferase ≤ 3.0 × ULN (≤ 5.0 × ULN if liver metastases are involved).

[0426] 8. All clinically relevant toxicities related to previous anticancer therapy must have recovered to ≤ Grade 1 or baseline (except alopecia or ototoxicity).

[0427] 9. Women of childbearing potential (WOCBP) and male patients must be willing to abstain from sex or use effective contraceptive methods or undergo surgical sterilization from the date of signing the informed consent form (ICF) throughout the study and within 30 days (female) and 90 days (male) after the last use of the study drug. According to the World Health Organization (WHO) standards, effective contraceptive methods for WOCBP include 1 "highly effective method" or 2 "effective" methods.

[0428] 10. Provide written informed consent and be willing and able to comply with the requirements of the study protocol. For patients <18 years old, consent must be obtained (Phase 2 Cohort 2d only), and parents / guardians must provide written consent.

[0429] Exclusion criteria: Patients meeting any of the following criteria were excluded from the study:

[0430] 1. The patient's cancer has a known primary driver alteration in addition to ALK.

[0431] 2. Known allergic / hypersensitivity reaction to the excipients of Compound 1.

[0432] 3. Major surgical procedures within 4 weeks prior to study entry. Minor surgical procedures (e.g., port insertion) are permitted, but sufficient time must be allowed for wound healing to meet clinical needs.

[0433] 4. Currently receiving or recently receiving anticancer therapy within the following time frame prior to the first dose of study drug (Compound 1 may be initiated within the limits of prior TKI or chemotherapy if deemed safe and in the best interest of the patient, with prior approval):

[0434] a. TKI or other non-chemotherapy / non-immunotherapy anticancer agent < 5 half-lives or < 7 days, whichever is longer

[0435] b. Chemotherapy < 21 days

[0436] c. Immunotherapy or cell therapy < 28 days

[0437] 5. Currently receiving or recently receiving radiotherapy within the following time range before the first dose of study drug:

[0438] a. Radiation therapy (except palliative radiation therapy to relieve bone pain) < 14 days

[0439] b. Palliative radiation therapy to relieve bone pain < 48 hours

[0440] c. Stereotactic or small field brain irradiation < 7 days

[0441] d. Whole brain radiotherapy < 14 days

[0442] 6. Previous high-dose chemotherapy requires stem cell rescue.

[0443] 7. Uncontrolled clinically relevant bacterial or fungal infection requiring systemic therapy.

[0444] 8. Known to have active tuberculosis or active hepatitis B or hepatitis C. Active hepatitis B is defined as a known positive HBsAg test result and a known HBV DNA quantitative result above the detection limit of the assay. Active hepatitis C is defined as a known positive hepatitis C antibody test result and a known HCV RNA quantitative result above the detection limit of the assay.

[0445] 9. The patient's QTcF is continuously >450 milliseconds. The patient has a history of long QT syndrome or torsade de pointes.

[0446] 10. Patients with the following clinically significant cardiovascular diseases:

[0447] a. Within 3 months after enrollment: cerebrovascular accident / stroke; myocardial infarction; unstable angina; uncontrolled atrial fibrillation of any grade

[0448] b. History of congestive heart failure (New York Heart Association classification ≥ II); second or third degree atrioventricular block (unless there is a pacemaker) or any atrioventricular block with a PR duration > 220 milliseconds; or persistent arrhythmia of NCI-CTCAE ≥ 2.

[0449] 11. Patients have central nervous system (CNS) metastases or primary CNS tumors with progressive neurological symptoms or requiring increased corticosteroid doses to control CNS disease. If patients require corticosteroids for management of CNS disease, the dose must be stable for 2 weeks prior to C1D1. Asymptomatic leptomeningeal carcinomatosis is permitted.

[0450] 12. Symptomatic spinal cord compression.

[0451] 13. Patients with moderate to severe cognitive impairment or psychiatric disorders that would jeopardize the patient's ability to comply with study requirements.

[0452] 14. Evidence of active malignancy requiring systemic therapy within the past 2 years (excluding current ALK-positive solid malignancies).

[0453] a. Exceptions: non-melanoma skin cancer, melanoma in situ, cervical cancer in situ, papillary thyroid cancer, ductal carcinoma in situ of the breast, or localized and presumed cured prostate cancer. Patients receiving long-term anti-hormonal therapy for a prior malignancy are permitted, provided that the malignancy has not been active within the past 2 years.

[0454] 15. Concurrent use (within 12 days after enrollment) of strong CYP3A4 inducers or strong CYP3A4 inhibitors.

[0455] 16. Manifestations of malabsorption due to previous gastrointestinal surgery, disease, or other conditions that may affect oral absorption, distribution, metabolism, or excretion of the study drug.

[0456] 17. The patient is pregnant or breastfeeding. WOCBP must undergo a serum pregnancy test at screening and have a negative serum or urine test before the first dose of study drug.

[0457] 18. Actively receiving systemic therapy or direct medical intervention in another therapeutic clinical study.

[0458] 19. Any evidence of current ILD or pneumonia, or previous history of ILD or non-infectious pneumonia.

[0459] 20. Any medical condition or laboratory abnormality that may pose a risk to the study patients or affect the ability to interpret the study results.

[0460] Study Drug, Dosage and Administration Route: Compound 1 is provided in tablet form for oral administration in 2 strengths: 5 mg and 50 mg. Compound 1 should be taken on an empty stomach, i.e. at least 1 hour before and no earlier than 2 hours after ingestion of food and / or beverages other than water.

[0461] Prior and concomitant medications and therapies:

[0462] In certain embodiments, the concomitant use (within 12 days after enrollment) of drugs known to be strong CYP3A4 inducers (such as phenobarbital, rifampicin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's wort) is prohibited. In certain embodiments, the concomitant use (within 12 days after enrollment) of drugs known to be strong CYP3A4 inducers (such as phenobarbital, rifampicin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's wort) is allowed. In certain embodiments, the concomitant use (within 12 days after enrollment) of drugs known to be strong CYP3A4 inducers (such as phenobarbital, rifampicin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's wort) is cautious.

[0463] In certain embodiments, the concomitant use of drugs known to be strong inhibitors of CYP3A4 (within 12 days after enrollment) is prohibited. In certain embodiments, the concomitant use of drugs known to be strong inhibitors of CYP3A4 (within 12 days after enrollment) is allowed. In certain embodiments, drugs known to be strong inhibitors of CYP3A4 (within 12 days after enrollment) should be used with caution. In certain embodiments, strong inhibitors of CYP3A4 are clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, and grapefruit (including juice).

[0464] In certain embodiments, drugs that are strong inhibitors of CYP3A4, sensitive substrates of CYP3A4 and / or CYP2C8, substrates of P-glycoprotein (P-gp) / multidrug resistance protein 1 (MDR1), substrates of BCRP / breast cancer resistance protein (ABCG2), substrates of OATP1B1, substrates of OATP1B3, or substrates of MATE1 are used with caution at the same time (within 12 days after enrollment). In certain embodiments, the simultaneous use (within 12 days after enrollment) or co-administration of Compound 1 and any one or more drugs that are strong inhibitors of CYP3A4, sensitive substrates of CYP3A4 and / or CYP2C8, substrates of P-glycoprotein (P-gp) / multidrug resistance protein 1 (MDR1), substrates of BCRP / breast cancer resistance protein (ABCG2), substrates of OATP1B1, substrates of OATP1B3, or substrates of MATE1 are allowed. In certain embodiments, concomitant use (within 12 days of enrollment) or co-administration of drugs that are strong inhibitors of CYP3A4, sensitive substrates of CYP3A4 and / or CYP2C8, substrates of P-glycoprotein (P-gp) / multidrug resistance protein 1 (MDR1), substrates of BCRP / breast cancer resistance protein (ABCG2), substrates of OATP1B1, substrates of OATP1B3, or substrates of MATE1 are prohibited.

[0465] In certain embodiments, simultaneous use (within 12 days after enrollment) or co-administration of gastric acid reducing agents and Compound 1 should be avoided. In certain embodiments, simultaneous use (within 12 days after enrollment) or co-administration of gastric acid reducing agents and Compound 1 should be used with caution. In certain embodiments, simultaneous use (within 12 days after enrollment) or co-administration of gastric acid reducing agents and Compound 1 should be allowed.

[0466] Exemplary agents provided herein include, but are not limited to:

[0467] CYP3A4 inducers: phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's wort

[0468] CYP3A4 inhibitors: clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, grapefruit (including juice)

[0469] CYP3A4 substrates (sensitive): buspirone, everolimus, lovastatin, midazolam, simvastatin, triazolam, maraviroc, conivaptan, darifenacin

[0470] CYP2C8 substrates (sensitive): repaglinide, montelukast, pioglitazone, rosiglitazone

[0471] P-gp substrates: digoxin, fexofenadine, loperamide, quinidine, talinolol, vinblastine

[0472] BCRP substrates: daidzein, dantrolene, estrone-3-sulfate, prazosin, sulfasalazine

[0473] OATP1B1 / OATP1B3 substrates: antiviral protease inhibitors (e.g., ritonavir), clarithromycin, cyclosporine, gemfibrozil, rifampin, similapin

[0474] MATE1 substrates: metformin, tetraethylammonium (TEA), cimetidine, procainamide

[0475] Example 2: Cholangiocarcinoma MR619 model

[0476] The MR619 model was derived from a patient with cholangiocarcinoma with STRN-ALK fusion who progressed after alectinib treatment and acquired the G1202R resistance mutation. Tumors were implanted subcutaneously into 8-week-old male NOD scid gamma (NSG) mice obtained from Charles River Laboratories (France). Animals were randomly divided into 5 groups of 5 animals each, with an average initial tumor volume of ~170 mm 3 and treated with vehicle (BID PO), alectinib (50 mg / kg QD PO), lorlatinib (5 mg / kg BID PO), compound 1 (0.5 mg / kg BID PO), or compound 1 (3 mg / kg BID PO) for 14 days. The vehicle was 20% HP-β-CD in water, which was used to formulate compound 1. Lorlatinib was formulated with 2 equivalents of HCl + 20% HP-β-CD in water. Alectinib was formulated in 0.02N HCl, 10% DMSO, 10% Cremophor EL, 15% PEG-400, and 15% HP-β-CD. Tumor volume was measured twice a week, and body weight was measured approximately 5 times a week. The results confirmed that the model was resistant to alectinib, which is consistent with clinical observations. Lorlatinib was able to induce regression, but both doses of compound 1 induced stronger regression than lorlatinib ( Figure 2 ). Abbreviations: QD = once daily dosing; BID = twice daily dosing; PO = oral administration; HP-β-CD = hydroxypropyl-β-cyclodextrin; DMSO = dimethyl sulfoxide; PEG = polyethylene glycol.

[0477] Example 3: Neuroblastoma Assay

[0478] Biochemical assays. The inhibitory activity of several kinase inhibitors, including compound 1, was evaluated in the biochemical PhosphoSens assay (AssayQuant Technologies, MA, USA). The compounds were premixed with AT, DTT, and the fluorescent substrate AQT0101 (AssayQuant Technologies) at 30°C for 30 minutes. The reaction was initiated by adding one of the following enzymes: 2nM ALK F1174L (SignalChem #A19-12EG); 0.5nM ALK F1174S (SignalChem #A19-12FG); 1nM ALK R1275Q (SignalChem #A19-12LG); or 0.5nM ALK T1151M (SignalChem #A19-12BG) in reaction buffer. Final reaction conditions included 54 mM HEPES pH 7.5, 1 mM ATP, 1.2 mM DTT, 0.012% Brij-35, 0.52 mM EGTA, 1% glycerol, 0.2 mg / mL BSA, 10 mM MgCl2, 15 μM AQT0101, and the indicated enzyme concentrations. ex / em =360 / 485 nm every 1-2 minutes for 240 minutes at 30°C. The initial reaction rate (v) was calculated from the change in fluorescence intensity over time during the initial linear portion of the reaction. The half-maximal inhibitory concentration (IC) was determined from the percentage inhibition of the initial reaction rate and the inhibitor concentration using a four-parameter logistic regression. 50 ).

[0479] Cell viability assay. Kelly (ALK F1174L), SH-SY5Y (ALK F1174L), or NB-1 (ALK Ex2-3del) cells were seeded at 1,000 cells / well (40 μL) in 384-well plates and cultured for 1 day. Test compounds (40 nL) were then added in a 3-fold dilution series using a TECAN EVO200 liquid handler and incubated for 72 hours. The plates were equilibrated at room temperature for 15 minutes, and then 40 μL of CellTiter-Glo reagent (Promega) was added. Luminescence was measured on a plate reader (PerkinElmer). The half-maximal inhibitory concentration (IC) was calculated based on the inhibition percentage and inhibitor concentration using a four-parameter logistic regression. 50 ).

[0480] The results of the biochemical assays and cell viability assays are summarized in Figure 3 .

[0481] Example 4: Anaplastic Large Cell Lymphoma Assay

[0482] Cell viability assay. Karpas299 cells were seeded at 1,000 cells / well (40 μL) in 384-well plates and cultured for 1 day. Test compounds (40 nL each) were then added in a 3-fold dilution series using a TECAN EVO200 liquid handler and incubated for 72 hours. The plates were equilibrated at room temperature for 15 minutes, and then 40 μL of CellTiter-Glo reagent (Promega) was added. Luminescence was measured on a plate reader (PerkinElmer). The half-maximal inhibitory concentration (IC) was calculated based on the inhibition percentage and inhibitor concentration using a four-parameter logistic regression. 50 ).

[0483] Cellular phosphorylation assay. Test compounds (100 nL each) were added to a 96-well plate in a 3-fold dilution series using a TECAN EVO200 liquid handler. Karpas299 cells were added at 60,000 cells / well and incubated for 6 hours. ALK phosphorylation was quantified using the PathScan Phospho-ALK (Tyr1604) Chemiluminescent Sandwich ELISA Kit (CellSignaling Technology #7020) according to the manufacturer's instructions. The half-maximal inhibitory concentration (IC) was calculated based on the inhibition percentage and inhibitor concentration using a four-parameter logistic regression. 50 ).

[0484] The results of the cell viability assay and cell phosphorylation assay are summarized in Figure 4 .

[0485] Example 5: Soft tissue sarcoma (SS) assay

[0486] Cell viability assay. Aska-SS cells carrying ALK deletions around exons 2-17 were seeded in 384-well plates at 1,000 cells / well (40 μL) and cultured for 1 day. Test compounds (40 nL each) were then added in a 3-fold dilution series using a TECAN EVO200 liquid handler and incubated for 72 hours. The plates were equilibrated at room temperature for 15 minutes, and then 40 μL CellTiter-Glo reagent (Promega) was added. Luminescence was measured on a plate reader (PerkinElmer). The half-maximal inhibitory concentration (IC) was calculated based on the inhibition percentage and inhibitor concentration using a four-parameter logistic regression. 50 ).

[0487] Cellular phosphorylation assay. Test compounds (100 nL each) were added to a 96-well plate in a 3-fold dilution series using a TECAN EVO200 liquid handler. Aska-SS cells were added at 60,000 cells / well and incubated for 6 hours. ALK phosphorylation was quantified using the PathScan Phospho-ALK (Tyr1604) Chemiluminescent Sandwich ELISA Kit (Cell Signaling Technology #7020) according to the manufacturer's instructions. The half-maximal inhibitory concentration (IC) was calculated based on the inhibition percentage and inhibitor concentration using a four-parameter logistic regression. 50 ).

[0488] The results of the cell viability assay and cell phosphorylation assay are summarized in Figure 5 .

[0489] Example 6: MR448re cell line carrying EML4-ALK v3 G1202R / T1151M mutation

[0490] The MR448re cell line was established from ascites (fluid in the abdominal cavity) of a patient with non-small cell lung cancer who carried an EML4-ALK v3 fusion and progressed after receiving lorlatinib treatment and acquired the G1202R / T1151M mutation. Ascites mononuclear cells were isolated by Ficoll centrifugation and cultured in culture medium (DMEM F12 Glutamax, 10% antibiotics / antimycotics, 10% FBS, hydrocortisone, adenine, Rock inhibitor, and 1 / 10 cholera toxin). After obtaining stable cancer cells, the presence of EML4-ALK fusion and G1202R / T1151M compound mutations were confirmed by PCR and sequencing. MR448re cells were treated with test compounds in a half-log dilution series (10 μM, 3 μM, 1 μM, 300 nM, 100 nM, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM and 0.1 nM) for 72 h, and then viability was determined using CellTiter-Glo reagent (Promega). The half-maximal inhibitory concentration (IC) was calculated from the percentage of inhibition and inhibitor concentration using a four-parameter logistic regression. 50 Representative data are shown in Figure 6 .

[0491] Example 7: Mutation Evaluation

[0492] The inhibitory activity of ALK inhibitors was evaluated in Ba / F3 cells carrying EML4-ALK fusions of different resistance mutations (G1202R, G1202R / T1151M, G1202R / L1196M, G1202R / L1198F, G1202R / G1269A, I1171N, I1171S, I1171T, L1196M, or D1203N), human cell lines NCI-H2228 and NCI-H3122 carrying EML4-ALK fusions, and Ba / F3 cells carrying ETV6-TRKB or TPM3-TRKA fusions using the following general procedure.

[0493] Cells were seeded in 384-well plates. Test compounds were then added in a 3-fold dilution series using a TECAN EVO200 liquid handler and incubated for 72 hours. The plates were equilibrated at room temperature for 15 minutes before adding CellTiter-Glo reagent (Promega). Luminescence was measured on a plate reader (PerkinElmer). Four-parameter logistic regression was used to calculate the half-maximal inhibitory concentration (IC) based on the percentage of inhibition and the inhibitor concentration. 50 Representative data are shown in Figure 7 .

[0494] Example 8: MR448re PDX Study

[0495] The MR448re cell line was established from ascites (fluid in the abdominal cavity) of NSCLC patients who progressed after receiving lorlatinib treatment. Ascites mononuclear cells were separated by Ficoll centrifugation and cultured in culture medium (DMEM F12 Glutamax, 10% antibiotics / antimycotics, 10% FBS, hydrocortisone, adenine, Rock inhibitor and 1 / 10 cholera toxin). After obtaining stable cancer cells, five million cells were injected into Swiss nude mice to obtain a xenograft model. After inoculation, mice were randomized and grouped according to tumor size. The test compound was administered orally twice a day over several days.

[0496] Example 9: Western blot analysis of PD markers

[0497] Summary. ALK gene rearrangement can induce constitutive activation of ALK kinase activity, leading to ALK autophosphorylation (pALK) and subsequent activation of MAP kinase (MAPK), PI3K / AKT and JAK / STAT pathways, thereby driving tumor cell proliferation and survival (Shaw AT and Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013; 31(8): 1105-1111). pALK was evaluated as a proximal PD marker, and phosphorylated-p44 / 42 MAPKERK1 / 2 (pERK) was evaluated as a downstream MAPK pathway marker, phosphorylated-AKT (pAKT) and phosphorylated S6 were evaluated as PI3K / AKT pathway markers, and cleaved PARP was evaluated as a marker of apoptosis.

[0498] Results. After QD × 1 day treatment, compound 1 reduced pALK levels in a dose-dependent manner at the 1-hour and 12-hour time points, with robust reductions observed at the 1.5 mg / kg dose (the dose that induced regression, also referred to as the “regression dose”, data not shown). Lorlatinib 5 mg / kg QD × 1 day reduced pALK levels at 1 hour and 12 hours after treatment. During this time period, 1.5 mg / kg compound 1 and 5 mg / kg lorlatinib modestly reduced total ALK levels ( Fig. 8A and Figure 8C Repeated dosing (BID × 5 days) of compound 1 and lorlatinib yielded similar results, with compound 1 dose-dependently reducing pALK levels, while lorlatinib reduced pALK levels. Over the same time period, compound 1 (1.5 mg / kg) and lorlatinib (5 mg / kg) modestly reduced total ALK levels, although ALK levels in vehicle-treated tumors were variable ( Figure 8B and Fig.8D The decrease in pALK is consistent with direct inhibition of ALK kinase activity by compound 1 and lorlatinib.

[0499] To evaluate the effects of compound 1 treatment on downstream signaling pathways, the levels of pERK, a phosphorylation marker of the MAPK pathway, and pAKT and pS6, phosphorylation markers of the PI3K / AKT pathway, were monitored. Compound 1 dose-dependently reduced pERK levels QD×1 day, with lower levels observed at 1 hour compared to 12 hours after treatment. Lorlatinib 5 mg / kg QD×1 day showed similar results ( Fig. 9A ). In contrast, compound 1 and lorlatinib reduced pAKT / AKT levels at 12 h after QD × 1 day treatment, but not at 1 h, although the response of the vehicle group varied ( Fig. 9C). For the pS6 / S6 readout, lorlatinib modestly reduced pS6 / S6 levels at 1 hour after QD × 1 day treatment, but not at 12 hours, while compound 1 did not dose-dependently reduce pS6 / S6 levels ( Fig.9E ).

[0500] The observation that compound 1 caused tumor regression prompted the evaluation of cleaved PARP, a marker of apoptosis. Treatment with a single dose of compound 1 (1.5 mg / kg) significantly increased the levels of cleaved PARP at the 12 hour time point. This was not observed with 0.06 mg / kg of compound 1, which did not induce regression. A single dose of 5 mg / kg of lorlatinib also increased cleaved PARP at the 12 hour time point ( Figure 9G ).

[0501] The effects of repeated dosing (BID × 5 days) of compound 1 and lorlatinib on signaling through the MAPK and AKT pathways were also evaluated. Repeated dosing of compound 1 or lorlatinib did not result in a sustained decrease in pERK levels ( Fig. 9B In contrast, the levels of pAKT / AKT and pS6 / S6 decreased after repeated administration ( Fig.9D and Fig.9F ).

[0502] Example 10: Biochemical Assays

[0503] Generation of Ba / F3 stable cell lines

[0504] The gene encoding CLIP1-LTK was synthesized, cloned into the retroviral construct pMSCV-puro (Biovector), and packaged into retroviral particles. The virus was used to infect Ba / F3 cells (RIKEN) with a multiplicity of infection of 1 or 10 for 1 day. The infected cells were revived in a medium (RPMI-1640 containing 10% fetal bovine serum and 1% streptomycin and penicillin) supplemented with mouse IL-3 (10 ng / mL) for 2 days, and then stable cell lines were screened by stopping IL-3 and culturing with puromycin (0.8 μg / mL) for 7 days. The transformation of the desired gene was confirmed by Sanger sequencing and Western blotting.

[0505] Cell proliferation assay

[0506] Stable cells were seeded at 1,000 cells / well (40 μL) in 384-well plates and cultured for 1 day. Test compounds (40 nL) were then added in a 3-fold dilution series using a TECANEVO200 liquid handler and incubated for 72 hours. The plates were equilibrated at room temperature for 15 minutes, and then 40 μL of CellTiter-Glo reagent (Promega) was added. Luminescence was measured on a plate reader (PerkinElmer). A four-parameter logistic regression was used to calculate the half-maximal inhibitory concentration (IC) based on the percentage of inhibition and the inhibitor concentration. 50 ). IC of several test compounds 50 The data are shown in the table...

Claims

1. A method for treating a subject having a solid tumor, comprising administering to the subject a therapeutically effective amount of Compound 1: or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the solid tumor is an advanced solid tumor.

3. The method of claim 2, wherein the advanced solid tumor has relapsed after, is refractory to, or is resistant to prior treatment with a tyrosine kinase inhibitor (TKI).

4. The method according to any one of claims 1 to 3, wherein the solid tumor is non-small cell lung cancer (NSCLC).

5. The method according to any one of claims 1 to 3, wherein the solid tumor is cholangiocarcinoma.

6. The method according to any one of claims 1 to 3, wherein the solid tumor is neuroblastoma.

7. The method according to any one of claims 1 to 3, wherein the solid tumor is a soft tissue sarcoma.

8. The method according to any one of claims 1 to 7, wherein the solid tumor is metastatic.

9. The method of claim 8, wherein the solid tumor is CNS metastatic.

10. The method according to any one of claims 1 to 9, wherein the solid tumor is ALK positive.

11. The method of claim 10, wherein the ALK-positive solid tumor is characterized by the presence of an ALK gene mutation. 12 . The method of claim 11 , wherein the ALK mutation comprises one or more ALK rearrangements, one or more ALK point mutations, or a combination thereof.

13. The method of claim 11 or claim 12, wherein the ALK mutation comprises one or more ALK fusions.

14. The method of claim 13, wherein the ALK fusion is with one of the fusion partners selected from the group consisting of: EML4, TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, NPM1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, ATIC, MSN, ALO17, MYH9, and KIF5B.

15. The method of claim 14, wherein the ALK fusion is with NPM1, STRN or EML4.

16. The method of any one of claims 11 to 15, wherein the ALK mutations include G1202R, F1174C, F1174L, I1171N, I1171S, I1171T, L1196M, V1180L, C1156Y, G1202del, G1202K, G1269A, G1269V, F1174S, F1174I, S1206Y, E1210K, T1180L, 51M, T1151_L1152insT, D1203N, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, E1129K, S1206F, L1198H, F1245C, T1151K, I1268V, F1174V, L1198Q, S1206A or F1245V, or a combination thereof.

17. The method of claim 16, wherein the ALK mutation comprises G1202R.

18. The method of claim 16, wherein the ALK mutation comprises F1174S or F1174L.

19. The method of claim 16, wherein the ALK mutation comprises R1275Q.

20. The method of claim 16, wherein the ALK mutation comprises T1151M.

21. The method of any one of claims 11 to 16, wherein the ALK mutation comprises one or more compound mutations.

22. The method of claim 21, wherein the compound mutation is G1202R / F1174L.

23. The method of claim 21, wherein the compound mutation is G1202R / T1151M, G1202R / L1196M, G1202R / G1269A, G1202R / L1198F or G1202R / F1174S.

24. The method of claim 21, wherein the compound mutation is C1156Y / L1256F, C1156Y / S1206F, C1156Y / F1174V or C1156Y / F1174I.

25. The method of claim 21, wherein the compound mutation is L1196M / L1198H, L1196M / I1179V or L1196M / L1256F.

26. The method of claim 10, wherein the ALK-positive solid tumor is characterized by the presence of partially deleted ALK protein.

27. The method of any one of claims 1 to 26, wherein the subject has not been treated with tyrosine kinase inhibitor (TKI) therapy.

28. The method of any one of claims 1 to 26, wherein the subject has been treated with one prior TKI therapy.

29. The method of any one of claims 1 to 26, wherein the subject has been treated with at least one prior TKI therapy.

30. The method of any one of claims 1 to 26, wherein the subject has been treated with at least two prior TKI therapies.

31. The method of any one of claims 27 to 30, wherein the TKI is an ALK TKI.

32. The method of claim 31, wherein the ALK TKI is crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib.

33. The method of any one of claims 1 to 32, wherein the subject has been treated with one or more prior systemic anti-cancer therapies.

34. The method of any one of claims 1 to 33, wherein the subject has not received prior chemotherapy treatment.

35. The method of any one of claims 1 to 33, wherein the subject has received prior chemotherapy treatment.

36. The method of claim 35, wherein the subject has received up to two lines of prior chemotherapy treatment.

37. The method of any one of claims 1 to 36, wherein the subject has not received prior immunotherapy treatment.

38. The method of any one of claims 1 to 36, wherein the subject has received prior immunotherapy treatment.

39. The method of claim 38, wherein the subject has received up to two lines of prior immunotherapy treatment.

40. The method of claim 1, wherein the solid tumor is advanced or metastatic ALK-positive NSCLC and the subject has been treated with at least one prior ALK TKI therapy.

41. The method of claim 40, wherein at least one prior ALK TKI therapy is ceritinib, crizotinib, alectinib, brigatinib, or lorlatinib.

42. The method of claim 1, wherein the solid tumor is advanced or metastatic ALK-positive NSCLC and the subject has been treated with one prior ALK TKI therapy.

43. The method of claim 42, wherein the prior ALK TKI therapy is ceritinib, crizotinib, alectinib, brigatinib, or lorlatinib.

44. The method of claim 1, wherein the solid tumor is advanced or metastatic ALK-positive NSCLC and the subject has been treated with two or three prior ALK TKI therapies.

45. The method of claim 44, wherein the two or three prior ALK TKI therapies are crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib.

46. ​​The method of claim 44 or 45, wherein the second or third prior ALK TKI therapy is lorlatinib.

47. The method of any one of claims 40 to 46, wherein the subject has been treated with ≤ 2 prior lines of chemotherapy and / or immunotherapy.

48. The method of any one of claims 40 to 46, wherein the subject has been treated with more than two prior lines of chemotherapy and / or immunotherapy.

49. The method of claim 1, wherein the solid tumor is an advanced or metastatic ALK-positive solid tumor and the subject has been treated with one or more prior systemic anticancer therapies.

50. The method of claim 1, wherein the solid tumor is advanced or metastatic ALK-positive NSCLC and the subject has progressed following prior therapy.

51. The method of any one of claims 1 to 50, wherein Compound 1 is administered to the patient for one or more days.

52. The method of any one of claims 1 to 51, wherein Compound 1 is administered to the patient for at least one treatment cycle.

53. The method of claim 52, wherein a treatment cycle is at least 7 days.

54. The method of claim 52, wherein a treatment cycle is at least 14 days.

55. The method of claim 52, wherein a treatment cycle is at least 21 days.

56. The method of any one of claims 1 to 55, wherein the patient experiences no Grade 4 adverse events (e.g., TRAEs) following administration of Compound 1.

57. The method of any one of claims 1 to 56, wherein the patient experiences no Grade 3 adverse events (e.g., TRAEs) following administration of Compound 1.

58. The method of any one of claims 1 to 57, wherein the patient experiences no Grade 2 adverse events (e.g., TRAEs) following administration of Compound 1.

59. The method of any one of claims 1 to 58, wherein the patient experiences no Grade 1 adverse event (e.g., TRAE) following administration of Compound 1.

60. The method of any one of claims 1 to 58, wherein the patient experiences no more than a Grade 1 adverse event (e.g., TRAE) following administration of Compound 1.

61. The method of any one of claims 1 to 60, wherein the patient experiences no CNS adverse events following administration of Compound 1.

62. The method of claim 61, wherein the CNS adverse event is one or more selected from the group consisting of dizziness, ataxia, gait disturbance, paresthesia, weight gain, increased appetite, paresthesia, movement abnormalities, cognitive changes, speech effects (e.g., dysarthria, slow speech, or speech disorders), mood disorders (e.g., irritability, anxiety, depression, mood swings, personality changes, mood swings, affective disorders, aggression, agitation, mood changes, depressed mood, euphoria, or mania), and cognitive disorders (e.g., memory impairment, cognitive impairment, amnesia, confusion, attention disorders, delirium, mental disorders, attention-deficit / hyperactivity disorder, dementia, sleep disorders, or reading disorders).

63. The method of any one of claims 1 to 62, wherein the patient does not experience adverse events of weight gain and / or glucose metabolism disorders.

64. The method of any one of claims 1 to 63, wherein the patient is a patient population.

65. The method of claim 64, wherein the patient population experiences no Grade 3 or 4 TRAEs following administration of Compound 1.

66. The method of any one of claims 1 to 65, wherein the patient has a complete response after one or more treatment cycles.

67. The method of any one of claims 1 to 65, wherein the patient has a partial response after one or more treatment cycles.

68. The method of any one of claims 1 to 67, wherein the patient achieves stable disease after one or more treatment cycles.

69. The method of any one of claims 1 to 68, wherein the patient has brain metastases.

70. The method of any one of claims 1 to 69, wherein the patient has brain metastases and has not experienced intracranial progression after at least one treatment cycle.

71. The method of any one of claims 1 to 70, wherein the patient has a reduction in ALK allelic variants in circulating tumor DNA of at least about 5% to about 100% after at least one treatment cycle.

72. The method of any one of claims 1 to 71, wherein the patient has at least about a 30% reduction in ALK allelic variants in circulating tumor DNA after at least one treatment cycle.

73. The method of any one of claims 1 to 72, wherein the patient has at least about a 50% reduction in ALK allelic variants in circulating tumor DNA after at least one treatment cycle.

74. The method of any one of claims 1 to 73, wherein the patient has at least about a 70% reduction in ALK allelic variants in circulating tumor DNA after at least one treatment cycle.

75. The method of any one of claims 1 to 74, wherein the patient has at least about a 100% reduction in ALK allelic variants in circulating tumor DNA after at least one treatment cycle.

76. The method of any one of claims 1 to 75, wherein the patient has undetectable ALK allelic variant in circulating tumor DNA after at least one treatment cycle.

77. The method of claim 76, wherein the ALK allelic variant is G1202R.

78. The method of any one of claims 1 to 49, wherein the compound is administered in an amount from about 5 mg to about 400 mg (by weight of Compound 1 free base) once daily.

79. The method of claim 78, wherein the compound is administered in an amount from about 15 mg to about 200 mg (by weight of Compound 1 free base) once daily.

80. The method of claim 79, wherein the compound is administered in an amount from about 25 mg to about 200 mg (by weight of Compound 1 free base) once daily.

81. The method of claim 80, wherein the compound is administered in an amount from about 15 mg to about 150 mg (by weight of Compound 1 free base) once daily.

82. The method of claim 81, wherein the compound is administered in an amount from about 15 mg to about 100 mg (by weight of Compound 1 free base) once daily.

83. The method of claim 78, wherein the compound is administered once a day in an amount of about 10 mg, about 15 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, or about 250 mg (based on the weight of free base Compound 1).

84. The method of any one of claims 1 to 49, wherein the compound is administered in an amount from about 5 mg to about 400 mg (by weight of Compound 1 free base) twice a day (BID).

85. The method of claim 84, wherein the compound is administered in an amount from about 15 mg to about 200 mg (by weight of Compound 1 free base) twice a day (BID).

86. The method of claim 85, wherein the compound is administered in an amount from about 25 mg to about 200 mg (by weight of Compound 1 free base) twice a day (BID).

87. The method of claim 86, wherein the compound is administered in an amount from about 15 mg to about 150 mg (by weight of Compound 1 free base) twice a day (BID).

88. The method of claim 87, wherein the compound is administered in an amount from about 15 mg to about 100 mg (by weight of Compound 1 free base) twice a day (BID).

89. The method of claim 84, wherein the compound is administered twice a day (BID) in an amount of about 10 mg, about 15 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, or about 250 mg (based on the weight of free base Compound 1).

90. The method of any one of claims 1 to 89, wherein the compound is administered orally.

91. The method of claim 90, wherein the compound is administered in the form of one or more tablets.

92. The method of claim 91, wherein the tablet has a unit dosage strength of about 5 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg by weight of free base Compound 1.

93. The method of any one of claims 90 to 92, wherein the compound is administered to a fasting patient.

94. The method of any one of claims 90 to 92, wherein the compound is administered to a patient on a full stomach.

95. The method of any one of claims 1 to 94, wherein the subject is not using any of a strong CYP3A4 inducer, a strong CYP3A4 inhibitor, a CYP3A4 and / or CYP2C8 sensitive substrate, a P-gp / multidrug resistance protein (MDR1) substrate, a BCRP / breast cancer resistance protein (ABCG2) substrate, an OATP1B1 substrate, an OATP1B3 substrate, a MATE1 substrate, or a gastric acid reducing agent.

96. The method of any one of claims 1 to 94, wherein the subject is taking any of a strong CYP3A4 inducer, a strong CYP3A4 inhibitor, a CYP3A4 and / or CYP2C8 sensitive substrate, a P-gp / multidrug resistance protein (MDR1) substrate, a BCRP / breast cancer resistance protein (ABCG2) substrate, an OATP1B1 substrate, an OATP1B3 substrate, a MATE1 substrate, or a gastric acid reducing agent.

97. The method of any one of claims 1 to 94, wherein the subject is taking any one of a strong CYP3A4 inducer or a strong CYP3A4 inhibitor.

98. The method of any one of claims 1 to 94, wherein the subject is not taking any of a strong CYP3A4 inducer or a strong CYP3A4 inhibitor.

99. The method of any one of claims 1 to 94, wherein the subject is not taking any of the strong inducers of CYP3A4.

100. The method of any one of claims 1 to 99, wherein the subject experiences improvement in one or more symptoms selected from the group consisting of cognitive impairment, mood disorders, sleep disorders, dizziness, ataxia, and weight gain following administration of the compound.

101. The method of any one of claims 1 to 99, wherein the subject does not experience one or more symptoms selected from the group consisting of cognitive impairment, mood disorders, sleep disorders, dizziness, ataxia, and weight gain after administration of the compound.

102. The method of any one of claims 1 to 101, wherein the subject experiences a decrease in the level of one or more of pALK, pERK, pAKT, and phosphorylated S6 following administration of the compound.

103. The method of any one of claims 1 to 102, wherein the subject experiences elevated levels of cleaved PARP following administration of the compound.

104. The method of any one of claims 1 to 103, wherein the subject experiences a decrease in activity of a MAP kinase pathway, a PI3K / AKT pathway, or a JAK / STAT pathway, or any combination thereof in a tumor following administration of the compound.

105. The method of any one of claims 1 to 104, wherein the subject experiences a decrease in activity of a MAP kinase pathway, a PI3K / AKT pathway, or a JAK / STAT pathway, or any combination thereof, in a solid tumor after administration of the compound.

106. The method of any one of claims 1 to 105, wherein the subject experiences increased expression levels of one or more apoptosis markers in the tumor following administration of the compound.

107. The method of any one of claims 1 to 106, wherein the subject experiences a decrease in the expression level of one or more proliferation markers in the tumor following administration of the compound.

108. The method of any one of claims 1 to 106, wherein the subject experiences increased expression levels of one or more apoptosis markers in a solid tumor following administration of the compound.

109. The method of claim 1, wherein the solid tumor is leukocyte receptor tyrosine kinase (LTK) positive.

110. The method of claim 109, wherein the solid tumor is LTK-positive lung cancer.

111. The method of claim 110, wherein the solid tumor is LTK-positive NSCLC.

112. The method of any one of claims 1 to 111, wherein the compound is Compound 1 free base.

113. The method of any one of claims 1 to 112, wherein the compound is a solid form of Compound 1.

114. The method of claim 113, wherein the solid form is characterized by an XRPD pattern comprising peaks at approximately 12.4, 18.9, and 21.1 ° 2θ (± 0.2°).

115. The method of any one of claims 1 to 114, wherein the subject is administered a pharmaceutical composition comprising the therapeutically effective amount of Compound 1, wherein the pharmaceutical composition further comprises a diluent, a disintegrant, a glidant, a binder, and a lubricant.

116. The method of claim 115, wherein the diluent is microcrystalline cellulose, the disintegrant is croscarmellose sodium, the glidant is colloidal silicon dioxide, the binder is hydroxypropyl cellulose (HPC), and the lubricant is magnesium stearate.

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