Methods for treating solid tumors using (19R)-5-chloro-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.02,6.08,12.013,18]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine

Abstract

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

Description

[Technical field]

[0001] This application claims the benefit of priority to U.S. Patent Application No. 63 / 328,609, filed April 7, 2022, U.S. Patent Application No. 63 / 328,620, filed April 7, 2022, U.S. Patent Application No. 63 / 356,702, filed June 29, 2022, and U.S. Patent Application No. 63 / 376,962, filed September 23, 2022, each of which is incorporated by reference herein in its entirety. [Background technology]

[0002] Receptor tyrosine kinases (RTKs) are cell surface enzymes that receive external signals, such as signals for growth and division, and transmit these signals in cells through kinase activity. Many RTKs are proto-oncogenes, and aberrant RTK activity can drive cell survival, growth, and proliferation leading to cancer and related disorders. This aberrant kinase activity can be caused by mutations, such as activating mutations in the kinase domain, gene rearrangements that result in fusion proteins containing intact kinase domains, amplification, 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 a RTK proto-oncogene with ALK rearrangements detected in many cancers, including NSCLC, anaplastic large cell lymphoma (ALCL), IMT, diffuse large B-cell lymphoma (DLBCL), esophageal squamous cell carcinoma (ESCC), renal medullary carcinoma, renal cell carcinoma, breast cancer, colorectal cancer, serous ovarian cancer, papillary thyroid carcinoma, cholangiocarcinoma, and Spitzoid tumors, and ALK-activating mutations have been detected in neuroblastoma and anaplastic thyroid carcinoma. Oncogenic ALK gene fusions contain the kinase domain (3' region) of ALK fused to the 5' region of more than 20 different partner genes, with the most common partner genes being 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.

[0004] NTRK1, NTRK2 and NTRK3 are RTK proto-oncogenes that encode TRK family kinases, and RTK proto-oncogenes have NTRK1, NTRK2 and NTRK3 chromosomal rearrangements that are detected in many cancers at low frequencies. 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 used to treat oncogenic ROS1 and ALK have significant deficiencies that may manifest themselves as one or more of the following: associated TRK inhibition, limited CNS activity, and inadequate activity against resistant mutations. Treatment of ROS1-positive or ALK-positive patients with TRK inhibition is associated with adverse reactions, particularly in the CNS, including dizziness / ataxia / gait disturbance, paresthesia, weight gain, and cognitive changes. In addition, there is a need for CNS-penetrant and TRK-sparing inhibitors of ROS1 with wild-type ROS1 kinase domain and acquired resistance mutations occurring either individually 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. Similarly, there is a need for CNS-penetrant and TRK-sparing inhibitors of ALK with acquired resistance mutations. A variety of ALK drug resistance mutations occurring either individually or in combination 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 combinations thereof. Summary of the Invention

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

[0007] In one embodiment, provided herein is a method of treating a solid tumor, the method comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1: [ka] or a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the compound is Compound 1.

[0008] 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).

[0009] 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.

[0010] In one embodiment, the subject is naive to 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 one 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, and lorlatinib. In one embodiment, the 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, and lorlatinib. In one embodiment, the subject with an ALK-positive solid tumor (e.g., NSCLC) has been treated with at least one previous systemic anti-cancer 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, the subject with progressive ALK-positive NSCLC has been treated with a previous first-generation ALK TKI therapy (e.g., crizotinib). In one embodiment, the subject with progressive ALK-positive NSCLC has been treated with a previous second-generation ALK TKI therapy selected from ceritinib, alectinib, and brigatinib. In one embodiment, the subject with progressive ALK-positive NSCLC has been treated with two or three previous first- or second-generation ALK TKI therapies selected from crizotinib, ceritinib, alectinib, and brigatinib. In one embodiment, a subject with advanced ALK-positive NSCLC has been treated with lorlatinib in a second or third line of therapy with two or three prior ALK TKI therapies. In one embodiment, a subject with a solid tumor harboring an ALK rearrangement or activating ALK mutation has been treated with at least one prior systemic anti-cancer therapy.In one embodiment, the subject has a solid tumor with ALK rearrangement or activating ALK mutation and has no existing satisfactory standard therapy. In certain embodiments, the subject has ALK resistance mutation (e.g., single mutation and / or 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 progressive or metastatic ALK-positive NSCLC is locally advanced or metastatic ALK-positive NSCLC. In certain embodiments, the progressive or metastatic ALK-positive NSCLC is locally advanced or metastatic ALK-positive NSCLC with ALK rearrangement.

[0011] In one embodiment, the compound is administered once (QD) or twice (BID) per day in an amount of about 5 mg to about 400 mg. In one embodiment, the compound is administered once (QD) or twice (BID) per day in an amount of about 15 mg to about 200 mg (by weight of compound 1). In one embodiment, the compound is administered once (QD) per day in an amount of about 15 mg to about 200 mg (by weight of compound 1). In one embodiment, the compound is administered once (QD) per day in an amount of about 15 mg, 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg (by weight of compound 1).

[0012] In one embodiment, the compound is administered once daily (QD) or twice daily (BID) in an amount of about 10 mg to about 150 mg (by weight of compound 1). In one embodiment, the compound is administered once daily (QD) in an amount of about 10 mg to about 150 mg (by weight of compound 1). In one embodiment, the compound is administered once daily (QD) in an amount of about 10 mg, 15 mg, 25 mg, 50 mg, 100 mg, or 150 mg (by weight of compound 1).

[0013] In one embodiment, the compound is administered once daily (QD) or twice daily (BID) in an amount of about 10 mg to about 100 mg (by weight of compound 1). In one embodiment, the compound is administered once daily (QD) in an amount of about 10 mg to about 100 mg (by weight of compound 1). In one embodiment, the compound is administered once daily (QD) in an amount of about 10 mg, 15 mg, 25 mg, 50 mg, or 100 mg (by weight of compound 1).

[0014] In one embodiment, the compound is administered once daily (QD) or twice daily (BID) in an amount of about 25 mg to about 250 mg (by weight of compound 1). In one embodiment, the compound is administered once daily (QD) in an amount of about 25 mg to about 250 mg (by weight of compound 1). In one embodiment, the compound is administered once daily (QD) in an amount of about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg (by weight of compound 1).

[0015] In one embodiment, the compound is administered to a subject with fasting (e.g., at least 1 hour before and 2 or more hours after ingestion of food and / or beverages other than water). In one embodiment, the compound is administered to the subject after ingestion of 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 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 absence of a gastric acid reducer (e.g., a proton pump inhibitor). In one embodiment, the compound is administered in the presence of a gastric acid reducer. 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]

[0016] [Figure 1] The phase 1 and phase 2 study designs are shown.

[0017] [Diagram 2]Figure 1 shows that Compound 1 induced regression in MR619 cholangiocarcinoma (STRN-ALK G1202R) patient-derived xenograft model 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 chosen to approximate the free drug exposure of a 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 HCl + 20% HP-β-CD in water. All treatments were well tolerated. Dosing was not performed on weekends, in other words, dosing was performed 5 days on / 2 days off. Means plotted ± SEM. BID = twice daily, PO = orally administered.

[0018] [Diagram 3] Activity of various inhibitors against ALK activating mutations in neuroblastoma. Biochemical assays were performed using purified ALK kinase and fluorogenic 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 (ALK Ex2-3del) human neuroblastoma cell lines. NB-1 is known to have ALK overexpression, but was also identified to have an ALK partial deletion around exons 2-3 (Okubo et al. Oncogene 2012;31(44):4667). All data from n>2 replicate studies. Means plotted.

[0019] [Figure 4]Figure 1 shows the activity of various ALK inhibitors against the human anaplastic large cell lymphoma cell line Karpas299 harboring the NPM1-ALK fusion in a 3-day cell viability assay or an ALK phosphorylation ELISA assay. Numeric IC50 values ​​are shown above the bars. All data from n > 2 replicates. Means plotted.

[0020] [Diagram 5] Activity of various ALK inhibitors against Aska-SS harboring an ALK deletion around exons 2-17 in a 3-day cell viability assay and an ALK phosphorylation ELISA assay. Numeric IC50 values ​​are indicated above the bars. All data from n>2 replicates. Means plotted.

[0021] [Figure 6] 1 shows the inhibition of cell viability by various inhibitors in MR448re cell lines harboring the EML4-ALK v3 G1202R / T1151M mutation. IC50 values ​​shown are in nM.

[0022] [Figure 7] Figure 1 shows inhibition of cell viability by various inhibitors in various cells harboring EML4-ALK fusions (with or without resistance mutations), ETV6-TRKB fusions, or TPM3-TRKA fusions. IC50 (nM) values ​​are plotted as a heat map.

[0023] [Figure 8A-D]Figure 8 shows inhibition of pALK in PDX tumors bearing HIP1-ALK. 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 were treated with vehicle (20% HP-β-CD), compound 1, or lorlatinib at a single dose (QD x 1) or PO BID x 5 days (BID x 5), followed by harvesting tumors at the indicated time points (n = 2 or 3) and analyzing by Western blot. Figure 8A shows quantification of pALK after QD x 1 administration. Figure 8B shows quantification of pALK after BID x 5 administration. Figure 8C shows quantification of ALK after QD x 1 administration. Figure 8D shows quantification of ALK after BID x 5 administration. Anti-β2m is a loading control that does not recognize mouse β2m.

[0024] [Figure 9]Figure 1 shows inhibition of signaling through MAPK and PI3K / AKT pathways and induction of apoptosis in PDX tumors bearing HIP1-ALK. Abbreviations: β2m=β2-microglobulin, BID=twice daily, HP-β-CD=2-hydroxypropyl-β-cyclodextrin, PDX=patient-derived xenograft, PO=orally, QD=once daily, SEM=standard error of the mean. Mice bearing PDX tumors bearing HIP1-ALK were treated with vehicle (20% HP-β-CD), compound 1, or lorlatinib at a single dose (QD×1) or BID×5 days (BID×5) PO, followed by harvesting tumors at the indicated time points (n=2 or 3) and Western blots. Anti-β2m is a loading control that does not recognize mouse β2m. pERK is a marker of MAPK signaling, pAKT and pS6 are markers of PI3K / AKT signaling, and cleaved PARP is a marker of apoptosis. A shows quantification of pERK / ERK after QD×1 administration. B shows quantification of pERK / ERK after BID×5 administration. C shows quantification of pAKT / AKT after QD×1 administration. D shows quantification of pAKT / AKT after BID administration. E shows quantification of pS6 / S6 after QD×1 administration. F shows quantification of pS6 / S6 after BID×5 administration. G shows quantification of cleaved PARP / β2m after QD×1 administration.

[0025] [Figure 10] 1 shows that compound 1 exhibited potent antitumor activity in a patient-derived cell line (PDC) xenograft mouse model (MR448re cells (EML4-ALK_G1202R / T1151M expressing PDC) were subcutaneously implanted into nude mice).

[0026] [Figure 11] We show that compound 1 can overcome the ALK G1202R compound mutation (BaF3 model).

[0027] [Figure 12] An outline of the food effect study design is presented.

[0028] [Figure 13] An overview of drug-drug interaction study design is provided.

[0029] [Figure 14] 1 is a representative XRPD pattern of Form 2 of the free base of Compound 1.

[0030] [Figure 15] 1 is a representative DSC thermogram of Form 2 of the free base of Compound 1.

[0031] [Figure 16] 1 is a representative DVS isotherm of Form 2 of the free base of Compound 1.

[0032] [Figure 17] FIG. 2 is a representative diagram of unit cell axes of a single crystal X-ray diffraction study of Form 2 of the free base of Compound 1.

[0033] [Figure 18] 1 shows the plate layout for the viability assay portion of the combination study with osimertinib.

[0034] [Figure 19] Layout of conditions for the in vitro signaling pathway study portion of the combination study with osimertinib is shown.

[0035] [Figure 20A] Patient treatment history of the YU-1077 cell line is shown. [Figure 20B] Sanger sequencing confirmation is shown. E6:A20 indicates EML4 exon 6 fusion with ALK exon 20. NCBI sequence numbers of EML4 and ALK are provided.

[0036] [Figure 21] 1 provides dose-response curves showing the activity of various compounds against YU-1077 cell line in a 3-day viability assay. Plotted mean ± SEM, n=5. IC50 values ​​were calculated using a fixed Emax=50%.

[0037] [Figure 22] Western blot showing the effect of ALK TKIs on ALK kinase activity (pALK) and downstream signaling (pERK, pAKT, pS6) in YU-1077 cell line. Cells were treated for 6 hours. p=phosphorylated form of each protein marker.

[0038] [Diagram 23] A shows representative MRI images showing YU-1077 tumor growth in the brain over a 2-week period, which was completely suppressed by Compound 1. Visible tumor masses are indicated by arrows. B shows 3D modeling of brain MRI scans to determine tumor volume. Visible tumor masses are highlighted with arrows and patterned fills. Images from individual mice are overlaid. 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.

[0039] [Figure 24] A shows that compound 1 inhibited YU-1077 tumor growth in the brain. Tumor volumes were determined via 3D modeling. Mean ± SEM plotted. Number of mice for each cohort is as indicated, except for the final data point for the alectinib cohort (n=6 instead of n=7). B shows survival analysis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art of this disclosure. The following references provide those skilled in the art with general definitions of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994), The Cambridge Dictionary of Science and Technology (Walker ed., 1988), The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991), and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the following meanings ascribed to them unless otherwise specified.

[0041] In some embodiments, chemical structures are disclosed with their corresponding chemical names. In case of conflict, the chemical structures, not the names, define the meaning.

[0042] As used herein, the terms "comprising" and "including" may be used interchangeably. The terms "comprising" and "including" are interpreted as specifying the presence of a described feature or a referenced component, but do not exclude the presence or addition of one or more features or components, or groups thereof. In addition, the terms "comprising" and "including" are intended to include examples encompassed by the term "consisting of". Thus, the term "consisting of" may be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0043] The term "consisting of" means that the object has at least 90%, 95%, 97%, 98%, or 99% of the recited features or components it comprises. In another embodiment, the term "consisting of" excludes any other features or components from the scope of any succeeding recitation, except those that are not essential to the technical effect being achieved.

[0044] As used herein, unless specifically stated or clear from the context, the term "or" is understood to be inclusive. As used herein, unless specifically stated otherwise or clear from the context, the terms "a," "an," and "the" are understood to be singular or plural. For example, when a compound provided herein is administered to a "patient," this includes administering the compound to an individual patient or a population of patients.

[0045] As used herein, unless otherwise specified, "stereoisomer" refers to various stereoisomeric forms of a compound that contain one or more asymmetric centers or steric hindrance in the structure. In some embodiments, a stereoisomer is an enantiomer, a mixture of enantiomers, an atropisomer, or a tautomer. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers (e.g., atropisomers), or in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, the compounds provided herein may be atropisomers. In certain embodiments, atropisomers are stereoisomers that arise due to rotational hindrance around a single bond, and the energy difference due to steric strain or other contributors results in a sufficiently high rotational hindrance to allow the isolation of individual conformers. Stereoisomers may be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SHTables of Resolving Agents and Optical Resolution sp. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses compounds as individual isomers substantially free of other isomers, or alternatively, as mixtures of various isomers.

[0046] In certain embodiments, the compounds provided herein may be racemic. In certain embodiments, the compounds provided herein may be enriched in one enantiomer. For example, the compounds provided herein may have more than about 30% ee, more than about 40% ee, more than about 50% ee, more than about 60% ee, more than about 70% ee, more than about 80% ee, more than about 90% ee, or even more than about 95% ee. In certain embodiments, the compounds provided herein may have two or more stereocenters. In certain such embodiments, the compounds provided herein may be enriched in one or more diastereomers. For example, the compounds provided herein may have more than about 30% de, more than about 40% de, more than about 50% de, more than about 60% de, more than about 70% de, more than about 80% de, more than about 90% de, or even more than about 95% de.

[0047] In certain embodiments, the therapeutic preparation may be enriched to provide mainly one enantiomer of the compound. An enantiomerically enriched mixture may, for example, contain at least about 60 mole percent of one enantiomer, or more particularly at least about 75, about 90, about 95, or even about 99 mole percent. In certain embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means that the substance in question constitutes, for example, 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% compared to the amount of the other enantiomer in the composition or compound mixture. For example, if a composition or compound mixture contains about 98 grams of a first enantiomer and about 2 grams of a second enantiomer, the composition or compound mixture is said to contain about 98 mole percent of the first enantiomer and only about 2% of the second enantiomer.

[0048] In certain embodiments, therapeutic preparations can be enriched to provide predominantly one diastereomer of a compound. A diastereomerically enriched mixture can contain, for example, at least about 60 mole percent of one diastereomer, or more particularly, at least about 75, about 90, about 95, or even about 99 mole percent.

[0049] In some embodiments, moieties in a compound exist as a mixture of tautomers. A "tautomer" is a structural isomer of a moiety or compound that is readily interconverted with another structural isomer. For example, a pyrazole ring has two tautomers: [ka] The two tautomers differ in the location of the pi bonds and hydrogen atoms. Unless otherwise specified, a tautomer diagram of one of the moieties or compounds includes all possible tautomers.

[0050] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals, e.g., cows, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds, e.g., chickens, ducks, geese, quail, and / or turkeys. In certain embodiments, the subject is a human adult. In certain embodiments, the subject is a human adult at least 40 years of age. In certain embodiments, the subject is a human adult at least 50 years of age. In certain embodiments, the subject is a human adult at least 60 years of age. In certain embodiments, the subject is a human adult at least 70 years of age. In certain embodiments, the subject is a human adult at least 18 years of age or at least 12 years of age. As used herein, unless otherwise specified, a human subject to whom administration of a therapeutic agent (e.g., a compound described herein) is contemplated to treat, prevent, or manage a disease, disorder, or condition, or a symptom thereof, is also referred to as a "patient."

[0051] As used herein, a therapeutic agent that "prevents" a disorder or condition refers to a compound that reduces or delays the onset of a disorder or condition in a statistical sample relative to an untreated control sample, or reduces the severity of one or more symptoms of a disorder or condition relative to an untreated control sample. These effects are also referred to as "prophylactic" effects. Thus, as used herein, unless otherwise specified, the terms "prevention" and "preventing" refer to an approach for obtaining a beneficial or desired result, which includes, but is not limited to, a prophylactic benefit. For prophylactic benefit, a therapeutic agent may be administered to a patient at risk of developing a particular disease or who reports one or more of the physiological symptoms of a disease, even if a diagnosis of the disease may not have been made. In one embodiment, a therapeutic agent is administered prior to clinical signs of an undesired condition (e.g., the subject's disease or other undesired condition) for a prophylactic benefit (e.g., the therapeutic agent protects the subject from developing an undesired condition).

[0052] As used herein, unless otherwise specified, the terms "treatment" and "treating" refer to a curative or palliative procedure. Beneficial or desired clinical results include, but are not limited to, a total or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, attenuation of the extent of the disease, a stabilized (i.e., not worsening) state of the disease, a delay or slowing of disease progression, remission or alleviation of a disease state (e.g., one or more symptoms of a disease), and remission (whether partial or complete). "Treatment" can also mean prolonging survival compared to the expected survival if not receiving treatment. In one embodiment, "treatment" includes administration of a therapeutic agent after the onset of an undesired condition (i.e., intended to attenuate, ameliorate, or stabilize an undesired condition or its side effects that exist).

[0053] As used herein, unless otherwise specified, "cancer" refers to any malignant and / or invasive growth or tumor caused by abnormal cell proliferation, including solid tumors named for the type of cell that forms them, cancer of the blood, bone marrow, or 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, leukemia, lymphoma, and myeloma. Cancer includes, but is not limited to, primary cancers that originate at a particular site in the body, metastatic cancers that have spread to other parts of the body from where it began, recurrence from the original primary cancer after remission, and second primary cancers, which are new primary cancers in people with a history of a previous cancer of a different type than the latter.

[0054] As used herein, unless otherwise specified, "abnormal cell growth" refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth can be benign (not cancerous) or malignant (cancerous). In some embodiments of the methods provided herein, the abnormal cell growth is cancer.

[0055] In some embodiments, the abnormal cell growth is cancer mediated by anaplastic lymphoma kinase (ALK). In some such embodiments, the ALK is genetically modified ALK. In other embodiments, the abnormal cell growth is cancer mediated by ROS1 kinase. In some such embodiments, the ROS1 kinase is genetically modified ROS1 kinase. In some embodiments, the abnormal cell growth is cancer, particularly NSCLC. In some such embodiments, the NSCLC is mediated by ALK or ROS1. In certain embodiments, the cancer is NSCLC mediated by genetically modified ALK or genetically modified ROS1.

[0056] As used herein, unless otherwise indicated, the term "managing" includes preventing the recurrence of a particular disease or disorder in a patient afflicted with the disease or disorder, extending the time that a patient afflicted with the disease or disorder remains in remission, reducing patient mortality, and / or maintaining a reduction in the severity or avoidance of symptoms associated with the disease or condition being managed.

[0057] As used herein, "effective amount" refers to an amount that is sufficient to achieve a desired biological effect.As used herein, "therapeutically effective amount" refers to an amount that is sufficient to achieve a desired therapeutic effect.For example, a therapeutically effective amount can refer to an amount that is sufficient to improve at least one sign or symptom of cancer.

[0058] A "response" to a therapeutic method can include, among others, a decrease in or amelioration of negative symptoms, a decrease in the progression of the disease or its symptoms, an increase in beneficial symptoms or clinical outcomes, a reduction in side effects, stabilization of the disease, or a partial or complete cure of the disease.

[0059] As used herein, unless otherwise indicated, the term "recurrent" refers to a disorder, disease, or condition that has responded (e.g., achieved a complete response) to a previous treatment and has then had a progression. The previous treatment may include one or more lines of therapy.

[0060] As used herein, unless otherwise indicated, the term "resistant" refers to a disorder, disease or condition that has not responded to previous treatment, which may include one or more lines of therapy.

[0061] As used herein, unless otherwise specified, the terms "about" and "approximately" when used in connection with a dose, amount, or weight percentage of a component of a composition or dosage form means a dose, amount, or weight percentage that is recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specific dose, amount, or weight percentage. In certain embodiments, when used in this context, the terms "about" and "approximately" contemplate a dose, amount, or weight percentage that is within 30%, within 20%, within 15%, within 10%, or within 5% of the specific dose, amount, or weight percentage.

[0062] As used herein, unless otherwise specified, the terms "about" and "approximately" when used in reference to a numerical value or range of values ​​provided to characterize a particular solid form, such as a specific temperature or temperature range, such as describing a melting, dehydration, desolvation, or glass transition temperature; mass change, such as mass change as a function of temperature or humidity; solvent or water content, such as solvent or water content in terms of mass or percentage; or peak position, such as peak position in an analysis by IR or Raman spectroscopy or XRPD, indicate that the value or range of values ​​may deviate to an extent that would be considered reasonable by a person skilled in the art, but still describe the particular solid form. For example, in certain embodiments, when used in this context, the terms "about" and "approximately" 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 recited value or range of values. For example, in some embodiments, XRPD peak position values ​​may vary by up to ±0.2 degrees 2θ, while still describing a particular XRPD peak. In one embodiment, XRPD peak position values ​​may vary by up to ±0.1 degrees 2θ. In one embodiment, XRPD peak position values ​​may vary by up to ±0.05 degrees 2θ.

[0063] The term "between" includes the endpoint numbers at both ends of a range. For example, a range described by "from 3 to 5" includes the numbers "3" and "5."

[0064] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissue of a subject without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. 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, deanol, 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, Na, Ca, K, Mg, Zn, or other metal salts.

[0065] Pharmaceutically acceptable acid addition salts may also exist as various solvates, for example with water, methanol, ethanol, dimethylformamide, etc. Also, mixtures of such solvates may be prepared. The source of such solvates may be from the solvent of crystallization, may be inherent in the solvent of preparation or crystallization, or may be exogenous to such solvent.

[0066] Pharmaceutically acceptable anionic salts include, but are not limited to, acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, teoclate, and tosylate.

[0067] As used herein, unless otherwise specified, the term "solid form" and related terms refer to a physical form that is not predominantly in a liquid or gaseous state. Solid forms may be crystalline, amorphous, or a mixture thereof.

[0068] compound In one embodiment, the compound used in the methods provided herein is a compound of the following formula, also referred to as "Compound 1," or a compound of formula (I): [ka] or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof. 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-decaen-22-amine and is described in International Patent Application Publication No. WO2021 / 226269, the entirety of which is 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.

[0069] Unless otherwise specified, when the compounds described herein are provided as their pharma- ceutically acceptable salts, it is to be understood that the amounts by weight refer to the moiety exclusive of the salt moiety (i.e., as Compound 1 free base).

[0070] In one embodiment, Compound 1 (free base) is used in the methods provided herein. In one embodiment, a tautomer of Compound 1 is used in the methods provided herein. In one embodiment, Compound 1 is used in the methods provided herein that is substantially free of the (S)-enantiomer. As used herein, "substantially free" means that the (S)-enantiomer is present in 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 of Compound 1). In one embodiment, Compound 1 is substantially pure and has an enantiomeric purity of at least about 98% (e.g., about 99%, 99.5%, 99.8%, or 99.9%).

[0071] 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 pharma- ceutically acceptable salt of the (S)-enantiomer of Compound 1 is used in the methods provided herein.

[0072] In one embodiment, a racemic mixture of Compound 1 is used in the methods provided herein. In one embodiment, a tautomer of a racemic mixture of Compound 1 is used in the methods provided herein. In one embodiment, a pharma- ceutically acceptable salt of a racemic mixture of Compound 1 is used in the methods provided herein.

[0073] 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. A representative XRPD pattern of Form 2 of Compound 1 is provided in Figure 14.

[0074] In one embodiment, a solid form comprising the free base of Compound 1 used in the methods provided herein is characterized in that one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or all of the XRPD peaks are located at approximately (e.g., ±0.2 degrees 2θ) the following positions as measured using Cu Kα radiation: 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. In one embodiment, the solid form is characterized by at least three of the peaks. In one embodiment, the solid form is characterized by at least five of the peaks. In one embodiment, the solid form is characterized by at least seven of the peaks. In one embodiment, the solid form is characterized by at least nine of the peaks. In one embodiment, the solid form is characterized by at least eleven of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0075] In one embodiment, a solid form comprising the free base of Compound 1 used in the methods provided herein is characterized by an XRPD pattern comprising at least three 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 when measured using Cu Kα radiation. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least four 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. 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.

[0076] In one embodiment, a solid form comprising 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 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.

[0077] In one embodiment, the solid form is characterized by an XRPD pattern that matches the XRPD pattern shown in FIG.

[0078] In one embodiment, the XRPD patterns described herein are obtained using Cu Kα radiation. In one embodiment, the XRPD patterns are obtained using Kα radiation having a wavelength of 1.5406 Å. 1 Radiation and Kα with a wavelength of 1.5444 Å 2 Measured by XRPD using Cu Kα radiation, including Kα 1 :Kα 2 The ratio is 0.5.

[0079] A representative DSC thermogram of Form 2 is provided in Figure 15. In one embodiment, the solid form comprising the free base of Compound 1 used in the methods provided herein exhibits a thermal event (endotherm) as characterized by DSC with an onset temperature of about 260°C (e.g., ±2°). In one embodiment, the thermal event also 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 consistent with the DSC thermogram shown in Figure 15. In one embodiment, the DSC thermogram is as measured by DSC using a scan rate of about 10°C / min.

[0080] A representative DVS isotherm for Form 2 is provided in Figure 16. In one embodiment, a solid form comprising the free base of Compound 1 used 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 consistent with the DVS isotherm shown in Figure 16. In one embodiment, the DVS isotherm is as measured at about 25°C.

[0081] In one embodiment, the solid form comprising the free base of Compound 1 used in the methods provided herein is characterized by unit cell dimensions of approximately a=8.2 Å, b=14.8 Å, c=18.7 Å, α=90°, β=90°, and γ=90°. In one embodiment, Form 2 has unit cell dimensions of approximately a=8.17 Å, b=14.75 Å, c=18.69 Å, α=90°, β=90°, and γ=90°. In one embodiment, Form 2 has unit cell dimensions of approximately a=8.169 Å, b=14.750 Å, c=18.694 Å, α=90°, β=90°, and γ=90°. In one embodiment, Form 2 is characterized by unit cell dimensions of approximately a=8.169 Å, b=14.750 Å, c=18.694 Å, α=90°, β=90°, and γ=90°. 1 2 1 2 1 In one embodiment, Form 2 has a unit cell of about 2252.4 Å. 3 / cell volume. In one embodiment, Form 2 has a Z value of 4. In one embodiment, Form 2 has a Z value of about 1.336 g / cm 3 has a density of

[0082] In one embodiment, the solid form comprising 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 salts of Compound 1. In one embodiment, the solid form is unsolvated. In one embodiment, one or more residual solvents may be present in the solid form, but the residual solvents do not form solvates 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 greater than about 95% chemically pure by weight. In one embodiment, the solid form is greater than about 96% chemically pure by weight. In one embodiment, the solid form is greater than about 97% chemically pure by weight. In one embodiment, the solid form is greater than about 98% chemically pure by weight. In one embodiment, the solid form is greater than about 99% chemically pure by weight. In one embodiment, the solid form is substantially enantiomerically pure. In one embodiment, the solid form is at least about 98% enantiomerically pure. In one embodiment, the solid form is at least about 99% enantiomerically pure. In one embodiment, the solid form is at least about 99.5% enantiomerically pure. In one embodiment, the solid form is substantially physically pure.

[0083] In one embodiment, the solid form comprising the free base of Compound 1 used in the methods provided herein is a solid form comprising Form 2 of the free base of Compound 1.

[0084] How to use In one embodiment, provided herein is a method of treating cancer comprising administering a heteroaromatic macrocyclic ether compound, e.g., Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0085] In one embodiment, provided herein is a method of using a heteroaromatic macrocyclic ether compound (e.g., Compound 1), or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, for treating, preventing, or managing solid tumors.

[0086] In one embodiment, provided herein is a method of treating a subject having a solid tumor, the method comprising administering to the subject a therapeutically effective amount of Compound 1: [ka] or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0087] In one embodiment, the cancer is lung cancer, cholangiocarcinoma, colorectal cancer, angiosarcoma, sarcoma, hemangioendothelioma, esophageal cancer, renal cancer, breast cancer, colon cancer, thyroid cancer, neuroblastoma, hematological 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 spitzoid neoplasm.

[0088] 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 is recurrent after, refractory to, or resistant to previous treatment with a tyrosine kinase inhibitor (TKI). In one embodiment, the solid tumor is a non-small cell lung cancer (NSCLC). In one embodiment, the solid tumor is an advanced NSCLC. In one embodiment, the solid tumor is metastatic. In one embodiment, the solid tumor is a CNS metastatic. In one embodiment, the solid tumor is a metastatic NSCLC. In one embodiment, the solid tumor is a CNS metastatic NSCLC. As used herein, unless otherwise specified, "advanced tumor" refers to either a locally advanced or metastatic tumor that cannot be cured or grows beyond the initial site of origin.

[0089] 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 with an ALK rearrangement or an activating ALK mutation.

[0090] 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, Spitzoid tumor, neuroblastoma, or anaplastic thyroid carcinoma.In certain embodiments, the ALK-positive solid tumor is anaplastic thyroid carcinoma.In one embodiment, the subject has not been treated with previous therapy.In one embodiment, the subject has not been treated with any tyrosine kinase inhibitor (TKI) therapy (i.e., has not been treated).

[0091] 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 second or third 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 anti-cancer therapy. In certain embodiments, the subject with a solid tumor has no satisfactory standard of care. In certain embodiments, the subject with locally advanced or metastatic ALK-positive NSCLC has received one previous second-generation ALK TKI (ceritinib, alectinib, brigatinib, or lorlatinib). In certain embodiments, the subject with locally advanced or metastatic ALK-positive NSCLC has received two to three previous first or second-generation ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib). In certain embodiments, the subject with locally advanced or metastatic ALK-positive NSCLC has received two to three previous ALK TKIs with second or third line lorlatinib.

[0092] In one embodiment, the subject has not been treated with a previous systemic anti-cancer therapy. In one embodiment, the subject has been treated with up to one previous systemic anti-cancer therapy. In one embodiment, the subject has been treated with at least one previous systemic anti-cancer therapy. In one embodiment, the subject has been treated with at least two previous systemic anti-cancer therapies. In one embodiment, the subject has been treated with one previous systemic anti-cancer therapy. In one embodiment, the subject has been treated with two previous systemic anti-cancer therapies.

[0093] In one embodiment, the subject has not been treated with a previous chemotherapy. In one embodiment, the subject has been treated with a previous chemotherapy. In one embodiment, the subject has been treated with up to two previous chemotherapy. In one embodiment, the subject has been treated with at least one previous chemotherapy. In one embodiment, the subject has been treated with at least two previous chemotherapy. In one embodiment, the subject has been treated with one previous chemotherapy. In one embodiment, the subject has been treated with two previous chemotherapy.

[0094] In one embodiment, the subject has not been treated with a previous immunotherapy. In one embodiment, the subject has been treated with a previous immunotherapy. In one embodiment, the subject has been treated with up to two previous immunotherapies. In one embodiment, the subject has been treated with at least one previous immunotherapy. In one embodiment, the subject has been treated with at least two previous immunotherapies. In one embodiment, the subject has been treated with one previous immunotherapy. In one embodiment, the subject has been treated with two previous immunotherapies.

[0095] As used herein, "immunotherapy" refers to the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to induce or amplify immune responses are classified as activating immunotherapies, while immunotherapies that reduce or suppress immune responses are classified as suppressing immunotherapies. Immunotherapies can act by modulating immune effector cells (e.g., lymphocytes, macrophages, dendritic cells, natural killer cells (NK cells), cytotoxic T lymphocytes (CTLs), etc.) to target abnormal antigens expressed on the surface of tumor cells together against cancer. Exemplary immunotherapies include, but are 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 cemiplimab (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).

[0096] In one embodiment, the solid tumor is progressive 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 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 anti-cancer therapies. In one embodiment, the solid tumor is progressive or metastatic ALK-positive NSCLC, and the subject has progressed on previous therapy.

[0097] In one embodiment, the solid tumor is progressive or metastatic ALK-positive NSCLC, and the subject has been treated with one previous ALK TKI therapy. In one embodiment, the 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 at least one previous ALK TKI therapy is crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib. In one embodiment, the subject has been treated with ≦2 previous chemotherapy and / or immunotherapy. In one embodiment, the subject has been treated with more than two previous chemotherapy and / or more than two previous immunotherapy.

[0098] In one embodiment, the solid tumor is advanced or metastatic ALK-positive NSCLC, and the subject has been treated with two or three previous ALK TKI therapies. In one embodiment, the two or three previous ALK TKI therapies are selected from crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In one embodiment, the subject has been treated with ≦2 previous chemotherapy and / or immunotherapy. In one embodiment, the subject has been treated with more than two previous chemotherapy and / or more than two previous immunotherapy.

[0099] In one embodiment, the solid tumor is progressive or metastatic ALK-positive NSCLC and the subject has been treated with two or three previous ALK TKI therapies. In one embodiment, the solid tumor is progressive or metastatic ALK-positive NSCLC and the subject has been treated with one previous ALK TKI therapy, where one ALK TKI is a second or third generation TKI (such as ceritinib, alectinib, brigatinib, or lorlatinib). In one embodiment, the second or third previous ALK TKI therapy is lorlatinib. In one embodiment, the subject has been treated with ≦2 previous chemotherapy and / or immunotherapy. In one embodiment, the subject has been treated with more than two previous chemotherapy and / or more than two previous immunotherapy.

[0100] In one embodiment, the subject has normal renal function. In one embodiment, the subject has a creatinine clearance of about 90 mL / min or more (e.g., by the Cockcroft-Gault formula). In one embodiment, the subject has a creatinine clearance of about 80 mL / min or more (e.g., by the Cockcroft-Gault formula). In one embodiment, the subject has a creatinine clearance of about 60 mL / min or more (e.g., by the Cockcroft-Gault formula).

[0101] In one embodiment, the compound used herein (Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof) is administered once a day (QD). In one embodiment, the compound is administered twice a day (BID). In a particular embodiment, the compound used herein is Compound 1.

[0102] In one embodiment, the compound used herein (Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof) is administered in an amount of about 5 mg to about 400 mg (by weight of free base Compound 1) per day. In one embodiment, the compound is administered in an amount of about 15 mg to about 200 mg per day. In one embodiment, the compound is administered in an amount of about 20 mg to about 200 mg per day. In one embodiment, the compound is administered in an amount of about 25 mg to about 200 mg per day. In one embodiment, the compound is administered in an amount of about 50 mg to about 200 mg per day. In one embodiment, the compound is administered in an amount of about 5 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of about 15 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of about 20 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of about 25 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of about 15 mg to about 125 mg per day. In one embodiment, the compound is administered in an amount of about 20 mg to about 125 mg per day. In one embodiment, the compound is administered in an amount of about 25 mg to about 125 mg per day. In one embodiment, the compound is administered in an amount of about 15 mg to about 100 mg per day. In one embodiment, the compound is administered in an amount of about 20 mg to about 100 mg per day. In one embodiment, the compound is administered in an amount of about 25 mg to about 100 mg per day. In one embodiment, the compound is administered in an amount of about 50 mg to about 250 mg per day. In one embodiment, the compound is administered in an amount of about 50 mg to about 200 mg per day. In one embodiment, the compound is administered in an amount of about 50 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of about 50 mg to about 125 mg per day. In one embodiment, the compound is administered in an amount of about 50 mg to about 100 mg per day. In one embodiment, the compound is administered in an amount of about 10 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of about 10 mg to about 100 mg per day.In one embodiment, the compound is administered in an amount of about 10 mg to about 50 mg per day. In one embodiment, the compound is administered in an amount of about 10 mg to about 25 mg per day. In one embodiment, the compound is administered in an amount of about 15 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of about 15 mg to about 100 mg per day. In one embodiment, the compound is administered in an amount of about 15 mg to about 50 mg per day. In one embodiment, the compound is administered in an amount of about 25 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of about 50 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of about 100 mg to about 150 mg per day.

[0103] 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.

[0104] In one embodiment, the amount is about 5 mg per day. In one embodiment, the amount is about 10 mg per day. In one embodiment, the amount is about 15 mg per day. In one embodiment, the amount is about 20 mg per day. In one embodiment, the amount is about 25 mg per day. In one embodiment, the amount is about 30 mg per day. In one embodiment, the amount is about 35 mg per day. In one embodiment, the amount is about 40 mg per day. In one embodiment, the amount is about 45 mg per day. In one embodiment, the amount is about 50 mg per day. In one embodiment, the amount is about 75 mg per day. In one embodiment, the amount is about 100 mg per day. In one embodiment, the amount is about 125 mg per day. In one embodiment, the amount is about 150 mg per day. In one embodiment, the amount is about 200 mg per day. In one embodiment, the amount is about 250 mg per day. As used herein, weight refers to the weight of free base Compound 1. In certain embodiments, the compound used herein is Compound 1.

[0105] In one embodiment, the compound used herein (Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof) is administered once daily in an amount of about 5 mg to about 400 mg (by weight of free base Compound 1). In one embodiment, the compound is administered once daily in an amount of about 10 mg to about 250 mg. In one embodiment, the compound is administered once daily in an amount of about 15 mg to about 200 mg. In one embodiment, the compound is administered once daily in an amount of about 25 mg to about 200 mg. In one embodiment, the compound is administered once daily in an amount of about 25 mg to about 200 mg. In one embodiment, the compound is administered once daily in an amount of about 50 mg to about 200 mg. In one embodiment, the compound is administered once daily in an amount of about 5 mg to about 150 mg. In one embodiment, the compound is administered once daily in an amount of about 10 mg to about 100 mg. In one embodiment, the compound is administered once daily in an amount of about 10 mg to about 150 mg. In one embodiment, the compound is administered once daily in an amount of about 15 mg to about 150 mg. In one embodiment, the compound is administered once daily in an amount of about 25 mg to about 150 mg. In one embodiment, the compound is administered once daily in an amount of about 50 mg to about 150 mg. In one embodiment, the compound is administered once daily in an amount of about 100 mg to about 150 mg. In one embodiment, the compound is administered once daily in an amount of about 20 mg to about 150 mg. In one embodiment, the compound is administered once daily in an amount of about 25 mg to about 150 mg. In one embodiment, the compound is administered once daily in an amount of about 25 mg to about 100 mg. In one embodiment, the compound is administered once daily in an amount of about 25 mg to about 50 mg. In one embodiment, the compound is administered once daily in an amount of about 25 mg to about 125 mg. In one embodiment, the compound is administered once daily in an amount of about 10 mg to about 100 mg. In one embodiment, the compound is administered once daily in an amount of about 15 mg to about 100 mg. In one embodiment, the compound is administered once daily in an amount of about 15 mg to about 50 mg. In one embodiment, the compound is administered once daily in an amount of about 25 mg to about 100 mg. In one embodiment, the compound is administered once daily in an amount of about 25 mg to about 100 mg.In one embodiment, the compound is administered once daily in an amount of about 50 mg to about 100 mg. In one embodiment, the compound is administered once daily in an amount of about 50 mg to about 125 mg. In one embodiment, the compound is administered once daily in an amount of about 50 mg to about 100 mg. 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 daily. In one embodiment, the amount is about 15 mg once daily. In one embodiment, the amount is about 20 mg once daily. In one embodiment, the amount is about 25 mg once daily. In one embodiment, the amount is about 30 mg once daily. In one embodiment, the amount is about 35 mg once daily. In one embodiment, the amount is about 40 mg once daily. In one embodiment, the amount is about 45 mg once daily. In one embodiment, the amount is about 50 mg once daily. In one embodiment, the amount is about 75 mg once daily. In one embodiment, the amount is about 100 mg once daily. In one embodiment, the amount is about 125 mg once daily. In one embodiment, the amount is about 150 mg once daily. In one embodiment, the amount is about 200 mg once daily. In one embodiment, the amount is about 250 mg once daily. As used herein, weight amount refers to the weight amount of free base Compound 1. In certain embodiments, the compound used herein is Compound 1.

[0106] In one embodiment, the compound used herein (Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof) is administered twice daily in an amount of about 5 mg to about 400 mg (by weight of free base Compound 1). In one embodiment, the compound is administered twice daily in an amount of about 5 mg to about 250 mg. In one embodiment, the compound is administered twice daily in an amount of about 15 mg to about 250 mg. In one embodiment, the compound is administered twice daily in an amount of about 25 mg to about 250 mg. In one embodiment, the compound is administered twice daily in an amount of about 15 mg to about 200 mg. In one embodiment, the compound is administered twice daily in an amount of about 10 mg to about 150 mg. In one embodiment, the compound is administered twice daily in an amount of about 10 mg to about 100 mg. In one embodiment, the compound is administered twice daily in an amount of about 20 mg to about 200 mg. In one embodiment, the compound is administered twice daily in an amount of about 25 mg to about 200 mg. In one embodiment, the compound is administered twice daily in an amount of about 5 mg to about 100 mg. In one embodiment, the compound is administered twice daily in an amount of about 15 mg to about 100 mg. In one embodiment, the compound is administered twice daily in an amount of about 10 mg to about 50 mg. In one embodiment, the compound is administered twice daily in an amount of about 15 mg to about 50 mg. In one embodiment, the compound is administered twice daily in an amount of about 10 mg to about 100 mg. In one embodiment, the compound is administered twice daily in an amount of about 25 mg to about 100 mg. In one embodiment, the compound is administered twice daily in an amount of about 50 mg to about 100 mg. In one embodiment, the compound is administered twice daily in an amount of about 5 mg to about 150 mg. In one embodiment, the compound is administered twice daily in an amount of about 10 mg to about 150 mg. In one embodiment, the compound is administered in an amount of about 15 mg to about 150 mg twice daily. In one embodiment, the compound is administered in an amount of about 20 mg to about 150 mg twice daily. In one embodiment, the compound is administered in an amount of about 25 mg to about 150 mg twice daily.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 daily. In one embodiment, the amount is about 5 mg twice daily. In one embodiment, the amount is about 10 mg twice daily. In one embodiment, the amount is about 15 mg twice daily. In one embodiment, the amount is about 20 mg twice daily. In one embodiment, the amount is about 25 mg twice daily. In one embodiment, the amount is about 30 mg twice daily. In one embodiment, the amount is about 35 mg twice daily. In one embodiment, the amount is about 40 mg twice daily. In one embodiment, the amount is about 45 mg twice daily. In one embodiment, the amount is about 50 mg twice daily. In one embodiment, the amount is about 75 mg twice daily. In one embodiment, the amount is about 100 mg twice daily. In one embodiment, the amount is about 125 mg twice daily. In one embodiment, the amount is about 150 mg twice daily. In one embodiment, the amount is about 200 mg twice daily. In one embodiment, the amount is about 250 mg twice daily. As used herein, weight amount refers to the weight amount of free base Compound 1. In certain embodiments, the compound used herein is Compound 1.

[0107] In one embodiment, the compound is administered orally.

[0108] In one embodiment, the compound is administered in the form of one or more tablets. In one embodiment, the tablet has a unit dose strength of about 5 mg by weight of free base Compound 1. In one embodiment, the tablet has a unit dose strength of about 50 mg by weight of free base Compound 1. In one embodiment, the tablet has a unit dose strength of about 75 mg by weight of free base Compound 1. In one embodiment, the tablet has a unit dose strength of about 100 mg by weight of free base Compound 1. In one embodiment, the tablet has a unit dose strength of about 125 mg by weight of free base Compound 1. In one embodiment, the tablet has a unit dose strength of about 150 mg by weight of free base Compound 1.

[0109] In one embodiment, the compound is administered to a subject with hunger. In one embodiment, the compound is administered to a subject at least 1 hour before and 2 hours or more after the intake of food and / or beverages other than water. In one embodiment, the compound is administered to a subject with a full stomach. In one embodiment, the compound is administered with the intake of food and / or beverages.

[0110] In one embodiment, the subject experiences improvement in one or more symptoms selected from the group consisting of cognitive impairment, mood disorder, sleep disorder, dizziness, ataxia, seizures, psychotic effects, speech disorder, and weight gain after administration of Compound 1 (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 disorder, sleep disorder, dizziness, ataxia, seizures, psychotic effects, speech disorder, and weight gain after administration of the compound. In one embodiment, the subject experiences reduced levels of one or more of pALK, pERK, pAKT, and phospho-S6 after administration of the compound. In one embodiment, the subject experiences reduced levels of pALK after administration of the compound. In one embodiment, the subject experiences reduced levels of pERK after administration of the compound. In one embodiment, the subject experiences reduced levels of pAKT after administration of the compound. In one embodiment, the subject experiences reduced levels of phospho-S6 after administration of the compound. In one embodiment, the subject experiences increased levels of cleaved PARP after administration of the compound. In one embodiment, the subject experiences reduced 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 reduced 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 reduced activity of the MAP kinase pathway in the tumor after administration of the compound. In one embodiment, the subject experiences reduced activity of the MAP kinase pathway in the solid tumor after administration of the compound. In one embodiment, the subject experiences reduced activity of the PI3K / AKT pathway in the tumor after administration of the compound. In one embodiment, the subject experiences reduced activity of the PI3K / AKT pathway in the solid tumor after administration of the compound. In one embodiment, the subject experiences reduced activity of the JAK / STAT pathway in the tumor after administration of the compound.In one embodiment, the subject experiences reduced activity of the JAK / STAT pathway in solid tumors after administration of the compound. In one embodiment, the subject experiences increased expression levels of one or more markers of apoptosis in tumors after administration of the compound. In one embodiment, the subject experiences increased expression levels of one or more markers of apoptosis in solid tumors after administration of the compound. In one embodiment, the subject experiences reduced levels of one or more markers of proliferation (e.g., Ki 67) in tumors after administration of the compound. In one embodiment, the change in the level of one or more markers provided herein is experienced 1 hour after administration of the compound. In one embodiment, the change in the level of one or more markers provided herein is experienced 12 hours after administration of the compound.

[0111] In some embodiments, cancer is a disease of uncontrolled cell proliferation resulting from alterations in certain genes. Some of these alterations occur in genes that code for receptor tyrosine kinases (RTKs), a family of 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 and thus cancer. In general, RTKs contain an N-terminal domain that binds to extracellular ligands, a transmembrane domain, and a C-terminal kinase domain that catalyzes intracellular signal transduction.

[0112] In some embodiments, compound 1 is an inhibitor of human anaplastic lymphoma kinase (ALK). ALK, also known as cluster of differentiation 246 (CD246), is a RTK encoded by the ALK gene. ALK and ROS1 are evolutionarily related, both belong to the insulin receptor superfamily, and their kinase domains share about 80% sequence similarity. Several ALK ligands in humans have been identified, including pleiotrophin and midkine growth factor. Although the role of ALK in humans is inconclusive, mounting evidence from mouse studies suggests that it is important for nervous system development. Similar to ROS1, ALK chromosomal rearrangements also result in constitutively active fusion proteins that promote oncogenic transformation via MAPK, JAK / STAT, or other signaling pathways. ALK rearrangements represent 3-5% of NSCLC, about half of anaplastic large cell lymphoma (ALCL), and a subset of many other cancers, with the predominant fusions being EML4-ALK for NSCLC and NPM1-ALK for ALCL. Oncogenic point mutations and amplifications of ALK 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, either as frontline therapy or after prior therapy. Crizotinib, for example, has shown 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. Despite initial responses, many resistance mutations have emerged in the aforementioned FDA-approved TKIs. Some of these mutations, such as the L1196M gatekeeper and G1202R solvent front mutations in combination, are resistant to all approved drugs. New treatments for ALK-positive cancers with resistance mutations are needed in the art.

[0113] In one embodiment, the compounds provided herein selectively inhibit ALK. In one embodiment, the compounds selectively inhibit ALK over ROS1. As a non-limiting example, the selectivity ratio can be greater than about 1.5-fold, greater than about 2-fold, greater than about 3-fold, greater than about 4-fold, greater than about 5-fold, or greater than about 10-fold, and selectivity can be measured by the ratio of IC50 values, among other means. In one embodiment, the selectivity of ALK over ROS1 is measured by the ratio of IC50 value for ROS1 to IC50 value for ALK.

[0114] In one embodiment, the compound selectively inhibits ALK over TRK (e.g., TRKA, TRKB, and / or TRBC). As a non-limiting example, the selectivity ratio can be greater than about 5-fold, greater than about 10-fold, greater than about 50-fold, greater than about 100-fold, greater than about 200-fold, greater than about 400-fold, greater than about 600-fold, greater than about 800-fold, greater than about 1000-fold, greater than about 1500-fold, greater than about 2000-fold, greater than about 5000-fold, or greater than about 10,000-fold, and selectivity can be measured by the ratio of IC50 values, among other means. In one embodiment, the selectivity of ALK over TRK is measured by the ratio of IC50 values ​​for TRK to IC50 values ​​for ALK.

[0115] In one embodiment, provided herein is a method for selectively inhibiting ALK over ROS1, where the inhibition occurs in a cell. In one embodiment, provided herein is a method for selectively inhibiting ALK over TRK (e.g., TRKA, TRKB and / or TRBC), where the inhibition occurs in a cell. In one embodiment, the method comprises contacting ALK with an effective amount of a compound provided herein. In one embodiment, such contacting occurs in a cell. In one embodiment, such contacting occurs in a cell in a mammal, e.g., a human. In one embodiment, such contacting occurs in a cell in a human subject with cancer provided herein.

[0116] In one embodiment, provided herein is a method for selectively inhibiting ALK over ROS1, wherein the inhibition occurs in a subject suffering from 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 for treating a subject suffering from a cancer associated with ALK, the method comprising selectively inhibiting ALK over ROS1 by administering to the subject an amount of a compound or pharmaceutical composition provided herein, the amount being sufficient to selectively inhibit ALK over ROS1.

[0117] In one embodiment, provided herein is a method for selectively inhibiting ALK over TRK (e.g., TRKA, TRKB, and / or TRBC), wherein the inhibition occurs in a subject suffering from 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 for treating a subject suffering from a cancer associated with ALK, the method comprising selectively inhibiting ALK over TRK (e.g., TRKA, TRKB, and / or TRBC) by administering to the subject an amount of a compound or pharmaceutical composition provided herein, the amount being sufficient to selectively inhibit ALK over TRK (e.g., TRKA, TRKB, and / or TRBC).

[0118] As used herein, unless otherwise specified, inhibition of ALK includes inhibition of wild-type ALK, or genetically altered ALK, such as a mutation, rearrangement, or amplification or copy gain thereof, or a partially deleted ALK protein.

[0119] Cancers that may be 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, cholangiocarcinoma, 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.

[0120] In one embodiment, the cancer treated by the method of the present disclosure includes cancer originating from one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB, and TRKC. In certain embodiments, the cancer treated by the method of the present disclosure includes cancer that is drug resistant to treatments directed against one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB, and TRKC.

[0121] In one embodiment, the cancer in the methods provided herein is anaplastic lymphoma kinase positive (ALK+). As used herein, unless otherwise specified, "ALK positive" (ALK+) cancer, disease or disorder refers to a cancer, disease or disorder characterized by inappropriate (e.g., inappropriately high) expression of the ALK gene and / or the presence of a mutation in the ALK gene and / or the presence of a partially deleted ALK protein and / or a mutation in the ALK protein and / or mediated by ALK and / or responsive to inhibition of ALK. In one embodiment, "ALK positive" (ALK+) cancer, disease or disorder refers to a cancer, disease or disorder characterized by inappropriately high expression of the ALK gene and / or the presence of a mutation in the ALK gene or mediated by ALK. In one embodiment, "ALK positive" (ALK+) cancer, disease or disorder refers to a cancer, disease or disorder 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 disorder carries an ALK wild-type gene or a genetically altered ALK gene. In one embodiment, the "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 one or more of the following amino acids: G1202R, G1202K, L1196M, G1269A, G1269V, C1156Y, I1171T, I1171N, I1171S, F1174I, F1174L, F1174S, V1180L, S1206Y, E1129K, E1210K, T1151M, T1151_L1152insT, F1152 ... and at least one mutation selected from the group consisting of 1174C, G1202del, D1203N, S1206C, S1206F, L1152R, L1196Q, L1198P, L1198F, L1198H, R1275Q, L1152P, C1156T, F1245C, T1151K, I1268V, F1174V, L1198Q, S1206A, and F1245V.

[0122] In one embodiment, the "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 the NPM gene. In some embodiments, the genetically modified 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 modified ALK is a TPR-ALK fusion protein. In some embodiments, the TPR-ALK fusion protein comprises 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 a L1196M mutation.

[0123] In one embodiment, the mutation alters the biological activity of the ALK nucleic acid molecule or polypeptide. As used herein, unless otherwise specified, an ALK "mutation" or "mutant" includes one or more deletions, substitutions, insertions, inversions, duplications, translocations, amplifications, or missense mutations in the amino acid or nucleotide sequence of ALK, or fragments thereof. As used herein, unless otherwise specified, an ALK "rearrangement" refers to a genetic translocation involving the ALK gene, which may result in an ALK fusion gene and / or ALK fusion protein. An ALK fusion may also include one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications, or fragments thereof, so long as the mutant retains kinase phosphorylation activity.

[0124] In some embodiments, provided herein is a method for treating cancer in a subject, the method comprising identifying genetically altered ALK in the subject and administering to the subject a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof.

[0125] In one embodiment, the ALK mutation comprises one or more ALK point mutations. In some embodiments, the cancer treated by the methods of the present disclosure comprises one or more mutations in 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 one embodiment, the one or more ALK point mutations are G1202R, G1202K, L1196M, G1269A, G1269V, C1156Y, I1171T, I1171N, I1171S, F1174I, F1174L, F1174S, V1180L, S1206Y, E1129K, E1210K, T1151M, T1151_L1152insT, The ALK mutation is selected from 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.

[0126] As used herein, unless otherwise specified, "comutation" refers to coexisting mutations, i.e., two or more mutations occurring simultaneously, e.g., within the same cell and on the same allele, within the same cell but on different alleles, or in different cells.

[0127] As used herein, unless otherwise specified, "compound mutation" refers to two or more mutations located on the same allele. Compound mutation is a subset of co-mutation. Compound mutation is sometimes also referred to as double mutation when there are two mutations located on the same allele.

[0128] 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 with 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 with 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.

[0129] 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.

[0130] 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 entirety of which is incorporated herein by reference. In one embodiment, the ALK fusion is EML4, TFG, KIF5B, KLC1, STRN, HIP1, TPR, BIRC6, DCTN1, SQSTM1, SOCS5, SEC31A, CLTC, PRKAR1A, PPM1B, EIF2AK3, CRIM1, CEBPZ, PICALM, CLIP1, BCL11A, GCC2, LMO7, PHACTR 1, CMTR1, VIT, DYSF, ITGAV, PLEKHA7, CUX1, VKORC1L1, FBXO36, SPTBN1, EML6, FBXO11, CLIP4, CA MKMT, NCOA1, MYT1L, SRBD1, SRD5A2, NYAP2, MPRIP, ADAM17, ALK, LPIN1, WDPCP, CEP55, ERC1, SLC1 and one of the fusion partners selected from the group consisting of 6A7, 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, TUBBB, SMPD4, SORCS1, LINC00211, SOS1, C9orf3, CYBRD1, MTA3, THADA, TSPYL6, WDR37 and PLEKHH2.In one embodiment, 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. In one embodiment, the ALK mutation is EML4-ALK, which is a fusion between the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK tyrosine kinase domain. There are many variants of EML4-ALK that differ by breakpoint junctions, with variant 1 (v1) and variant 3 (v3) being the most frequent clinically. In one embodiment, the ALK mutation is NPM1-ALK. In one embodiment, the ALK mutation is STRN-ALK.

[0131] In one embodiment, the ALK mutation comprises 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 (variants 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.

[0132] In one embodiment, an 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.

[0133] In one embodiment, a partially deleted ALK protein affects the proliferation and metastatic properties of cancer cells. ALK protein can be partially deleted through various mechanisms. The first mechanism is shedding, in which the 80 kDa extracellular domain of the ALK protein is post-translationally cleaved near residue Asn654, leaving the 140 kDa C-terminal transmembrane domain and the intracellular domain on the cell. Shedding has been observed in many ALK-expressing cell lines, especially from neuroblastoma disease backgrounds. Shedding increases cancer cell migration and proliferation in preclinical models of cancer both in vitro and in vivo (Moog-Lutz, JBC (2005), Huang, Cell Reports (2021)). The second mechanism is alternative transcription initiation (ATI), in which transcription of the ALK gene initiates at an alternative initiation site downstream of the original site, resulting in the absence of exons 1-18 and part of exon 19. ALK ATI has been identified in 11% of melanomas and a small proportion of lung and anaplastic thyroid cancers. Expression of ALK ATI transforms Ba / F3 and NIH3T3 cells, endowing them with oncogenic potential. One patient with ALK ATI showed a clinical response to ALK inhibitor therapy, suggesting that ALK ATI may be a targetable driving mutation (Wiesner, Nature (2015)). The third mechanism is partial deletion of the ALK gene, for example, via chromosomal rearrangement events. Multiple deletion variants have been identified, including deletions of exons 2-3, 1-5, 4-11, and 2-17, and some of these variants have been shown to activate ALK signaling and transform Ba / F3 or NIH3T3 cells. ALK partial deletions 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)).

[0134] In one embodiment, ALK+ cancer is determined by an FDA approved test or other test known in the art. Tests that may be used include, for example, FoundationOne CDx™ (F1CDx) (a sequencing-based in vitro diagnostic device for the detection of substitution, insertion, and deletion alterations (indels), as well as copy number alterations (CNAs) and selected gene rearrangements, and genomic signatures including microsatellite instability (MSI) and tumor mutation 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 BenchMark XT or BenchMark ULTRA automated stainers); and Vysis ALK Break Apart FISH Probe Examples of suitable ALK Break Apart FISH Probe Kit test include, but are not limited to, a qualitative test for detecting rearrangements involving the ALK gene via fluorescent in situ hybridization (FISH) in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens. In one embodiment, the test is a fluorescent in situ hybridization (FISH) test, such as the Vysis ALK Break Apart FISH Probe Kit test. Additional information on FDA approved tests can be found, for example, at https: / / www.fda.gov / MedicalDevices / ProductsandMedicalProcedures / InVitroDiagnostics / ucm303030.htm, and additional information on the Vysis ALK Break Apart FISH Probe Kit can be found, for example, at https: / / www.molecular.abbott / us / en / products / oncology / vysis-alk-break-apart-fish-probe-kit, the entire contents of which are incorporated herein by reference.

[0135] In one embodiment of any of the methods described herein, the presence of an ALK mutation in the sample indicates that the subject is at risk or has an increased risk of developing an ALK-positive (e.g., ALK-driven) cancer. In other embodiments, the presence of a mutation in the sample indicates that the subject is at risk or has an increased risk of developing an ALK-positive (e.g., ALK-driven) cancer that is resistant to treatment with a TKI. In certain embodiments, the presence of a mutation in the sample indicates that the subject is at risk or has an increased risk of developing an ALK-positive (e.g., ALK-driven) cancer that is resistant to one or more of the following treatments: crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, and ASP3026. In certain embodiments, the presence of a mutation in the sample indicates that the subject is at risk or has an increased risk of developing an ALK-positive (e.g., ALK-driven) cancer that is resistant to one or more of the following treatments: crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In some embodiments, the ALK protein or ALK fusion protein comprises a contiguous sequence of 30 to 1620 amino acids having at least 95% identity with the amino acid sequence of ALK [Homo sapiens] (NCBI Reference Sequence: NP_004295.2 or UniProt SEQ ID NO: Q9UM73 sequence). In another non-limiting embodiment, the ALK protein or ALK fusion protein comprises a contiguous sequence of 30 to 1620 amino acids having at least about 85% identity with the amino acid sequence of ALK [Homo sapiens] (NCBI Reference Sequence: NP_004295.2 or UniProt SEQ ID NO: Q9UM73 sequence). In another non-limiting embodiment, the ALK protein or ALK fusion protein comprises a contiguous sequence of 30 to 1620 amino acids having at least about 90% identity with the amino acid sequence of ALK [Homo sapiens] (NCBI Reference Sequence: NP_004295.2 or UniProt SEQ ID NO: Q9UM73 sequence).In another non-limiting embodiment, the ALK protein or ALK fusion protein comprises a contiguous sequence of 30-1620 amino acids having at least about 95% identity to the amino acid sequence of ALK [Homo sapiens] (NCBI Reference Sequence: NP_004295.2 or UniProt SEQ ID NO: Q9UM73 sequence). In another non-limiting embodiment, the ALK protein or ALK fusion protein comprises a contiguous sequence of 30-1620 amino acids having at least about 85-90%, 91%-93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of ALK [Homo sapiens] (NCBI Reference Sequence: NP_004295.2 or UniProt SEQ ID NO: Q9UM73 sequence).

[0136] Also provided herein is a method of treating a subject with cancer (e.g., ALK-positive cancer), comprising: determining whether cancer cells in a sample obtained from a subject with cancer and previously administered a first ALK inhibitor have one or more ALK inhibitor-resistant mutations; and if the subject has cancer cells with one or more ALK inhibitor-resistant mutations, administering to the subject Compound 1 (e.g., Form 2) or a pharma- ceutically acceptable salt thereof, either as monotherapy or in combination with another anti-cancer agent. In some embodiments, the one or more ALK inhibitor-resistant mutations confer increased resistance to treatment with the first ALK inhibitor to the cancer cells or tumor. In some embodiments, the one or more ALK inhibitor-resistant mutations include one or more ALK inhibitor-resistant mutations. For example, the one or more ALK inhibitor resistance mutations may be 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, e.g., G1202R, L1196M, G1269A, C1156Y, I1171T, I117 1N, 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, the other anti-cancer agent is any anti-cancer agent known in the art. For example, the other anti-cancer agent can be another ALK inhibitor (e.g., a second ALK inhibitor).

[0137] In one embodiment, the compound provided herein is a CNS penetrating compound.In one embodiment, after an effective amount of the compound provided herein is administered (for example, orally or intravenously), the compound can penetrate the CNS (for example, the blood-brain barrier) and achieve a concentration in the CNS (for example, the brain) that is still sufficient to inhibit (for example, selectively inhibit) ALK.

[0138] In one embodiment, a method for treating CNS metastasis of cancer is provided herein, comprising administering to a subject in need thereof an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof. In one embodiment, the CNS metastasis is brain metastasis. In one embodiment, the cancer is an ALK+ cancer.

[0139] In one embodiment, the solid tumor (or cancer) is leukocyte receptor tyrosine kinase (LTK) positive. In one embodiment, the solid tumor is LTK positive invasive ductal breast 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 an LTK mutation. In one embodiment, the LTK mutation is G269A, F218I, N257T, A13fs or A214fs. In one embodiment, the solid tumor (or cancer) has an 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-small cell 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 by reference in their entirety.

[0140] In one embodiment, the compound is an inhibitor of human tropomyosin receptor kinase A, B, or C. In certain embodiments, the IC50 of the compound for inhibition of mutant or non-mutated ALK is at least 5-fold lower than the IC50 of the compound for inhibition of wild-type tropomyosin receptor kinase A, B, or C. TRK inhibition, particularly in the central nervous system (CNS), is associated with adverse reactions including dizziness / ataxia / gait disturbance, paresthesia, weight gain, and cognitive changes.

[0141] In some embodiments, a method of minimizing adverse events in a subject in need of treatment for cancer (e.g., ALK-positive cancer) is provided, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, the method minimizing adverse events associated with a TRK inhibitor. In some embodiments, the cancer is an ALK-associated (or ALK+) cancer. In some embodiments, the adverse event is a TRK-associated CNS adverse event.

[0142] As used herein, "minimizing" an adverse event refers to a reduction in the incidence of an adverse event in a subject or patient population compared to the paradigm incidence of the adverse event in a subject or patient population treated with a TRK inhibitor (e.g., entrectinib, repotrectinib, or lorlatinib). In some embodiments, the incidence of an adverse event refers to the frequency or percentage of a specific adverse event across a subject or patient population. In some embodiments, the incidence of an adverse event refers to the total number of adverse events experienced by an individual subject. In some embodiments, minimizing an adverse event refers to minimizing a TRK-related CNS adverse event. In some embodiments, minimizing a TRK-related CNS adverse event means that less than 40% of a patient population has a TRK-related CNS adverse event. In some embodiments, minimizing a TRK-related CNS adverse event means that less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5% of a patient population has a TRK-related CNS adverse event. In some embodiments, minimizing TRK-related CNS adverse events means that less than 12% of the patient population has two or more TRK-related CNS adverse events. In some embodiments, minimizing TRK-related CNS adverse events means that 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 two or more TRK-related CNS adverse events.

[0143] In some embodiments, a TRK-related CNS adverse event refers to one or more of the following: dizziness, ataxia, gait disturbance, paresthesias, weight gain, overeating, paresthesias, abnormal movements, cognitive changes, speech effects (e.g., dysarthria, slow speech or speech disorder), mood disorders (e.g., irritability, anxiety, depression, emotional lability, personality changes, mood swings, affective disorders, aggression, agitation, mood changes, depressed mood, euphoric mood or mania), and cognitive disorders (e.g., memory impairment, cognitive impairment, amnesia, confusion, attention disorder, delirium, mental impairment, attention deficit hyperactivity disorder, dementia, sleep disorder or dyslexia).

[0144] In one embodiment, provided herein is a method for preventing or limiting TRK-related CNS side effects or adverse events in cancer treatment, the method comprising administering to a subject in need thereof an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof. In one embodiment, the method prevents the occurrence of a TRK-related CNS adverse event. In one embodiment, the method limits the frequency of occurrence of a TRK-related CNS adverse event. In one embodiment, the method limits the severity of a TRK-related side effect. In one embodiment, provided herein is a method for treating CNS metastasis of cancer with reduced TRK-related side effects, the method comprising administering to a subject in need thereof an effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof. In one embodiment, the reduction / limitation / prevention in CNS side effects or adverse events is determined in a statistical sample compared to standard of care, e.g., an approved ALK inhibitor for ALK+ cancer (e.g., crizotinib, entrectinib, lorlatinib, or repotrectinib). In one embodiment, the TRK-related side effect is a TRKB-related CNS side effect. In one embodiment, the TRK-related CNS side effect or adverse event is dizziness, ataxia, gait disturbance, paresthesia, weight gain, cognitive impairment, mood disorder, or sleep disorder.

[0145] In one embodiment, provided herein is a method for treating cancer, the method 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 pharma- ceutically acceptable salt thereof. In one embodiment, the cancer is an ALK-mediated cancer. In one embodiment, the cancer is an ALK-associated cancer. In one embodiment, the cancer is an ALK+ cancer. In one embodiment, the cancer is identified as ALK+.

[0146] In one embodiment, provided herein is a method for treating ALK+ cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1 (e.g., Form 2) or a pharma- ceutical acceptable salt thereof.

[0147] In one embodiment, provided herein is a method for treating cancer in a subject, the method comprising: (i) identifying that the cancer in the subject is ALK+; and (ii) administering to the subject a therapeutically effective amount of Compound 1 (e.g., Form 2) or a pharmaceutically acceptable salt thereof.

[0148] 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), cholangiocarcinoma, e.g., cholangiocarcinoma, ovarian cancer, e.g., serous ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, e.g., spitzoid 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, spitzoid 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, pediatric renal cell carcinoma, breast cancer, ER. + Breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian carcinoma, gastric adenocarcinoma, colorectal carcinoma, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, spitzoid neoplasm, sarcoma, astrocytoma, low-grade glioma of the brain, secretory breast carcinoma, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, cutaneous melanoma of the skin, squamous cell carcinoma of the head and neck, childhood glioma CML, prostate cancer, squamous cell carcinoma of the lung, ovarian serous cystadenocarcinoma, cutaneous melanoma of the skin, castration-resistant prostate cancer, Hodgkin's lymphoma, and serous and clear cell endometrial carcinoma.

[0149] 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 recurrent or resistant non-small cell lung cancer. In one embodiment, the cancer is recurrent or resistant 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.

[0150] In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is recurrent or resistant glioblastoma. In one embodiment, the cancer is recurrent or resistant ALK+ glioblastoma. In one embodiment, the cancer is newly diagnosed glioblastoma. In one embodiment, the cancer is newly diagnosed ALK+ glioblastoma.

[0151] In one embodiment, the cancer is IMT. In one embodiment, the cancer is ALK+ IMT. In one embodiment, the cancer is recurrent or resistant IMT. In one embodiment, the cancer is recurrent or resistant ALK+ IMT. In one embodiment, the cancer is newly diagnosed IMT. In one embodiment, the cancer is newly diagnosed ALK+ IMT.

[0152] 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 resistant cholangiocarcinoma. In one embodiment, the cancer is recurrent or resistant 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 is progressing on alectinib treatment. In one embodiment, the cholangiocarcinoma patient has acquired a G1202R resistance mutation.

[0153] 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 resistant ovarian cancer. In one embodiment, the cancer is recurrent or resistant 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.

[0154] 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 resistant gastric cancer. In one embodiment, the cancer is recurrent or resistant ALK+ gastric cancer. In one embodiment, the cancer is newly diagnosed gastric cancer. In one embodiment, the cancer is newly diagnosed ALK+ gastric cancer.

[0155] 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 resistant colorectal cancer. In one embodiment, the cancer is recurrent or resistant ALK+ colorectal cancer. In one embodiment, the cancer is newly diagnosed colorectal cancer. In one embodiment, the cancer is newly diagnosed ALK+ colorectal cancer.

[0156] 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 newly diagnosed angiosarcoma. In one embodiment, the cancer is newly diagnosed ALK+ angiosarcoma.

[0157] 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 sarcoma, and uterine leiomyosarcoma.

[0158] In one embodiment, the cancer is melanoma. In one embodiment, the cancer is a spitzoid tumor. In one embodiment, the cancer is spitzoid melanoma. In one embodiment, the cancer is ALK+ spitzoid melanoma. In one embodiment, the cancer is recurrent or resistant spitzoid melanoma. In one embodiment, the cancer is recurrent or resistant ALK+ spitzoid melanoma. In one embodiment, the cancer is newly diagnosed spitzoid melanoma. In one embodiment, the cancer is newly diagnosed ALK+ spitzoid melanoma.

[0159] In one embodiment, the cancer is epithelioid hemangioendothelioma. In one embodiment, the cancer is ALK+ epithelioid hemangioendothelioma. In one embodiment, the cancer is recurrent or refractory epithelioid hemangioendothelioma. In one embodiment, the cancer is recurrent 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.

[0160] 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 resistant ESCC. In one embodiment, the cancer is recurrent or resistant ALK+ ESCC. In one embodiment, the cancer is newly diagnosed ESCC. In one embodiment, the cancer is newly diagnosed ALK+ ESCC.

[0161] In one embodiment, the cancer is kidney cancer. In one embodiment, the cancer is renal medullary cancer. In one embodiment, the cancer is ALK+ renal medullary cancer. In one embodiment, the cancer is recurrent or resistant renal medullary cancer. In one embodiment, the cancer is recurrent or resistant ALK+ renal medullary cancer. In one embodiment, the cancer is newly diagnosed renal medullary cancer. In one embodiment, the cancer is newly diagnosed ALK+ renal medullary cancer. 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 resistant renal cell carcinoma. In one embodiment, the cancer is recurrent or resistant 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.

[0162] In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is ALK+ breast cancer. In one embodiment, the cancer is recurrent or resistant breast cancer. In one embodiment, the cancer is recurrent or resistant 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.

[0163] 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 resistant colon cancer. In one embodiment, the cancer is recurrent or resistant ALK+ colon cancer. In one embodiment, the cancer is newly diagnosed colon cancer. In one embodiment, the cancer is newly diagnosed ALK+ colon cancer.

[0164] 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.

[0165] 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 resistant glioma. In one embodiment, the cancer is a recurrent or resistant 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 resistant glioma. In one embodiment, the cancer is a recurrent or resistant 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 resistant neuroblastoma. In one embodiment, the cancer is a recurrent or resistant ALK+ neuroblastoma. In one embodiment, the cancer is a newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ALK+ neuroblastoma.

[0166] In one embodiment, the cancer is ALK+ pancreatic cancer. In one embodiment, the cancer is recurrent or resistant pancreatic cancer. In one embodiment, the cancer is recurrent or resistant ALK+ pancreatic cancer. In one embodiment, the cancer is newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ALK+ pancreatic cancer.

[0167] In one embodiment, the cancer is ALK+ inflammatory hepatocellular adenoma. In one embodiment, the cancer is recurrent or resistant inflammatory hepatocellular adenoma. In one embodiment, the cancer is recurrent or resistant 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.

[0168] In one embodiment, the cancer is a hematological cancer. In one embodiment, the cancer is an ALK+ hematological cancer.

[0169] In one embodiment, the cancer is ALK+ lymphoma. In one embodiment, the lymphoma is non-Hodgkin's lymphoma. In one embodiment, the lymphoma is ALK+ non-Hodgkin's lymphoma. In one embodiment, the lymphoma is ALK+ anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL) or large B-cell lymphoma.

[0170] In one embodiment, the cancer is ALCL. In one embodiment, the cancer is ALK+ALCL. In one embodiment, the cancer is recurrent or resistant ALCL. In one embodiment, the cancer is recurrent or resistant ALK+ALCL. In one embodiment, the cancer is recurrent or resistant ALK+ALCL. In one embodiment, the cancer is newly diagnosed ALCL. In one embodiment, the cancer is newly diagnosed ALK+ALCL.

[0171] In one embodiment, the cancer is DLBCL. In one embodiment, the cancer is ALK+ DLBCL. In one embodiment, the cancer is recurrent or resistant DLBCL. In one embodiment, the cancer is recurrent or resistant ALK+ DLBCL. In one embodiment, the cancer is newly diagnosed DLBCL. In one embodiment, the cancer is newly diagnosed ALK+ DLBCL.

[0172] In one embodiment, the cancer is large B-cell lymphoma. In one embodiment, the cancer is ALK+ large B-cell lymphoma. In one embodiment, the cancer is relapsed or refractory large B-cell lymphoma. In one embodiment, the cancer is relapsed or refractory ALK+ large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed large B-cell lymphoma. In one embodiment, the cancer is 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) has not been previously treated.

[0173] In one embodiment, the cancer is 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, renal clear cell carcinoma, colorectal adenocarcinoma, cutaneous melanoma, diffuse large B-cell lymphoma, diffuse gastric carcinoma, cervical adenocarcinoma, endometrial adenocarcinoma, epithelial ovarian carcinoma, esophageal carcinoma, Ewing's sarcoma, serous fallopian tube carcinoma, fibrosarcoma, gallbladder carcinoma, ganglioglioma, esophagogastric junction adenocarcinoma, glioblastoma, head and neck cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, high-grade serous carcinoma, inflammatory myofibroblastic tumor, leiomyosarcoma, neurofibroma ...leiomyosarcoma, neurofibroma, leiomyosarcoma, neurofibroma, leiomyosarcoma, neurofibroma, leiomyosarcoma, neurofibroma, leiomyosarcoma, neurofibroma, leiomyosarcoma, neurofibroma, leiomyosarcoma, neurofibroma, leiomyosarcoma, neurofibroma, leiomyosarcoma, neurofibro and / or sarcoma, soft tissue sarcoma, invasive ductal carcinoma, low-grade serous carcinoma, lung adenocarcinoma, medulloblastoma, melanoma, mucinous cystadenocarcinoma, mucoepidermoid carcinoma, mucoepidermoid carcinoma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, serous ovarian cystadenocarcinoma, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, papillary cell renal cell carcinoma, papillary thyroid carcinoma, pericardial mesothelioma, peritoneal mesothelioma, prostate adenocarcinoma, lung sarcoma, renal cell carcinoma, salivary gland carcinoma, small cell lung carcinoma, small intestine carcinoma, smooth muscle tumor of unknown malignancy, squamous cell carcinoma, gastric cancer, thyroid cancer, urothelial carcinoma, uterine sarcoma, endometrial carcinoma, uterine leiomyosarcoma, uterine body serous carcinoma, and uterine sarcoma.

[0174] In one embodiment, the cancer (or ALK+ cancer) is newly diagnosed. In one embodiment, the cancer (or ALK+ cancer) has not been previously treated.

[0175] In one embodiment, the cancer (or ALK+ cancer) is recurrent or resistant. In one embodiment, the cancer is recurrent. In one embodiment, the cancer (or ALK+ cancer) is resistant. In one embodiment, the cancer (or ALK+ cancer) is resistant to an inhibitor of wild-type ALK. In one embodiment, the cancer (or ALK+ cancer) is resistant to an inhibitor of genetically altered ALK. In one embodiment, the cancer (or ALK+ cancer) is resistant to one or more of crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In one embodiment, the cancer (or ALK+ cancer) is resistant to one or more of crizotinib, ceritinib, alectinib, and brigatinib. In one embodiment, the cancer (or ALK+ cancer) is resistant to one or more of crizotinib, ceritinib, alectinib, brigatinib, ASP3026, and lorlatinib.

[0176] 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) who must discontinue or interrupt treatment with the drug due to unacceptable side effects. The subject (e.g., a patient) may be intolerant from the first dose of the therapy or may become intolerant over time in response to the therapy.

[0177] In one embodiment, the subject has not been previously treated. In one embodiment, the subject is naïve with tyrosine kinase inhibitor (TKI) therapy. In one embodiment, the subject has received one or more prior lines of therapy. In one embodiment, the subject has received two or more prior lines of therapy. In one embodiment, the subject has developed resistance to one or more of the prior lines of therapy. In one embodiment, the subject has progressed on one or more of the prior lines of therapy. In one embodiment, the prior therapy comprises a tyrosine kinase inhibitor (TKI). In one embodiment, the prior TKI therapy comprises treatment with one or more of crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taretrectinib, merestinib, masitinib, and ensartinib. In one embodiment, the subject has progressed on a previous treatment with crizotinib, alectinib, ceritinib, brigatinib, or lorlatinib. In one embodiment, the subject has progressed on a previous treatment with crizotinib, alectinib, ceritinib, brigatinib, or lorlatinib, and at least one other TKI. In one embodiment, the subject has progressed on a previous treatment with crizotinib. In one embodiment, the subject has progressed on a previous treatment with alectinib. In one embodiment, the subject has progressed on a previous treatment with ceritinib. In one embodiment, the subject has progressed on a previous treatment with brigatinib. In one embodiment, the subject has progressed on a previous treatment with lorlatinib. In one embodiment, the previous therapy comprises one or more chemotherapy. In one embodiment, the subject has progressed on a previous treatment with a TKI (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 previous therapy includes one or more immunotherapies.In one embodiment, the subject has progressed on a previous treatment with a TKI (e.g., one or more of crizotinib, alectinib, ceritinib, brigatinib, and lorlatinib) and one or more immunotherapies. In one embodiment, the previous therapy includes two or more immunotherapies. In one embodiment, the one or more chemotherapy and / or one or more immunotherapies are in addition to the TKI therapy.

[0178] In one embodiment, the cancer is an advanced cancer, for example, an advanced cancer that has relapsed after, is resistant to, is progressing in, or is resistant to a previous treatment with a TKI. In some embodiments, the cancer is locally advanced.

[0179] 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).

[0180] 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.

[0181] In one embodiment, the cancer is lung cancer (e.g., NSCLC). In one embodiment, the cancer is advanced lung cancer, for example, advanced lung cancer that has relapsed after or is resistant to previous treatment with a TKI.

[0182] In one embodiment, the compound provided herein is administered as a first line of therapy. In one embodiment, the compound provided herein is administered as a second line of therapy. In one embodiment, the compound provided herein is administered as a third or fourth line of therapy.

[0183] 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.

[0184] In one embodiment, provided herein is a method for treating a subject having metastatic ALK+ non-small cell lung cancer (NSCLC), 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 pharma- ceutical acceptable salt thereof.

[0185] In one embodiment, the subject is an adult subject over the age of 18. In one embodiment, the subject is a pediatric subject under the age of 18. In one embodiment, the subject is a pediatric subject who is at least 12 years old, but under the age of 18. In one embodiment, the subject is a patient.

[0186] In one embodiment, provided herein is a method for treating an adult subject having metastatic ALK+ NSCLC, 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.

[0187] In one embodiment, provided herein is a method for treating an adult subject with metastatic ALK+ NSCLC, the method comprising administering a therapeutically effective amount of Compound 1, or a pharma- ceutical acceptable salt thereof, to the subject, wherein the subject has progressed on or is intolerant to at least one prior TKI therapy.

[0188] In one embodiment, provided herein is a method of treating an ALK-associated (or ALK+) cancer in a subject in need thereof, wherein the cancer has developed resistance 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 pharmaceutical acceptable salt thereof.

[0189] In one embodiment, provided herein is a method of treating an ALK-associated (e.g., ALK+) cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), and 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, e.g., Compound 1 (e.g., Form 2), or a pharma- ceutically acceptable salt thereof. In one embodiment, the one or more ALK inhibitor resistance mutations comprise 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 comprise 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 is G1202R. In one embodiment, the one or more ALK inhibitor resistance mutations include G1202R and one or more of L1196M, L1198F, G1269A, and T1151M.

[0190] In one embodiment, provided herein is a method for treating an adult subject having metastatic NSCLC that is ALK+ containing the mutation G1202R, the method comprising administering a therapeutically effective amount of a compound provided herein, e.g., Compound 1 (e.g., Form 2), or a pharmaceutical acceptable salt thereof, to the subject, wherein the subject has progressed on or is intolerant to at least one prior TKI therapy.

[0191] In one embodiment, provided herein is a method of treating an ALK-associated (e.g., ALK+) cancer in a subject in need thereof, where the cancer has developed resistance 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 pharmaceutical acceptable salt thereof.

[0192] In one embodiment, the cancer or disease is in a pediatric subject (including an infant subject). In one embodiment, the cancer is systemic anaplastic large cell lymphoma (ALCL) that is ALK+ in a pediatric subject aged 1 year or older and a young adult. In another embodiment, the cancer is relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) that is ALK+ in a pediatric subject aged 1 year or older and a young adult.

[0193] In one embodiment, the TKI is an ALK inhibitor. In one embodiment, the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, merestinib, taretrectinib, 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., cerutinib, alectinib, or brigatinib). In one embodiment, the TKI is a third generation ALK TKI (e.g., lorlatinib).

[0194] In certain embodiments, the subject relapses after the first line of cancer treatment. In certain embodiments, the subject relapses after the first line of cancer treatment with one ALK TKI selected from crizotinib, cerutinib, alectinib, and brigatinib. In certain embodiments, the subject relapses after cancer treatment with at least one ALK TKI selected from crizotinib, cerutinib, alectinib, brigatinib, and lorlatinib. In other embodiments, the subject relapses after the second line of cancer treatment. In other embodiments, the subject relapses after the second line of cancer treatment with one or more ALK TKIs selected from crizotinib, cerutinib, alectinib, brigatinib, and lorlatinib. In other embodiments, the subject relapses after the third line of cancer treatment. In other embodiments, the subject relapses after the second or third line of cancer treatment with lorlatinib in the second or third line.

[0195] In certain embodiments, the subject develops resistance after the first line of cancer treatment. In certain embodiments, the subject develops resistance after the first line of cancer treatment with one ALK TKI selected from crizotinib, cerutinib, alectinib, and brigatinib. In certain embodiments, the subject develops resistance after cancer treatment with at least one ALK TKI selected from crizotinib, cerutinib, alectinib, brigatinib, and lorlatinib. In other embodiments, the subject develops resistance after the second line of cancer treatment. In other embodiments, the subject develops resistance after the second line of cancer treatment with one or more ALK TKIs selected from crizotinib, cerutinib, alectinib, brigatinib, and lorlatinib. In other embodiments, the subject develops resistance after the third line of cancer treatment. In other embodiments, the subject has developed resistance after a second or third line of cancer treatment with lorlatinib in the second or third line.

[0196] In one embodiment, compound 1 is administered to a patient QD for one or more days. In one embodiment, compound 1 is administered to a patient BID for one or more days. In one embodiment, compound 1 is administered to a patient QD for at least one treatment cycle. In one embodiment, compound 1 is administered to a patient BID for at least one treatment cycle. In one embodiment, one treatment cycle is at least 7 days. In one embodiment, one treatment cycle is at least 14 days. In one embodiment, one treatment cycle is at least 15 days. In one embodiment, one treatment cycle is at least 21 days. In one embodiment, one treatment cycle is at least 28 days. In one embodiment, compound 1 is administered to a patient for at least one treatment cycle (e.g., 21 days). In one embodiment, compound 1 is administered to a patient for at least two treatment cycles (e.g., 42 days). In one embodiment, compound 1 is administered to a patient for at least three treatment cycles (e.g., 63 days).

[0197] In one embodiment, the patient does not experience a grade 4 adverse event after administration of Compound 1. In one embodiment, the patient does not experience a grade 3 adverse event after administration of Compound 1. In one embodiment, the patient does not experience a grade 2 adverse event after administration of Compound 1. In one embodiment, the patient does not experience a grade 1 adverse event after administration of Compound 1. As used herein, unless otherwise specified, the grade of the adverse event is in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grades, which are incorporated herein by reference. In some embodiments, the adverse event is a TEAE. In some embodiments, the adverse event is a TRAE.

[0198] In one embodiment, the patient does not experience a neurological adverse event after administration of Compound 1. In one embodiment, the patient does not experience a psychiatric event (e.g., sleep disorder) 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, abnormal movement, cognitive changes, seizures, hallucinations, speech disorders (e.g., aphasia, dysarthria, slow speech or speech disorder), mood disorders (e.g., irritability, anxiety, depression, affective disorders, emotional lability, personality changes, mood swings, affective disorders, aggression, stress, agitation, mood changes, depressed mood, euphoric mood, suicidal ideation or mania), mental conditions, sleep disorders and cognitive disorders (e.g., memory disorders, cognitive disorders, amnesia, confusion, attention disorders, delirium, mental impairment, attention deficit hyperactivity disorder, dementia, sleep disturbance, disorientation or dyslexia). In one embodiment, the neurological adverse event is one or more selected from the group consisting of cognitive impairment, mood disorder, sleep disorder, dizziness, and ataxia. In one embodiment, the patient does not experience weight gain and / or glucose metabolism disorder adverse events. 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 administration of Compound 1. In one embodiment, the patient experiences a grade 1 TRAE after administration of Compound 1. In one embodiment, the patient experiences a grade 2 TRAE after administration of Compound 1. In one embodiment, the patient experiences a grade 2 TRAE after administration of Compound 1. In one embodiment, the patient experiences a grade 3 TRAE after administration of Compound 1. In one embodiment, the patient experiences a grade 3 TRAE after administration of Compound 1. In one embodiment, the patient experiences a grade 1 treatment-emergent adverse event (TEAE) after administration of Compound 1. In one embodiment, the patient experiences up to a Grade 1 TEAE following administration of Compound 1. In one embodiment, the patient experiences a Grade 2 TEAE following administration of 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.

[0199] In one embodiment, the patient does not experience substantial hepatotoxicity after administration of Compound 1 or a pharma- ceutically acceptable salt. In some embodiments, the patient does not experience substantial elevation of transaminases after administration of Compound 1 or a pharma- ceutically acceptable salt. In some embodiments, the patient does not experience substantial elevation of alanine aminotransferase (ALT) after administration of Compound 1 or a pharma- ceutically acceptable salt. In some embodiments, the patient experiences up to grade 3 elevation of ALT as a treatment-emergent adverse event (TEAE) or treatment-related adverse event (TRAE) after administration of Compound 1 or a pharma- ceutically acceptable salt. In some embodiments, the patient experiences up to grade 2 elevation of ALT as a TEAE or TRAE after administration of Compound 1 or a pharma- ceutically acceptable salt. In some embodiments, the patient experiences up to grade 1 elevation of ALT as a TEAE or TRAE after administration of Compound 1 or a pharma- ceutically acceptable salt. In some embodiments, the patient does not experience substantial elevation of aspartate aminotransferase (AST) after administration of Compound 1 or a pharma- ceutically acceptable salt. In some embodiments, the patient experiences an increase in AST as a TEAE or TRAE of up to Grade 3 after administration of Compound 1 or a pharma- ceutically acceptable salt. In some embodiments, the patient experiences an increase in AST as a TEAE or TRAE of up to Grade 2 after administration of Compound 1 or a pharma- ceutically acceptable salt. In some embodiments, the patient experiences an increase in AST as a TEAE or TRAE of up to Grade 1 after administration of Compound 1 or a pharma- ceutically acceptable salt. In some embodiments, the increase in ALT or AST occurs within about 2 months after administration of Compound 1 or a pharma- ceutically acceptable salt, and then returns to the normal range or baseline. In some embodiments, the increase in ALT or AST occurs within about 2 months after administration of Compound 1 or a pharma- ceutically acceptable salt, and returns to the normal range or baseline within about 3 months after the onset of the increase in ALT or AST.In some embodiments, the elevation of ALT or AST occurs within about 2 months after administration of Compound 1 or a pharma- ceutically acceptable salt thereof, and returns to the normal range or baseline within about 2 months after the onset of the elevation of ALT or AST. In some embodiments, the elevation of ALT or AST occurs within about 2 months after administration of Compound 1 or a pharma- ceutically acceptable salt thereof, and returns to the normal range or baseline within about 1 month after the onset of the elevation of ALT or AST. In some embodiments, the elevation of ALT or AST occurs within about 2 months after administration of Compound 1 or a pharma- ceutically acceptable salt thereof, and returns to the normal range or baseline within about 3 weeks after the onset of the elevation of ALT or AST. In some embodiments, the elevation of ALT or AST occurs within about 2 months after administration of Compound 1 or a pharma- ceutically acceptable salt thereof, and returns to the normal range or baseline within about 2 weeks after the onset of the elevation of ALT or AST. In one embodiment, the patient does not experience a substantial increase in ALT or AST after administration of Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the administration is once daily. In some embodiments, the administration is twice daily. In some embodiments, administration is once daily for the duration of the administration period. In some embodiments, administration is twice daily for the duration of the administration period.

[0200] In some embodiments, after administering Compound 1 or a pharmaceutically acceptable salt thereof to a patient at a dose level, the patient experiences a grade 1 increase in ALT or AST as a TEAE or TRAE, and 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 dose level, the patient experiences a grade 2 increase in ALT or AST as a TEAE or TRAE, and administration continues at the same dose level (in a further embodiment, under weekly monitoring (e.g., until the increase in ALT or AST returns to grade 1 or less)). In some embodiments, after administering Compound 1 or a pharmaceutically acceptable salt thereof to a patient at a dose level, the patient experiences a grade 3 increase in ALT or AST as a TEAE or TRAE, and administration is subjected to a dose interruption (i.e., administration is stopped / withheld for a period of time). In some embodiments, after administering Compound 1 or a pharmaceutically acceptable salt thereof to a patient at a dose level, the patient experiences a grade 3 increase in ALT or AST as a TEAE or TRAE, and administration is subjected to a dose modification (i.e., reduction). In some embodiments, the patient resumes the same dose level after dose interruption when the increase in ALT or AST returns to Grade 1 or below, or when ALT or AST returns to baseline. In some embodiments, the patient resumes the same dose level (first dose level) after dose interruption and experiences the same grade increase in ALT or AST (which in one embodiment resolves within 30 days (e.g., severity returns to Grade 1 or below, or ALT or AST returns to baseline)), and then the patient is exposed to a lower dose level (e.g., a second dose level 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 dose.

[0201] In some embodiments, after administration of Compound 1 or a pharmaceutically acceptable salt thereof, less than 40% of the patient population has an elevated ALT or AST adverse event (e.g., TEAE or TRAE). 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 an elevated ALT or AST adverse event (e.g., TEAE or TRAE). In some embodiments, less than about 15% of the patient population has an elevated ALT or AST adverse event. In some embodiments, less than about 14% of the patient population has an elevated ALT or AST adverse event. In some embodiments, less than about 13% of the patient population has an elevated ALT or AST adverse event. In some embodiments, less than about 12% of the patient population has an elevated ALT or AST adverse event. In some embodiments, less than about 11% of the patient population has elevated ALT or AST adverse events. In some embodiments, less than about 10% of the patient population has elevated ALT or AST adverse events. In some embodiments, less than about 9% of the patient population has elevated ALT or AST adverse events. In some embodiments, less than about 8% of the patient population has elevated ALT or AST adverse events. In some embodiments, less than about 7% of the patient population has elevated ALT or AST adverse events. In some embodiments, less than about 6% of the patient population has elevated ALT or AST adverse events. In some embodiments, less than about 5% of the patient population has elevated ALT or AST adverse events. In certain embodiments, the elevated ALT or AST adverse events are grade 1. In certain embodiments, the elevated ALT or AST adverse events are grade 2 (or less). In certain embodiments, the elevated ALT or AST adverse events are grade 3 (or less).

[0202] In one embodiment, the patient does not experience substantial hyperlipidemia after administration of Compound 1 or a pharma- ceutically acceptable salt. In one embodiment, the patient does not experience substantial increases in blood triglycerides after administration of Compound 1 or a pharma- ceutically acceptable salt. In one embodiment, the patient experiences an increase in blood triglycerides of up to Grade 3 as a TEAE or TRAE after administration of Compound 1 or a pharma- ceutically acceptable salt. In one embodiment, the patient experiences an increase in blood triglycerides of up to Grade 2 as a TEAE or TRAE after administration of Compound 1 or a pharma- ceutically acceptable salt. In one embodiment, the patient experiences an increase in blood triglycerides of up to Grade 1 as a TEAE or TRAE after administration of Compound 1 or a pharma- ceutically acceptable salt. In one embodiment, the patient does not experience substantial increases in total cholesterol after administration of Compound 1 or a pharma- ceutically acceptable salt. In one embodiment, the patient experiences an increase in total cholesterol as a TEAE or TRAE of up to Grade 3 after administration of Compound 1 or a pharma- ceutically acceptable salt. In one embodiment, the patient experiences an increase in total cholesterol as a TEAE or TRAE of up to Grade 2 after administration of Compound 1 or a pharma- ceutically acceptable salt. In one embodiment, the patient experiences an increase in total cholesterol as a TEAE or TRAE of up to Grade 1 after administration of Compound 1 or a pharma- ceutically acceptable salt. In certain embodiments, the patient is further administered with a lipid-lowering drug. In some embodiments, after administration of Compound 1 or a pharma- ceutically acceptable salt to the patient at a dose level, the patient experiences an increase in total cholesterol or triglycerides as a TEAE or TRAE of up to Grade 1, and administration continues at the same dose level. In some embodiments, after administration of Compound 1 or a pharma- ceutically acceptable salt to the patient at a dose level, the patient experiences an increase in total cholesterol or triglycerides as a TEAE or TRAE of up to Grade 1, and administration continues at the same dose level with further administration of a lipid-lowering drug.In some embodiments, after administering Compound 1 or a pharmaceutically acceptable salt thereof to a patient at a dose level, the patient experiences a grade 2 increase in total cholesterol or triglycerides as a TEAE or TRAE, and 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 dose level, the patient experiences a grade 2 increase in total cholesterol or triglycerides as a TEAE or TRAE, and administration continues at the same dose level with further administration of a lipid-lowering drug. In some embodiments, after administering Compound 1 or a pharmaceutically acceptable salt thereof to a patient at a dose level, the patient experiences a grade 3 increase in total cholesterol or triglycerides as a TEAE or TRAE, and 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 dose level, the patient experiences a grade 3 increase in total cholesterol or triglycerides as a TEAE or TRAE, and administration is subject to a dose interruption (i.e., administration is stopped / withheld for a period of time) or modification (e.g., reduction). In some embodiments, the patient resumes the same dose level after the dose interruption or modification when the increase in total cholesterol or triglycerides returns to Grade 2 or less, or when total cholesterol or triglycerides return to baseline. In some embodiments, the patient experiences a Grade 3 increase in total cholesterol or triglycerides as a TEAE or TRAE, and administration continues at the same dose level with further administration of lipid-lowering drug. In some embodiments, the patient experiences a Grade 3 increase in total cholesterol or triglycerides as a TEAE or TRAE, and administration is subject to a dose interruption or modification (e.g., reduction) with further administration of lipid-lowering drug. In some embodiments, the lipid-lowering drug is selected from statins, fibrates, niacin, lecithin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, omega-3, PCSK9 inhibitors, choline, L-arginine, flaxseed oil, and pycnogenol. In one embodiment, the dose reduction is performed according to Table A.

[0203] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt is administered once a day. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt is administered twice a day. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt is administered once a day continuously throughout the administration period. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt is administered twice a day continuously throughout the administration period.

[0204] In one embodiment, the patient does not experience a substantial increase in total bilirubin as a TEAE or TRAE after administration of Compound 1. In one embodiment, the patient does not experience a substantial increase in alkaline phosphatase after administration of Compound 1.

[0205] As used herein in connection with adverse events, and unless otherwise specified, "substantial" refers to at least about 10% compared to baseline. In some embodiments, "substantial" refers to at least about 20% compared to baseline. In some embodiments, "substantial" refers to at least about 30% compared to baseline. In some embodiments, "substantial" refers to at least about 40% compared to baseline. In some embodiments, "substantial" refers to at least about 50% compared to baseline. In some embodiments, "substantial" refers to at least about 60% compared to baseline. In some embodiments, "substantial" refers to at least about 70% compared to baseline. In some embodiments, "substantial" refers to at least about 80% compared to baseline. In some embodiments, "substantial" refers to at least about 90% compared to baseline. In some embodiments, administration is once daily. In some embodiments, administration is twice daily. In some embodiments, administration is once daily continuously throughout the administration period. In some embodiments, administration is twice daily continuously throughout the administration period.

[0206] In one embodiment, the patient does not experience gastrointestinal disorders (e.g., constipation, diarrhea, oral numbness, nausea, or vomiting) after administration of Compound 1 or a pharma- ceutically acceptable salt thereof. In one embodiment, the patient experiences up to grade 3 gastrointestinal disorders (e.g., constipation, diarrhea, oral numbness, nausea, or vomiting) as a treatment-emergent adverse event (TEAE) or treatment-related adverse event (TRAE). In one embodiment, the patient experiences up to grade 2 gastrointestinal disorders (e.g., constipation, diarrhea, oral numbness, nausea, or vomiting) TEAE or TRAE. In one embodiment, the patient experiences up to grade 1 gastrointestinal disorders (e.g., constipation, diarrhea, oral numbness, nausea, or vomiting) TEAE or TRAE. In certain embodiments, the patient does not experience substantial nausea, constipation, or diarrhea. In certain embodiments, the patient experiences up to grade 3 nausea, constipation, or diarrhea as a TEAE or TRAE. In certain embodiments, the patient experiences up to grade 2 nausea, constipation, or diarrhea as a TEAE or TRAE. In certain embodiments, the patient experiences up to grade 1 nausea, constipation, or diarrhea as a TEAE or TRAE. In some embodiments, after administering Compound 1 or a pharmaceutically acceptable salt thereof to a patient at a dose level, the patient experiences grade 1 gastrointestinal disturbance as a TEAE or TRAE, and 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 dose level, the patient experiences grade 2 gastrointestinal disturbance as a TEAE or TRAE, and administration continues at the same dose level. In some embodiments, after administering Compound 1 or a pharma- ceutically acceptable salt thereof to a patient at a dose level, the patient experiences grade 2 gastrointestinal distress as a TEAE or TRAE, and administration is subject to dose interruption (i.e., administration is stopped / withheld for a period of time) or modification (e.g., reduction). In some embodiments, after administering Compound 1 or a pharma- ceutically acceptable salt thereof to a patient at a dose level, the patient experiences grade 3 gastrointestinal distress as a TEAE or TRAE, and administration is subject to dose interruption or modification (e.g., reduction).In some embodiments, the patient resumes the same dose level after dose interruption or modification when the level of gastrointestinal adverse events returns to Grade 2 or less. In some embodiments, the patient resumes the same dose level after dose interruption or modification when the level of gastrointestinal adverse events returns to Grade 1 or less. In certain embodiments, the patient is further administered an antiemetic (e.g., bismuth subsalicylate, antihistamine, metoclopramide, etc.) to manage nausea. In certain embodiments, the patient is further 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 further 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.

[0207] In one embodiment, the patient does 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 does not experience musculoskeletal and connective tissue disorders (e.g., back pain, musculoskeletal chest pain, musculoskeletal pain, or pain in the extremities) as a TEAE or TRAE after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the patient experiences up to Grade 3 musculoskeletal and connective tissue disorders (e.g., back pain, musculoskeletal chest pain, musculoskeletal pain, or pain in the extremities) as a TEAE or TRAE after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the patient experiences up to Grade 2 musculoskeletal and connective tissue disorders (e.g., back pain, musculoskeletal chest pain, musculoskeletal pain, or pain in the extremities) as a TEAE or TRAE 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 limb pain) as a TEAE or TRAE after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the patient does not experience substantial pain after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the patient experiences grade 1 level 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 level 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 level 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 level musculoskeletal and connective tissue disorders as a TEAE or TRAE and is subject to dose interruption or modification (e.g., reduction).In some embodiments, after administering Compound 1 or a pharma- ceutically acceptable salt thereof to a patient at a dose level, the patient experiences a grade 3 level of musculoskeletal and connective tissue disorder as a TEAE or TRAE, and administration is subject to a dose interruption (i.e., administration is stopped / withheld for a period of time) or modification (e.g., reduction). In some embodiments, the patient resumes the same dose level after the dose interruption or modification when the level of musculoskeletal and connective tissue disorder adverse events returns to grade 2 or less. In some embodiments, the patient resumes the same dose level after the dose interruption or modification when the level of musculoskeletal and connective tissue disorder adverse events returns to grade 1 or less. In one embodiment, the patient is further administered an analgesic (e.g., acetaminophen, an NSAID, a COX-2 inhibitor such as etoricoxib). In one embodiment, the dose reduction is performed according to Table A.

[0208] In one embodiment, the patient does not experience respiratory, thoracic, and mediastinal disorders (e.g., cough, dyspnea, exertional dyspnea, or increased bronchial secretions). In one embodiment, the patient does not experience respiratory, thoracic, and mediastinal disorders (e.g., cough, dyspnea, exertional dyspnea, or increased bronchial secretions) as a TRAE or TEAE. In one embodiment, the patient experiences up to Grade 3 respiratory, thoracic, and mediastinal disorders (e.g., cough, dyspnea, exertional dyspnea, or increased bronchial secretions) as a TRAE or TEAE. In one embodiment, the patient experiences up to Grade 2 respiratory, thoracic, and mediastinal disorders (e.g., cough, dyspnea, exertional dyspnea, or increased bronchial secretions) as a TRAE or TEAE. In one embodiment, the patient experiences up to Grade 1 respiratory, thoracic, and mediastinal disorders (e.g., cough, dyspnea, exertional dyspnea, or increased bronchial secretions) as a TRAE or TEAE. In one embodiment, the patient experiences respiratory, chest, and mediastinal disorders (e.g., cough, dyspnea, dyspnea on exertion, or increased bronchial secretions) of up to Grade 1 as a TRAE or TEAE. In one embodiment, the patient experiences cough of up to Grade 1 as a TRAE or TEAE. In one embodiment, the patient experiences cough of up to Grade 2 as a TRAE or TEAE. In one embodiment, the patient experiences cough of up to Grade 3 as a TRAE or TEAE. In one embodiment, the patient is further administered an antitussive (e.g., dextromethorphan, guaifenesin, menthol, antihistamines (e.g., chlorpheniramine and clemastine), decongestants (e.g., pseudoephedrine or phenylephrine), benzonatate, albuterol, promethazine, steroids (e.g., prednisone, prednisolone, dexamethasone, fluticasone propionate, budesonide, salbutamol plus ipratropium bromide, montelukast, nociceptive opioid-1 receptor agonists, codeine, and gelatin, etc.). In one embodiment, the patient is further administered prednisone (e.g., up to 10 mg / day) as an antitussive.In some embodiments, after Compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient at a dose level, the patient experiences Grade 1 respiratory, thoracic, and mediastinal disorders (e.g., cough, dyspnea, exertional dyspnea, or increased bronchial secretions), and administration continues at the same dose level. In some embodiments, after Compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient at a dose level, the patient experiences Grade 2 respiratory, thoracic, and mediastinal disorders (e.g., cough, dyspnea, exertional dyspnea, or increased bronchial secretions) as a TEAE or TRAE, and administration continues at the same dose level. In some embodiments, after Compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient at a dose level, the patient experiences Grade 2 respiratory, thoracic, and mediastinal disorders (e.g., cough, dyspnea, exertional dyspnea, or increased bronchial secretions) as a TEAE or TRAE, and administration is subject to dose interruption (i.e., administration is stopped / withheld for a period of time) or modification (e.g., reduction). In some embodiments, after Compound 1 or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose level, the patient experiences respiratory, thoracic, and mediastinal disorders of grade 2 as a TEAE or TRAE (e.g., cough, dyspnea, dyspnea on exertion, or increased bronchial secretions), and administration is subject to dose interruption until the adverse event is grade 1 or less in severity. In some embodiments, after Compound 1 or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose level, the patient experiences respiratory, thoracic, and mediastinal disorders of grade 3 as a TEAE or TRAE (e.g., cough, dyspnea, dyspnea on exertion, or increased bronchial secretions), and administration is subject to dose interruption or modification (e.g., reduction). In some embodiments, the patient resumes the same dose level after dose interruption or modification when the respiratory, thoracic, and mediastinal adverse events return to grade 2 or less. In some embodiments, the patient resumes the same dose level after dose interruption or modification when the respiratory, thoracic, and mediastinal adverse events return to grade 1 or less. In certain embodiments, the respiratory, thoracic, or mediastinal disorder is cough. In one embodiment, dose reduction is performed according to Table A.

[0209] In one embodiment, the patient does not experience substantial weight gain after administration of Compound 1 or a pharma- ceutically acceptable salt. 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% of baseline) weight gain after administration of Compound 1 or a pharma- ceutically acceptable salt. In one embodiment, the patient population does not experience statistically significant weight gain after administration of Compound 1 or a pharma- ceutically acceptable salt once daily for about one month. In one embodiment, the patient population does not experience statistically significant weight gain after administration of Compound 1 or a pharma- ceutically acceptable salt once daily for about two months. In one embodiment, the patient population does not experience statistically significant weight gain after administration of Compound 1 or a pharma- ceutically acceptable salt once daily for about three months. In one embodiment, the patient population does not experience statistically significant weight gain after administration of Compound 1 or a pharma- ceutically acceptable salt once daily for about four months. In one embodiment, the patient population does not experience a statistically significant weight gain after about 5 months of administration of Compound 1 or a pharma- ceutically acceptable salt once a day. In one embodiment, the patient population does not experience a statistically significant weight gain after about 6 months of administration of Compound 1 or a pharma- ceutically acceptable salt once a day. In one embodiment, the patient population does not experience a statistically significant weight gain after about 8 months of administration of Compound 1 or a pharma- ceutically acceptable salt once a day. In one embodiment, the patient population does not experience a statistically significant weight gain after about 10 months of administration of Compound 1 or a pharma- ceutically acceptable salt once a day. In one embodiment, the patient population does not experience a statistically significant weight gain after about 12 months of administration of Compound 1 or a pharma- ceutically acceptable salt once a day. 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 (eg, diabetes (eg, type 2), cardiovascular comorbidities, depression or increased risk of osteoarthritis, thrombosis, severe infectious processes).

[0210] In one embodiment, the patient does not experience a treatment-related serious adverse event (SAE). In one embodiment, the patient does not experience a treatment-related CNS adverse event. In one embodiment, the patient does not experience treatment-related dizziness.

[0211] In one embodiment, the patient has a complete response after one or more cycles of treatment. In one embodiment, the patient has a partial response after one or more cycles of treatment. In one embodiment, the patient achieves stable disease after one or more cycles of treatment. In one embodiment, the patient does not experience progressive disease after one or more cycles of treatment.

[0212] In one embodiment, the patient is a patient population. In one embodiment, the patient population does not experience a statistically significant adverse event (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%) as described herein. In one embodiment, the patient population does not experience a statistically significant adverse event (e.g., TEAEs or TRAEs) of > about 7% of baseline as described herein. In one embodiment, the patient population does not experience a statistically significant adverse event (e.g., TEAEs or TRAEs) of > about 8% of baseline as described herein. In one embodiment, the patient population does not experience a statistically significant adverse event (e.g., TEAEs or TRAEs) of > about 9% of baseline as described herein. In one embodiment, the patient population does not experience a statistically significant adverse event (e.g., TEAEs or TRAEs) of > about 10% of baseline as described herein. In one embodiment, the patient population does not experience > about 15% of baseline statistically significant adverse events (e.g., TEAEs or TRAEs) as described herein. In one embodiment, the patient population does not experience > about 20% of baseline statistically significant adverse events (e.g., TEAEs or TRAEs) as described herein. In one embodiment, the patient population does not experience > about 25% of baseline statistically significant adverse events (e.g., TEAEs or TRAEs) as described herein. In one embodiment, the patient population does not experience > about 30% of baseline statistically significant adverse events (e.g., TEAEs or TRAEs) as described herein. In one embodiment, the patient population does not experience > about 35% of baseline statistically significant adverse events (e.g., TEAEs or TRAEs) as described herein. In one embodiment, the patient population does not experience > about 40% of baseline statistically significant adverse events (e.g., TEAEs or TRAEs) as described herein. In one embodiment, the patient population does not experience > about 45% of baseline statistically significant adverse events (e.g., TEAEs or TRAEs) as described herein. 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 numbness, 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 a 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 up to grade 1. In one embodiment, the adverse event is up to grade 2. In one embodiment, the adverse event is up to grade 3.

[0213] As used herein, unless otherwise specified, complete response (CR) refers to the disappearance of all target lesion(s). In some embodiments of CR, any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to <10 mm. Partial response (PR) refers to at least a 30% reduction in the sum of the diameters of the target lesion(s). Progressive disease (PD) refers to at least a 20% increase in the sum of the diameters of the target lesion(s). In some embodiments of PD, in addition to a relative increase of 20%, the sum also demonstrates an increase of at least 5 mm. In some embodiments, the appearance of one or more new lesion(s) is also considered progression. Stable disease (SD) refers to neither a sufficient reduction in the minimum sum diameter during the study to qualify as PR, nor a sufficient increase to qualify as PD. Additional explanations of these terms according to RECIST 1.1 can be found in European Journal of Cancer 45(2009)228-247.

[0214] In one embodiment, provided herein is a method of reducing pathology in a subject having an ALK-positive solid tumor (e.g., NSCLC), the method comprising: (i) obtaining a first radiological measurement of a size of the lesion; (ii) administering a pharma- tically effective amount of Compound 1 once daily for one or more days; (iii) obtaining a second radiological measurement of the size of the lesion; The size of the lesion determined from the second measurement is up to 100% of the size of the lesion determined from the first measurement.In some embodiments, the measurement of the size of the lesion is defined in RECIST 1.1 response criteria.In one embodiment, the lesion is, for example, the target lesion as described in Example 1 or Example 15.

[0215] In one embodiment, the size of the lesion is characterized as the sum of the lesion diameters. In one embodiment, the sum of the lesion diameters determined from the second measurement is at most about 90% of the sum of the lesion diameters determined from the first measurement. In one embodiment, the sum of the lesion diameters determined from the second measurement is at most about 80% of the sum of the lesion diameters determined from the first measurement. In one embodiment, the sum of the lesion diameters determined from the second measurement is at most about 70% of the sum of the lesion diameters determined from the first measurement. In one embodiment, the sum of the lesion diameters determined from the second measurement is at most about 60% of the sum of the lesion diameters determined from the first measurement. In one embodiment, the sum of the lesion diameters determined from the second measurement is at most about 50% of the sum of the lesion diameters determined from the first measurement. In one embodiment, the sum of the lesion diameters determined from the second measurement is at most about 0.01% to about 90% of the sum of the lesion diameters determined from the first measurement. In one embodiment, the second measurement does not show detectable lesions.

[0216] In one embodiment, the patient has brain metastases. In one embodiment, the patient has brain metastases and does not experience intracranial progression after at least one treatment cycle. In one embodiment, the patient has brain metastases and does not experience intracranial progression after at least two treatment cycles.

[0217] In one embodiment, the patient has at least about 5% to about 100% reduction of ALK variant allele(s) in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 5% to about 100% reduction of ALK variant allele(s) in circulating tumor DNA after at least 15 days of treatment. In one embodiment, the patient has at least about 30% reduction of ALK variant allele(s) in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 40% reduction of ALK variant allele(s) in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 50% reduction of ALK variant allele(s) in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 60% reduction of ALK variant allele(s) in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about a 70% reduction in ALK variant allele(s) in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about an 80% reduction in ALK variant allele(s) in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about a 90% reduction in ALK variant allele(s) in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has about a 100% reduction in ALK variant allele(s) in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has undetectable ALK variant allele(s) in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has undetectable ALK variant allele(s) in circulating tumor DNA 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.

[0218] In one embodiment, the previous therapy is a previous ALK TKI therapy. In one embodiment, the ALK TKI is one or more selected from lorlatinib, crizotinib, ceritinib, alectinib, and brigatinib. In one embodiment, the previous therapy is an ALK TKI therapy and a systemic therapy. In one embodiment, the ALK TKI is one or more selected from lorlatinib, crizotinib, ceritinib, alectinib, and brigatinib, and the systemic therapy is one or more selected from pemetrexed, cisplatin, carboplatin, bevacizumab, datopotamab deruxtecan, trastuzumab deruxtecan (T-DXd, DS-8201a), and checkpoint inhibitors (e.g., pembrolizumab, nivolumab, atezolizumab). In certain embodiments, the checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor, a cytotoxic T lymphocyte-associated 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, cemiplimab, and dostarimab. In certain embodiments, the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, cemiplimab (LIBTAYO®), sintilimab, spartalizumab (PDR001), pidilizumab (CureTech), MEDI0680 (Medimmune), dostarimab (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-TheraSolutions), GLS-010 (Gloria Pharmaceuticals; WuXi Biologics), AK103, AK104, AK105 (Akesio Biopharma; Hangzhou Hansi Biologics; Hanzhong Biologics), LZM009 (Livzon), HLX-10 (Henlius Biotech), 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 atezolizumab, FAZ053 (Novartis), and BMS-936559 (Bristol-Myers Squibb), KN035 (Alphamab; 3DMed; Ascletis Pharma), embafolimab (TRACON Pharmaceuticals), BMS 936559 (Bristol-Myers Squibb), CS1001 (CStone Pharmaceuticals, Ligand Pharmaceuticals), CX-072 (CytomX Therapeutics), FAZ053 (Novartis), SHR-1316 (Hengrui Medicine), TQB2450 (Chiatai Tianqing), STI-A1014 (Zhaoke Pharm; Lee's Pharm, Lonza, Sorrento Therapeutics, NantWorks), LYN00102 (Lynkcell), A167 (Harbour BioMed, Kelun Group), BGB-A333 (Beigene), MSB2311 (Mabspace Biosciences), HLX-20 (Henlius Biotech), cosibelimab (Fortress Biotech), LY3300054 or iodapolimab (Eli Lilly), GS-4224 (GileadSciences), 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), Icaritin 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 Project (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).

[0219] In certain embodiments, methods for treating or preventing cancer may be demonstrated by one or more responses, such as increased apoptosis, inhibition of tumor growth, reduction in tumor metastasis, inhibition of tumor metastasis, reduction in microvascular density, decreased neovascularization, inhibition of tumor migration, tumor regression, and increased survival of the subject.

[0220] In one embodiment, administration of Compound 1 is inducible by measuring the area under the curve (AUC 0-24In one embodiment, administration of Compound 1 provides a 0-24 hour area under the curve (AUC 0-24 In one embodiment, the area under the curve (AUC) of the compound from 0 to 24 hours is provided in the range of about 100 to about 10,000 ng*h / mL. 0-24 ) ranges from about 200 to about 15,000 ng*h / mL after at least about 15 days of treatment (e.g., once daily for at least about 15 days). In one embodiment, the area under the curve (AUC) from 0 to 24 hours for the compound 0-24 ) ranges from about 300 to about 10,000 ng*h / mL after about 15 days of treatment (e.g., once daily for about 15 days). In one embodiment, the area under the curve (AUC) of the compound from 0 to 24 hours 0-24 ) ranges from about 1000 to about 9000 ng*h / mL after about 15 days of treatment (e.g., once daily for 15 days).

[0221] In one embodiment, such administration is based on the area under the curve (AUC) from 0 to 24 hours after administration of the compound. 0-24 ) in the range of (80%-125% of 10 ng*h / mL) to (80%-125% of 300 ng*h / mL) for every mg of compound administered. In one embodiment, such administration provides an area under the curve (AUC 0-24 ) in the range of about 15 to about 200 ng*h / mL for every mg of compound administered. In one embodiment, such administration provides an area under the curve (AUC 0-24 ) in the range of about 20 to about 200 ng*h / mL after at least about 15 days of treatment (e.g., once daily for at least about 15 days). In one embodiment, such administration provides an area under the curve (AUC 0-24 ) in the range of about 20 to about 150 ng*h / mL after about 15 days of treatment (e.g., once daily for about 15 days).

[0222] In one embodiment, such administration results in a maximum plasma concentration of the compound (Cmax ) in the range of (80%-125% of 20 ng / mL) to (80%-125% of 2000 ng / mL). In one embodiment, such administration provides a maximum plasma concentration (C max ) in the range of about 40 to about 1500 ng / mL. In one embodiment, such administration provides a maximum plasma concentration (C max In one embodiment, administration of Compound 1 provides a C max in the range of about 50 to about 2000 ng*h / mL after about at least about 15 days of treatment (e.g., once a day for at least about 15 days). In one embodiment, administration of Compound 1 provides a C max in the range of about 70 to about 1500 ng*h / mL after about 15 days of treatment (e.g., once a day for about 15 days). In one embodiment, administration of Compound 1 provides a C max in the range of about 100 to about 1100 ng*h / mL after about 15 days of treatment (e.g., once daily for about 15 days).

[0223] In one embodiment, such administration results in a maximum plasma concentration of the compound (C max ) in the range of about 2 to about 70 ng / mL for every mg of compound administered. In one embodiment, such administration provides a maximum plasma concentration (C max ) in the range of about 2 to about 50 ng / mL per mg of Compound 1 administered. In one embodiment, administration of Compound 1 provides a C max in the range of about 3 to about 40 ng / mL for every mg of Compound 1 administered after at least about 15 days of treatment (e.g., once daily for at least about 15 days). In one embodiment, administration of Compound 1 provides a C max in the range of about 3 to about 30 ng / mL for every mg of Compound 1 administered after about 15 days of treatment (e.g., once daily for about 15 days). In one embodiment, administration of Compound 1 provides a C max in the range of about 3 to about 20 ng / mL for every mg of compound 1 administered after about 15 days of treatment (eg, once daily for about 15 days).

[0224] In one embodiment, such administration reduces the T max In one embodiment, such administration provides a T of the compound after administration in the range of about 0.25 hours to about 5 hours. max In one embodiment, such administration provides a T of the compound after administration in the range of about 0.25 hours to about 4 hours. max in the range of about 0.5 hours to about 5 hours after at least about 15 days of treatment (e.g., once a day for at least about 15 days). In one embodiment, such administration provides a T max in the range of about 0.5 hours to about 4 hours after about 15 days of treatment (e.g., once a day for about 15 days). In one embodiment, such administration provides a T max is provided for a range of about 0.5 hours to about 3.0 hours after treatment for about 15 days (eg, once a day for about 15 days).

[0225] In one embodiment, such administration involves the t 1 / 2 In one embodiment, such administration provides a t 1 / 2 In one embodiment, such administration provides a t 1 / 2 is provided for a period ranging from about 10 hours to about 50 hours after about 15 days of treatment.

[0226] In one embodiment, such administration provides a post-administration unbound plasma concentration of greater than about 1.4 ng / mL. In one embodiment, such administration provides a post-administration unbound plasma concentration of greater than about 4.2 ng / mL. In one embodiment, such administration provides a post-administration unbound plasma concentration of greater than about 12.5 ng / mL.

[0227] 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 a 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, t 1 / 2 refers to the arithmetic mean of a patient population. max refers to the median range for a patient population. In certain embodiments, AUC 0-24、 AUC last,unbound , AUC tau , AUC tau_DN , AUC inf , AUC inf_DN , C max , C max_DN , C max_unbound , and C min Each refers to the geometric mean of a patient population.

[0228] In some embodiments, a subject or a population of subjects has QD administration of Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, a subject or a population of subjects has BID administration of Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0229] In certain embodiments, the measurement is after one administration of compound 1 or a mixture of stereoisomers or stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, the measurement is after one cycle (e.g., 21 days) of administration of compound 1 or a mixture of stereoisomers or stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, the measurement is after about 15 days of administration of compound 1 or a mixture of stereoisomers or stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, the measurement is after two cycles (e.g., 42 days) of administration of compound 1 or a mixture of stereoisomers or stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, the measurement is after three cycles (e.g., 63 days) of administration of compound 1 or a mixture of stereoisomers or stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, the measurements are after four cycles (eg, 84 days) of administration of Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0230] Combination treatment In some embodiments, methods of treating or preventing cancer may include administering Compound 1 in combination with one or more other chemotherapeutic agent(s).

[0231] As used herein, unless otherwise specified, "concomitantly" or "in combination with" is not intended to imply that the other agent and Compound 1 must be administered at the same time and / or formulated together for delivery, although these delivery methods are within the scope of this disclosure. The compounds provided herein may be administered simultaneously with, prior to (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 at a dose and / or time schedule determined for that particular agent. The other therapeutic agents may be administered in a single composition together with the compounds provided herein or separately in different compositions. Triple therapy is also contemplated herein.

[0232] Chemotherapeutic agents that may be administered in conjunction 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-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, afatinib maleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (bcg), bicalutamide, bleomycin, bortezomib, beta-methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, camptothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridine, dexamethasone, diquafos Loroacetate, 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, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N-(4-sulfamoylphenylcarbamothioyl)pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemetrexed, pentostatin, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer , PPADS, procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may 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 may 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-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylcarbamothioyl)pivalamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolofylline sodium 2,4-dinitrobenzenesulfonate, sumarine and tonapophilin.

[0233] Many combination therapies have been developed for the treatment of cancer.In certain embodiments, the compound or pharmaceutical composition provided herein (e.g., compound 1) can be administered in combination with one or more combination therapies.Examples of combination therapies that the compound provided herein can be administered in combination with are included in Table 1. [Table 1] TIFF2025512921000007.tif231165TIFF2025512921000008.tif229165TIFF20255129210 00009.tif233165TIFF2025512921000010.tif232165TIFF2025512921000011.tif156165

[0234] In certain embodiments, the conjoint therapy of the present disclosure includes the conjoint administration of other types of therapeutic agents, such as immuno-oncological agents. Cancer cells often have specific cell surface antigens that can be recognized by the immune system. Thus, immuno-oncological agents, such as monoclonal antibodies, can selectively bind to tumor antigens and cause cell death. Other immuno-oncological agents can suppress tumor-mediated inhibition of innate immune responses or can otherwise activate immune responses, thus facilitating the recognition of tumors by the immune system. Exemplary antibody immuno-oncology agents include, but are not limited to, abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intetumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, and tremelimumab. In some embodiments, the antibody immuno-oncology agent is selected from an anti-CD73 monoclonal antibody (mAb), an anti-CD39 mAb, an anti-PD-1 mAb, an anti-PD-L1 mAb, and an anti-CTLA4 mAb. Thus, in some embodiments, the methods of the disclosure include the conjoint administration of one or more immuno-oncology agents, such as those listed above.

[0235] In some embodiments, the combination therapy includes co-administration of a compound of the disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), with an SH2 inhibitor, e.g., CGP78850, CPG85793, C90, C126, G7-18NATE, G7-B1, and NSC642056.

[0236] Acquired ALK fusions confer EGFR inhibitor resistance. See von Buttlar, X. et al JTO Clin Res Rep. 2021 Jun;2(6):100179, Schrock, AB et al J Thorac Oncol. 2018 Sep;13(9):1312-1323. In some embodiments, the combination therapy includes co-administration of a compound of the disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), with an EGFR inhibitor, e.g., 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.

[0237] In some embodiments, provided herein are methods of treating epidermal growth factor receptor (EGFR)-associated cancer, the methods comprising administering to a subject in need thereof a combination comprising a therapeutically effective amount of Compound 1 (e.g., Form 2 of Compound 1), or a pharma- ceutically acceptable salt or stereoisomer thereof, and a therapeutically effective amount of a second agent, 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, 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. In some embodiments, the subject has at least one EGFR mutation. In some embodiments, the at least one EGFR mutation is within one or more of exons 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-associated cancer is NSCLC, pancreatic cancer, breast cancer, or colon cancer. In some embodiments, the EGFR-associated cancer is mediated by EGFR.

[0238] In some embodiments, the combination therapy includes the joint administration of a compound of the present disclosure, such as Compound 1 (e.g., Form 2 of Compound 1), 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 a Raf mutant. In certain embodiments, the Raf inhibitor is a B-Raf inhibitor. In certain embodiments, the B-Raf inhibitor inhibits a B-Raf mutant. 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 (toborafenib), CCT196969, CCT241161, BGB659, PLX7904, naporafenib, PLX-8394, or lifirafenib.

[0239] In some embodiments, the combination therapy includes co-administration of a compound of the disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), with a PIK3CA inhibitor, e.g., 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine, inavolisib, gedatrisib, buparlisib, zandelisib, milansertib mesylate, izorulisib, or panulisib. In some embodiments, the PIK3CA inhibitor is a PI3K inhibitor, such as dactolisib, apitolisib, gedatolisib, SF1126, omipalisib, samotricisib, bimiralisib, paxalisib, voxtalisibbupallisib, CH5132799, piralalisib, ZSTK474, sonolisib, pictilisib, copanlisib, B591, TG-100-115, RIDR-PI-103 alpelisib (alpha), or seravelisib (alpha).

[0240] ALK tyrosine kinase inhibitors are used to treat cancers (e.g., solid tumors) driven by constitutive ALK activity. In some embodiments, the combination therapy includes the co-administration of a compound of the present disclosure, such as Compound 1 (e.g., Form 2 of Compound 1), with a CDK4 inhibitor or a CDK6 inhibitor, such as ribociclib, palboclib, trilaciclib, abemaciclib, or dalpiciclib.

[0241] Signal Transducer and Activator of Transcription 3 (STAT3) is activated in many cancers, including those with constitutively active tyrosine kinases such as ALK. See Taniguchi, K et al Sci.Rep.2021 Mar 23;11(1):6685, which is incorporated by reference in its entirety. In some embodiments, the combination therapy includes co-administration of a compound of the disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), with a STAT3 inhibitor, e.g., HL-237, OPB-111077, dambatirsen, C-188-9, KT-333, DUET-01, ENMD-1198 or WP-1066.

[0242] T-LAK cell-directed protein kinase (TOPK, also called 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 antitumor activity. See Xiao, J. et al Cell Death Dis. 2022 Sep 27; 13(9): 828, which is incorporated by reference in its entirety. In some embodiments, the combination therapy includes co-administration of a compound of the disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), with a STAT3 inhibitor, e.g., SKLB-C05, ADA-07, OTS-964, or HI-032 (HITOPK-032).

[0243] In ALK fusion-driven NSCLC, EML4 is the main fusion partner. Wild-type EML4 is a microtubule-associated protein that has been reported to promote microtubule stabilization during interphase. More than 10 different EML4-ALK variants have been identified, with variants 1 and 3 (V1 and V3) being the most frequent. EML4-ALK V3 localizes to microtubules and the interphase of the mitotic spindle. Thus, treatment of EML3-ALK V3-expressing cells with a combination of an ALK inhibitor and a microtubule modulating agent (e.g., a stabilizer or destabilizer) results in synergistic antiproliferative activity in vitro. See Lucken, K. et al Mol.Cancer Res.2022 Jun 3;20(6):854, which is incorporated herein by reference in its entirety. In some embodiments, the combination therapy includes co-administration of a compound of the disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), with 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, narcosine, vincristine sulfate, or vinblastine sulfate colchicine.

[0244] HER2-directed therapy in combination with ALK inhibitor therapy may be beneficial for patients with HER2 amplification and ALK fusions. See Tsui, DCC et al Clin. Lung Cancer 2022 Mar;23(2):e99. In some embodiments, the combination therapy includes co-administration of a compound of the disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), with a HER2-directed therapy, e.g., trastuzumab, pertuzumab, margetuximab, ado-trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (fam-trastuzumab deruxtecan), tucatinib, neratinib, lapatinib, dicitamab vedotin, mobocertinib, trastuzumab heiruronidase, pyrotinib maleate, dacomitinib, or afatinib.

[0245] The combination of an ALK TKI and an antiangiogenic agent may provide patient benefit, for example, 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 includes the co-administration of a compound of the disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), with an antiangiogenic agent, e.g., axitinib, bevacizumab, cabozantinib, everolimus, lenalidomide (Revlimid®), lenvatinib mesylate, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, thalidomide, vandetanib, dib-aflibercept, surufatinib, aplidine, anlotinib hydrochloride, fruquintinib, tivozanib, conbercept, apatinib mesylate, ponatinib, cabozantinib S-malate, aflibercept, sunitinib malate, or anecortave acetate.

[0246] In vitro, the JNK pathway has been determined to be active upon long-term high-dose treatment of ALK fusion-driven cells with ALK tyrosine kinase inhibitors (TKIs), which may allow resistance to ALK TKIs to emerge (Cancer Lett, 2021 Dec 1;522:119-128). Thus, JNK inhibition can sensitize ALK fusion-driven cells to ALK TKIs in vitro and increase the durability of anti-tumor activity. In some embodiments, the combination therapy includes the co-administration of a compound of the present disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), with a JNK inhibitor, e.g., SP600125, BMS-986360, or JNK-401.

[0247] Patients with ALK fusion-positive and TP53-mutated NSCLC may have worse progression-free survival compared to patients with ALK fusion-positive and wild-type TP53 NSCLC. In preclinical studies, p53-mutated ALK fusion-positive cells were resistant to apoptosis induction by ALK tyrosine kinase inhibition, but combination treatment with a proteosome inhibitor appeared to induce apoptosis and increase 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 includes co-administration of a compound of the disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), with a proteosome inhibitor, e.g., izazomib, carfilzomib, or bortezomib.

[0248] In ALK fusion-driven cells, ALK signaling can include activation of mammalian target of rapamycin (mTOR). The combination of an ALK inhibitor and an mTOR inhibitor can induce increased cell cycle arrest in ALK fusion-positive anaplastic large cell lymphoma (ALCL) cells. See Kim, D. et al Anticancer Res. 2020 Mar; 40(3): 1395. In some embodiments, the combination therapy includes co-administration of a compound of the disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), with an mTOR inhibitor, e.g., everolimus, ABI-009, temserolimus, zotarolimus, rapamycin, or umirolimus.

[0249] The transcription factor YAP1 can be activated after treatment of ALK+ cells with an ALK inhibitor. 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 includes co-administration of a compound of the present disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), with a YAP1 inhibitor, e.g., narciclasine, MYF-03-69, verteporfin, IAG-933, ION-537, IK-930, or VT-3989.

[0250] In some embodiments, the combination therapy includes co-administration of a compound of the disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), with a MEK inhibitor, e.g., 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," Identification Number: NCT03202940 (last updated March 9, 2021), which is incorporated by reference herein in its entirety.

[0251] In some embodiments, the combination therapy includes the co-administration of a compound of the present disclosure, such as compound 1 (e.g., form 2 of compound 1), with a MET inhibitor selected from JNJ-38877605, PF-04217903, foretinib, AMG 458, tivantinib, cabozantinib, crizotinib, capmatinib hydrochloride, tepotinib hydrochloride, and savolitinib. See Tanizaki J. et al Br J Cancer, 2012 Feb 14; 106(4): 763-7, which is incorporated herein by reference in its entirety.

[0252] In some embodiments, the combination therapy includes co-administration of a compound of the disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), with an SHP2 inhibitor, e.g., TNO-155, RMC-4630, JAB-3068, or RLY-1971.

[0253] In some embodiments, the combination therapy includes co-administration of a compound of the disclosure, such as Compound 1 (e.g., Form 2 of Compound 1), with a RAS inhibitor, such as adagrasib and sotrasib.

[0254] In some embodiments, the combination therapy includes the co-administration of a compound of the present disclosure, such as Compound 1 (e.g., Form 2 of Compound 1), 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 a TROP2-ADC may provide additional therapeutic benefit over each monotherapy, particularly for patients with ALK-independent resistance mechanisms. In some embodiments, the TROP2 ADC is DS-1062.

[0255] In some embodiments, the combination therapy includes the co-administration of a compound of the present disclosure, such as Compound 1 (e.g., Form 2 of Compound 1), with an AXL ADC (e.g., enapotamab vedotin). AXL is a receptor tyrosine kinase, with increased expression associated with acquired ALK TKI resistance and epithelial-mesenchymal transition (see Debruyne et al, Oncogene 2016). The combination of Compound 1 and an AXL-ADC may provide additional therapeutic benefit over each monotherapy, particularly in ALK TKI-resistant patients with increased AXL expression.

[0256] In some embodiments, the combination therapy includes administering a compound provided herein, for example, 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, repotrectinib, cabozantinib, foretinib, merestinib, taretrectinib, 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.

[0257] In some embodiments, the combination therapy comprises the conjoint administration of a compound of the disclosure, e.g., Compound 1 (e.g., Form 2 of Compound 1), and an anti-PD-1 therapy. In certain embodiments, the combination therapy comprises the conjoint administration of a compound of the disclosure, e.g., Compound 1, and oxaliplatin. In other embodiments, the combination therapy comprises the conjoint administration of a compound of the disclosure, e.g., Compound 1, and doxorubicin.

[0258] In certain embodiments, the concurrent use (within 12 days of enrollment) of drugs that are known strong CYP3A4 inducers (e.g., phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's Wort) is prohibited. In certain embodiments, the concurrent use (within 12 days of enrollment) of drugs that are known strong CYP3A4 inducers (e.g., phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's Wort) is permitted. In certain embodiments, the concurrent use (within 12 days of enrollment) of drugs that are known strong CYP3A4 inducers (e.g., phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's Wort) is used with caution. In certain embodiments, the subject is not taking any one of a strong inducer of CYP3A4, a strong inhibitor of CYP3A4, a sensitive substrate of CYP3A4 and / or CYP2C8, a substrate of P-gp / multidrug resistance protein (MDR1), a substrate of BCRP / breast cancer resistance protein (ABCG2), a substrate of OATP1B1, a substrate of OATP1B3, a substrate of MATE1, or a gastric acid reducer.

[0259] In certain embodiments, the concomitant use (within 12 days of registration) or coadministration of Compound 1 with 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 is permitted. In certain embodiments, the concurrent use (within 12 days of enrollment) or coadministration 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 is prohibited. In certain embodiments, the subject is taking any one of a strong inducer of CYP3A4, a strong inhibitor of CYP3A4, a sensitive substrate of CYP3A4 and / or CYP2C8, substrates of P-gp / multidrug resistance protein (MDR1), substrates of BCRP / breast cancer resistance protein (ABCG2), substrates of OATP1B1, substrates of OATP1B3, substrates of MATE1, or a gastric acid reducer. In certain embodiments, the subject is taking either a strong inducer of CYP3A4 or a strong inhibitor of CYP3A4.

[0260] In certain embodiments, the simultaneous use (within 12 days of registration) or co-administration of gastric acid reducers with Compound 1 should be avoided. In certain embodiments, the simultaneous use (within 12 days of registration) or co-administration of gastric acid reducers with Compound 1 should be used with caution. In certain embodiments, the simultaneous use (within 12 days of registration) or co-administration of gastric acid reducers with Compound 1 is permitted.

[0261] In certain embodiments, the compounds of the present disclosure can be administered in conjunction with non-chemical methods of cancer treatment.In certain embodiments, the compounds of the present disclosure can be administered in conjunction with radiation therapy.In certain embodiments, the compounds of the present disclosure can be administered in conjunction with surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination thereof.

[0262] In certain embodiments, the compounds of the present disclosure may be administered in conjunction with one or more other compounds of the present disclosure. Such combinations may also be administered in conjunction with other therapeutic agents, such as other agents suitable for the treatment of cancer, immunological or neurological diseases, such as those identified above. In certain embodiments, administering one or more additional chemotherapeutic agents in conjunction with the compounds of the present disclosure provides a synergistic effect. In certain embodiments, administering one or more additional chemotherapeutic agents in conjunction with the compounds of the present disclosure provides an additive effect. In certain embodiments, the chemotherapeutic agent is an alkylating agent, an antimetabolite, an antitumor antibiotic, a topoisomerase inhibitor, a platinum agent, a mitotic inhibitor, a hormone therapy, or a corticosteroid. In some embodiments, compound 1 (e.g., Form 2) may be administered in conjunction with a pain therapy. In some embodiments, the pain therapy is an anti-inflammatory, such as a nonsteroidal anti-inflammatory drug (NSAID). In some embodiments, the NSAID is ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, indomethacin, aspirin.

[0263] Pharmaceutical Compositions In certain embodiments, provided herein are pharmaceutical preparations suitable for use in human subjects, the pharmaceutical compositions comprising a compound provided herein (e.g., Compound 1, and one or more pharma- ceutically acceptable excipients). In certain embodiments, the pharmaceutical preparations may be for use in the treatment or prevention of a condition or disease described herein. The compounds provided herein may be used in the manufacture of a medicament for the treatment of any disease or condition disclosed herein.

[0264] The compositions and methods provided herein may be used to treat a subject in need thereof. In certain embodiments, the subject is a mammal, e.g., a human or a non-human mammal. When administered to a subject, e.g., a human, the composition or compound is preferably administered as a pharmaceutical composition, e.g., a pharmaceutical composition comprising a compound provided herein and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, e.g., aqueous solutions, e.g., water or buffered saline, or other solvents or vehicles, e.g., glycols, glycerol, oils, e.g., olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solutions are pyrogen-free or substantially pyrogen-free. Excipients may be selected, e.g., to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition can be in unit dosage form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized powders for reconstitution, solutions, syrups, suppositories, or injections. The composition can also be in a transdermal delivery system, such as a skin patch. The composition can also be in a solution suitable for topical administration, such as eye drops.

[0265] A pharma- ceutically acceptable carrier can contain, for example, a physiologically acceptable agent that acts to stabilize, increase the solubility or increase the absorption of a compound, for example, a compound provided herein. Such physiologically acceptable agents include, for example, carbohydrates, for example, glucose, sucrose or dextran, antioxidants, for example, ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of a pharma- ceutical acceptable carrier that includes a physiologically acceptable agent depends, for example, on 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, for example, a compound provided herein can be incorporated within the liposome or other polymer matrix. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, metabolizable carriers that are relatively simple to prepare and administer.

[0266] In one embodiment, Compound 1: [ka] or a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, diluents, disintegrants, flow agents, binders, and lubricants.

[0267] In one embodiment, Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, is the 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°).

[0268] In one embodiment, Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is a pharma- ceutically acceptable salt of Compound 1. In one embodiment, the salt is amorphous.

[0269] In one embodiment, the diluent is microcrystalline cellulose. In one embodiment, the disintegrant is croscarmellose sodium. In one embodiment, the flow agent is colloidal silicon dioxide. In one embodiment, the binder is hydroxypropyl cellulose (HPC). In one embodiment, the lubricant is magnesium stearate.

[0270] The pharmaceutical composition can be conveniently presented in a 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 strength of 5 mg (by weight of free base compound 1). In certain embodiments, the unit dosage form is a tablet with a dosage strength of 25 mg (by weight of free base compound 1). In certain embodiments, the unit dosage form is a tablet with a dosage strength of 50 mg (by weight of free base compound 1). In certain embodiments, the unit dosage form is a tablet with a dosage strength of 75 mg (by weight of free base compound 1). In certain embodiments, the unit dosage form is a tablet with a dosage strength of 100 mg (by weight of free base compound 1). In certain embodiments, the unit dosage form is a tablet with a dosage strength of 125 mg (by weight of free base compound 1). In certain embodiments, the unit dosage form is a tablet with a dosage strength of 150 mg (by weight of free base compound 1). The amount of active ingredient that can be combined with carrier materials to produce a single dosage form varies depending on the subject being treated, the particular mode of administration. In one embodiment, the oral dosage form is an immediate release tablet. In one embodiment, the pharmaceutical composition is film coated.

[0271] In certain embodiments, the present disclosure provides a pharmaceutical preparation suitable for use in a human patient, comprising a compound as set forth above (e.g., a compound of the present disclosure, such as Compound 1) and one or more pharma- ceutically acceptable excipients. In certain embodiments, the pharmaceutical preparation may be for use in the treatment or prevention of a condition or disease described herein. Any of the disclosed compounds may be used in the manufacture of a medicament for the treatment of any disease or condition disclosed herein.

[0272] In certain embodiments, a pharmaceutical composition is provided that comprises Form 2 and a pharma- ceutically acceptable carrier. In certain embodiments, a pharmaceutical composition is provided that comprises Form 2 that is substantially free of impurities (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% by weight). In certain embodiments, a pharmaceutical composition that comprises Form 2 is substantially free of other crystalline forms of Compound 1.

[0273] The phrase "pharmacologically acceptable" is used herein to indicate that these compounds, materials, compositions and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0274] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the subject. Some examples of materials that can function as pharma- ceutically 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, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, (10) glycols, such as propylene glycol, (11) polyols, such as glycerin, 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) ethyl alcohol, (20) phosphate buffer solution, and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0275] Pharmaceutical compositions (preparations) can be administered to a subject by any of several routes of administration, including, for example, oral (e.g., as drenches, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue, as aqueous or non-aqueous solutions or suspensions); absorption through the oral mucosa (e.g., sublingual); anal, rectal, or vaginal (e.g., as pessaries, creams, or foams); parenteral (e.g., as sterile solutions or suspensions, including intramuscular, intravenous, subcutaneous, or intrathecal); nasal; 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 compounds can also be formulated for inhalation. In certain embodiments, the compounds can be simply dissolved or suspended in sterile water. Details of suitable administration routes and compositions suitable therefor can be found, for example, in 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.

[0276] The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. In certain embodiments, the unit dosage form is a tablet. In certain embodiments, the unit dosage form is a tablet of 5 mg dosage strength (by weight of free base Compound 1). In certain embodiments, the unit dosage form is a tablet of 50 mg dosage strength (by weight of free base Compound 1). The amount of active ingredient that can be combined with carrier materials to produce a single dosage form varies depending on the subject being treated, the particular mode of administration. The amount of active ingredient that can be combined with carrier materials to produce a single dosage form is generally that amount of compound that produces a therapeutic effect. Generally, out of 100 percent, this amount ranges from about 1 percent to about 99 percent of active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0277] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, e.g., a compound provided herein, with a carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound provided herein with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0278] Formulations provided herein suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia, or tragacanth), lyophilized, powdered, granulated; or as a solution or suspension in an aqueous liquid 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 pastille (using an inert base, e.g., gelatin and glycerin, or sucrose and acacia); and / or as a mouthwash, each containing a predetermined amount of a compound provided herein as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0279] To prepare solid dosage forms for oral administration (such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, and granules), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers, for example, sodium citrate or dicalcium phosphate, and / or with one or more of the following: (1) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, for example, glycerol; (4) disintegrants, for example, agar-agar; The pharmaceutical composition may be mixed with any of the following: calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, (5) solution retarders such as paraffin, (6) absorption enhancers such as quaternary ammonium compounds, (7) wetting agents such as cetyl alcohol and glycerol monostearate, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, 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 sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also include buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0280] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of powdered compound moistened with an inert liquid diluent in a suitable machine.

[0281] Tablets, as well as other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may be optionally scored or prepared with 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 sustained or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres in various proportions to provide a desired release profile. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that may be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents, and may be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0282] Liquid dosage forms useful for oral administration include pharma- ceutically acceptable emulsions, lyophilized agents for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active ingredients, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, groundnut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0283] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0284] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0285] Formulations of pharmaceutical compositions 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, a suppository wax or a salicylate; suppositories are solid at room temperature but liquid at body temperature and therefore will melt in the rectal or vaginal cavity and release the active compounds.

[0286] Formulations of the pharmaceutical composition for administration to the buccal cavity may be presented as a mouthwash or a mouth spray or an oral ointment.

[0287] Alternatively or additionally, the compositions may be formulated for delivery via a catheter, stent, wire or other intraluminal device, which may be particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine.

[0288] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0289] 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 pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0290] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0291] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0292] Transdermal patch has the additional advantage of providing controlled delivery of the compound provided herein to the body.Such dosage forms can be prepared by dissolving or dispersing active compound in suitable medium.Also, absorption enhancers can be used to increase the flux of compound across skin.The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing compound in a polymer matrix or gel.

[0293] Also contemplated within the scope of the present disclosure are eye drop formulations, eye ointments, powders, solutions, and the like.Exemplary eye drop formulations are described in U.S. Patent Application Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697, and 2005 / 004074, and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference.If desired, the liquid eye drop formulation has properties similar to those of tears, aqueous humor, or vitreous humor, or is compatible with such fluids.The preferred route of administration is topical administration (e.g., external administration, e.g., eye drops, or administration via implants).

[0294] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to 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, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0295] Pharmaceutical compositions suitable for parenteral administration contain one or more active compounds in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or in combination with sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before 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.

[0296] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0297] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action may be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenol sorbic acid. It may also be desirable to include isotonic agents, such as sugars and sodium chloride, in the composition. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0298] In some cases, it is desirable to slow down the absorption of drugs from subcutaneous or intramuscular injections in order to prolong the effect of drugs.This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility.The rate of absorption of the drug then depends on its dissolution rate, which in turn depends on the crystal size and crystalline form.As an alternative, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0299] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0300] For use in the methods provided herein, the active compounds may be administered per se or as pharmaceutical compositions containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of the active ingredient in combination with a pharma- ceutically acceptable carrier.

[0301] Also, the method of introduction can be provided by rechargeable or biodegradable devices. Recently, various sustained release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. Various biocompatible polymers, including both biodegradable and non-degradable polymers (including hydrogels), can be used to form implants for sustained release of compounds at specific target sites.

[0302] Actual dosage levels of the active ingredients in pharmaceutical compositions may be varied 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.

[0303] The selected dosage level will depend on a variety of factors, including the activity of the particular compound or combination of compounds, or esters, salts or amides thereof, being used, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being used, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) being used, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and similar factors well known in the medical arts.

[0304] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start with a dose of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and the dosage can be gradually increased until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of the compound that is sufficient to induce the desired therapeutic effect. In general, it is understood that the effective amount of the compound varies according to the subject's weight, sex, age, and medical history. Other factors that affect the effective amount may include, but are not limited to, the severity of the subject's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered together with the compound provided herein. A larger total dose may 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 13 ed., 1814-1882, incorporated herein by reference).

[0305] If desired, the effective daily dose of active compound can be administered as 1, 2, 3, 4, 5, 6 or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage form.In certain embodiments provided herein, active compound can be administered 2 or 3 times a day.In a preferred embodiment, active compound is administered once a day.

[0306] In certain embodiments, the compounds provided herein may be used alone or may be administered in combination with another type of therapeutic agent. As used herein, the phrase "co-administration" refers to any administration form of two or more different therapeutic compounds, in which the previously administered therapeutic compound is still effective in the body while the second compound is administered (e.g., 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 either simultaneously or sequentially, either in the same formulation or in separate formulations. In certain embodiments, the different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week of each other. Thus, the subject receiving such treatment can benefit from the combined effect of the different therapeutic compounds.

[0307] In certain embodiments, the co-administration of a compound provided herein with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved efficacy over separate administration of the compound provided herein or each of the one or more additional therapeutic agent(s). In certain such embodiments, the co-administration provides an additive effect, where additive effect refers to the sum of the effects of separate administration of a compound provided herein and one or more additional therapeutic agent(s).

[0308] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0309] Examples of pharma- ceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha tocopherol; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0310] The disclosure, having now been generally described, will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the disclosure and are not intended to limit the disclosure. EXAMPLES

[0311] Example 1: Phase 1 / 2 Clinical Study An FIH Phase 1 / 2 multicenter, open-label, dose escalation and expansion study will be conducted to evaluate the safety and tolerability of Compound 1, determine the RP2D, and, if applicable, the MTD, and evaluate antitumor activity in patients with advanced ALK-positive NSCLC and other advanced ALK-positive solid tumors.

[0312] Phase 1 objectives:

[0313] Primary objective: To determine the RP2D and / or maximum tolerated dose (MTD) of Compound 1 in patients with advanced ALK-positive solid tumors.

[0314] Secondary objectives: to assess the overall safety and tolerability of Compound 1; to characterize the PK profile of Compound 1; to evaluate the preliminary antitumor activity of Compound 1 in patients with advanced ALK-positive solid tumors.

[0315] Exploratory objectives: to evaluate additional tumor and blood-based molecular markers of response and resistance to Compound 1; to evaluate the metabolite profile of Compound 1; to evaluate extracranial activity.

[0316] Phase 2 objectives:

[0317] Primary Objective: To evaluate the efficacy of Compound 1 at the RP2D in patients with advanced ALK-positive NSCLC, including patients with ALK resistance mutations and other solid tumors.

[0318] Secondary objectives: To evaluate additional measures of clinical efficacy in patients with ALK-positive NSCLC, including those with ALK resistance mutations, and other solid tumors; to evaluate the intracranial antitumor activity of Compound 1 at the RP2D in patients with advanced ALK-positive NSCLC and other solid tumors; to characterize the safety and tolerability of Compound 1 at the RP2D; to determine the PK profile of Compound 1 at the RP2D.

[0319] Exploratory objectives: to evaluate additional tumor and blood-based molecular markers of response and resistance to Compound 1; to evaluate progression-free survival on subsequent therapies; to evaluate extracranial activity.

[0320] Phase 1 Endpoints:

[0321] Primary endpoints: incidence of dose-limiting toxicities (DLTs) during cycle 1, overall safety profile, RP2D determined by PK, PD and preliminary efficacy, and MTD, if applicable.

[0322] Secondary Endpoints: Incidence and severity of treatment-emergent adverse events (TEAEs) and changes in clinically relevant laboratory parameters Pharmacokinetic parameters of compound 1: Maximum plasma concentration (C max );C max - Dose normalization; plasma concentration at the end of the dosing interval (C tau ); mean plasma concentration (Cavg ); Time of maximum concentration (T max ); area under the curve at the end of the dosing interval (AUC tau );AUC tau - Dose normalized; area under the curve (AUC 0-24 );AUC 0-24 - Dose normalized; area under the curve from time 0 to infinity (AUC inf );AUC inf -Dose normalized; oral clearance (CL / F); volume of distribution (V z / F); and half-life (t 1 / 2 ) Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - defined as the percentage of patients with a complete response (CR) or partial response (PR) by RECIST 1.1 Duration of response (DOR) by RECIST 1.1 - defined as the time from first response by RECIST 1.1 to radiographic disease progression or death in responders - Intracranial ORR (IC-ORR) by RECIST 1.1 - In patients with measurable metastatic CNS disease, up to five intracranial target lesions will be assessed for response per RECIST 1.1 Intracranial DOR by RECIST 1.1 (IC-DOR) - defined as the time from first IC response by RECIST 1.1 to radiographic IC disease progression or death in responders with metastatic CNS disease Clinical benefit rate (CBR) by RECIST 1.1 - defined as the percentage of patients with confirmed CR or PR or stable disease (SD) lasting at least 24 weeks according to RECIST 1.1 Time to response by RECIST 1.1 - defined as the time from first dose to first confirmed radiographic response per RECIST 1.1 Progression-free survival (PFS) by RECIST 1.1 - defined as the time from first dose to radiographic disease progression by RECIST 1.1 or death

[0323] Exploratory Endpoints: - baseline levels and / or post-treatment changes in tumor and blood biomarker levels, including but not limited to expression of proteins, phospho-proteins, genes, variant allele frequencies, and genetic mutations; Identification and quantification of Compound 1 metabolites in post-treatment blood samples Extracranial ORR: Defined as the percentage of patients with extracranial metastatic disease who have an extracranial response according to investigator-assessed RECIST 1.1

[0324] Phase 2 Endpoints:

[0325] Primary Endpoint: ORR by RECIST 1.1 - defined as the proportion of patients with confirmed CR or PR according to RECIST 1.1 by BICR among patients with measurable disease at baseline by Blinded Independent Central Review (BICR).

[0326] Secondary Endpoints - DOR-responders by RECIST 1.1, defined as the time from first confirmed BICR response by RECIST 1.1 to radiographic disease progression or death -CBR-BICR by RECIST 1.1 -Defined as the percentage of patients with confirmed CR or PR or SD according to RECIST 1.1 lasting at least 24 weeks Time to response by RECIST 1.1 - defined as the time from first dose to first confirmed radiographic response according to RECIST 1.1 by BICR PFS by RECIST 1.1 - defined as the time from first dose to radiographic disease progression or death by RECIST 1.1 based on BICR assessment Overall Survival (OS) – defined as the time from first dose to death from any cause - IC-ORR by RECIST 1.1 - In patients with measurable metastatic CNS disease, up to five intracranial target lesions will be assessed for response according to RECIST 1.1 by BICR in patients with confirmed measurable intracranial disease at baseline by BICR IC-DOR by RECIST 1.1 – defined as the time from first BICR-assessed confirmed response by RECIST 1.1 to radiographic disease progression or death in responders with metastatic CNS disease. Time to IC response by RECIST 1.1 - defined as the time from first dose to first confirmed radiographic IC response per RECIST 1.1 by BICR in patients with metastatic CNS disease Intracranial PFS by RECIST 1.1 (IC-PFS) - defined as the time from first dose to radiographic disease progression or death by RECIST 1.1 based on BICR assessment in patients with metastatic CNS disease Incidence and severity of TEAEs and changes in clinically relevant laboratory parameters Pharmacokinetic parameters of compound 1-C max , C max -Dose normalization, 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

[0327] Exploratory Endpoints: - baseline levels and / or post-treatment changes in tumor and blood biomarker levels, including but not limited to expression of proteins, phospho-proteins, genes, variant allele frequencies, and genetic mutations; PFS2: defined as the time from initiation of treatment with compound 1 to disease progression on subsequent therapy (based on local assessment or medical record report of progression on subsequent therapy) or death from any cause. - EC-ORR: In patients with extracranial metastatic disease, defined as the percentage of patients with an extracranial response according to investigator-assessed RECIST 1.1

[0328] Study Design: The study will be conducted in two phases (Figure 1).

[0329] Phase 1 dose escalation includes patients with locally advanced or metastatic solid tumors harboring ALK rearrangements or activating ALK mutations. Patients with ALK fusion-positive NSCLC must have received ≥1 prior ALK TKI, one of which must be a second- or third-generation TKI (ceritinib, alectinib, brigatinib, or lorlatinib), and those with other solid tumors must have received ≥1 prior systemic anticancer therapy or for whom no satisfactory standard therapy exists. The phase 1 portion of the study is designed to determine the RP2D and, if applicable, the MTD, and evaluate the safety of compound 1.

[0330] The Phase 1 portion of the study will evaluate dose escalation using a BOIN design with a 3+3 lead-in period. The DLT observation period will be defined as from the first dose of C1D1 to the end of the first cycle (21-day cycle duration). After each group of patients is treated at a given dose level and monitored for 21 days, available data (including but not limited to incidence of DLT / other AEs and preliminary PK) will be reviewed. Initiation of the next dose group will depend on the occurrence of DLTs, the performance of the BOIN analysis, and recommendations, taking into account the overall safety profile. The BOIN dose escalation will be declared complete when the number of evaluable patients treated at the current dose reaches 12 and a decision is made to remain at the current dose, or when the maximum sample size is reached. However, if the optimal biological dose or maximum feasible dose is reached prior to the completion of the BOIN dose escalation, the RP2D may be declared. Patients with DLTs will not be replaced. Patients who are not evaluable for DLT (do not receive ≧16 days of intended dosing and / or do not complete the 21-day observation period during the first cycle for reasons other than DLT) may be replaced.

[0331] After a DLT occurs, treatment with Compound 1 may be resumed at a reduced dose if it is determined that continued treatment with Compound 1 would be in the patient's interest. If an AE resulting in dose interruption meets the definition of a DLT, study drug will be resumed at the previous safe dose level or at a reduced dose level (see Table A for recommended reduced dose levels). Upon resolution of the AE and dose interruption, the patient may resume therapy at one dose level reduction. Study treatment may be resumed without a dose reduction if it is determined to be in the patient's interest. If an AE recurs with the same or worsening intensity, treatment will be interrupted and once the dose has been reduced, study treatment should be continued. Up to three dose reductions are permitted for any patient. [Table 2]

[0332] During dose escalation, when available data support the safety, PK, and clinical activity of a given dose level, additional patients (up to a total of 12 patients including those already included in the BOIN dose escalation) may be enrolled at this dose level. These patients will be monitored for DLTs and included in the evaluation for the implementation of the BOIN dose escalation. A total of up to about 54 patients may be treated in the Phase 1 dose escalation.

[0333] Selection of the RP2D will occur after a sufficient number of patients have been enrolled and completed the first imaging / efficacy assessments and the data have been reviewed. The RP2D is the dose level that is expected to be the MTD or lower optimal biological dose, or maximum feasible dose, and is considered suitable for testing in the Phase 2 portion of the study. Selection of the RP2D will be performed using the totality of data generated from Phase 1, including evaluation of clinical PK, pharmacodynamics, safety, and antitumor activity.

[0334] Phase 2 includes four cohorts: Cohort 2a: Patients with locally advanced or metastatic NSCLC harboring ALK rearrangements who received one prior second-generation ALK TKI (ceritinib, alectinib, or brigatinib). Cohort 2b: Patients with locally advanced or metastatic NSCLC harboring ALK rearrangements who have received 2-3 prior first- or second-generation ALK TKIs (crizotinib, ceritinib, alectinib, or brigatinib). ● Cohort 2c: Patients with locally advanced or metastatic NSCLC harboring ALK rearrangements who have received 2-3 prior first- or second-generation ALK TKIs (crizotinib, ceritinib, alectinib, or brigatinib). Cohort 2d: Patients with other solid tumors harboring ALK rearrangements or activating ALK mutations, including patients with NSCLC ineligible for Cohorts 2a-c who have received ≥1 prior systemic anticancer therapy or for whom no satisfactory standard therapy exists.

[0335] The phase 2 portion of the study is designed to estimate the ORR and corresponding 95% CI for the following patient populations: all treated patients with ALK-positive NSCLC pooled across cohorts 2a, 2b, and 2c; each individual cohort 2a, 2b, and 2c; and patients with the ALK resistance mutation of interest (i.e., any ALK resistance mutation; ALK G1202R mutation with or without other ALK mutations) pooled across cohorts 2a, 2b, and 2c.

[0336] Phase 1 Dose Levels: Phase 1 will evaluate escalating doses of Compound 1 monotherapy administered orally once daily (QD) continuously until disease progression, unacceptable toxicity, or voluntary withdrawal of consent. Under the BOIN design, up to approximately 54 patients will be enrolled and treated at the dose levels presented in the table below. [Table 3]

[0337] Intermediate dose levels may be explored during dose escalation; lower dose levels (e.g., 10 mg QD) may be explored based on the results of BOIN.

[0338] Recommended Phase 2 Dose: The recommended phase 2 dose (RP2D) is the dose level that is expected to be the MTD or lower optimal biological dose, or maximum feasible dose, and is considered suitable for testing in the Phase 2 portion of the study. The selection of the RP2D is made using the totality of data generated from Phase 1, including evaluation of clinical PK, pharmacodynamics, safety, and antitumor activity.

[0339] Duration of Treatment: Across both phases, patients will receive study drug continuously from the first dose until independent radiological confirmation of disease progression, unacceptable toxicity, patient withdrawal, study termination, or commercial availability. Patients may continue to receive Compound 1 following progression in the body or brain suitable for local ablation.

[0340] Definition of End of Study: End of study is defined as the date of the last visit of the last patient in the study or the end date of the study.

[0341] Participation Criteria: Patients must meet all of the following criteria to be eligible for enrollment in the study. 1. Age ≥ 18 years. (Phase 2 cohort 2d only: Age ≥ 12 years and weight > 40 kg.) 2.Disease criteria Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumors with documented ALK rearrangements or activating ALK mutations detected by a validated assay (i.e. CLIA in the US). 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). c. Cohort 2d: Patients with any other histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented ALK rearrangement or activating ALK mutation as detected by a validated assay (i.e., CLIA in the US), 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 carcinoma, and NSCLC not eligible for Cohorts 2a-c. 3. Previous anti-cancer treatment Phase 1: Patients with ALK fusion-positive NSCLC must have received ≥1 prior ALK TKI, one of which must be a second- or third-generation TKI (ceritinib, alectinib, brigatinib, or lorlatinib). Patients with other solid tumors must have received ≥1 prior systemic anticancer therapy or for which no satisfactory standard therapy exists. b. Cohort 2a: One prior second-generation ALK TKI (ceritinib, alectinib, or brigatinib). c. Cohort 2b: 2-3 prior 1st or 2nd generation ALK TKIs (crizotinib, ceritinib, alectinib, or brigatinib). d. Cohort 2c: 2–3 prior ALK TKIs who received lorlatinib in second or third line of therapy. e. All patients except Phase 2 Cohort 2d: ≦2 prior chemotherapy and / or immunotherapy lines in the locally advanced or metastatic setting. Patients who have received >2 prior chemotherapy and / or immunotherapy lines in the locally advanced or metastatic setting may be enrolled in Phase 2 Cohort 2d. 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 Cohort 2d and Phase 2 Cohort 2d. 4. Phase 1: Must have evaluable disease (target or non-target) according to RECIST 1.1. Phase 2: Must have measurable disease defined as ≧1 radiologically measurable target lesion according to RECIST 1.1 (Oken et al., Am. J. Clin. Oncol. 1982, 5(6):649-655). 5. Pre-treatment tumor tissue submitted for central analysis (archived or fresh biopsy, if applicable). Submitted tumor tissue is preferably obtained during or after the most recent disease progression. If suitable tissue is not available and a biopsy is not deemed safe and medically feasible by the investigator, the patient may be approved for enrollment after consultation with the sponsor's medical monitor. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 6.0, 1 or 2 (Eisenhauer et al., Eur. J. Cancer 2009, 45(2):228-247). 7. Adequate organ function and bone marrow reserve as demonstrated by the following laboratory evaluations performed prior to the first dose of study drug. Bone marrow function: absolute neutrophil count (ANC) ≥ 1500 / μL; platelet count > 75,000 / μL; hemoglobin ≥ 8 g / dL. b. Renal function: estimated creatinine clearance ≥ 60 mL / min; Hepatic function: bilirubin < 1.5 x ULN unless there is evidence of Gilbert's syndrome in which case patients should have total bilirubin < 3.0 mg / dL; aspartate aminotransferase and alanine aminotransferase ≤ 3.0 x ULN (if concomitant liver metastases ≤ 5.0 x ULN). 8. All clinically relevant toxicities associated with prior anticancer therapy must be grade ≤1 or have resolved to baseline (except for alopecia or ototoxicity). 9. Women of childbearing potential (WOCBP) and male patients must be willing to abstain from sexual activity, use effective contraception, or be surgically sterilized from the time they sign the Informed Consent Form (ICF), for the duration of the study, and for 30 days for women and 90 days for men after the last dose of study drug. Effective contraception for WOCBP includes one "highly effective" method or two "effective" methods based on World Health Organization (WHO) criteria. 10. Willing and able to provide written informed consent and comply with the requirements of the study protocol. For patients <18 years of age (Phase 2 cohort 2d only), assent must be obtained and a parent / guardian must provide written consent.

[0342] Exclusion Criteria: Patients who meet any of the following criteria will be excluded from the study. 1. The patient's cancer has a known primary driver alteration other than ALK. 2. Known allergy / hypersensitivity to any of the Compound 1 excipients. 3. Major surgery within 4 weeks of study entry. Minor surgical procedures (e.g., port insertion) will be permitted, but with sufficient time for wound healing as deemed clinically appropriate. 4. Ongoing or recent anti-cancer therapy within the following time frames prior to the first dose of study drug (Compound 1 may be initiated within limits for prior TKI or chemotherapy if deemed safe and within the patient's best interest and with prior approval): a. TKIs or other non-chemotherapy / non-immunotherapy anticancer drugs with less than 5 half-lives or less than 7 days, whichever is longer. b. Chemotherapy for <21 days c. Immunotherapy or cell therapy for less than 28 days 5. Ongoing or recent radiation therapy within the following time frames prior to the first dose of study drug: Radiation therapy for less than 14 days (excluding palliative radiation to relieve bone pain) b. Palliative radiation to relieve bone pain for less than 48 hours c. Stereotactic or small-field brain irradiation for less than 7 days d. Whole brain radiation for less than 14 days 6. Prior high-dose chemotherapy requiring stem cell rescue. 7. Uncontrolled clinically relevant bacterial or fungal infection requiring systemic therapy. 8. Known active tuberculosis, or active hepatitis B or C. Active hepatitis B is defined by a known positive HBsAg result and a known quantitative HBV DNA result above the lower limit of detection of the assay. Active hepatitis C is defined by a known positive hepatitis C Ab result and a known quantitative HCV RNA result above the lower limit of detection of the assay. 9. The patient has a consistent QTcF of >450 ms. The patient has a history of Long QT Syndrome or Torsades de Pointes. 10. Patients with clinically significant cardiovascular disease, including: Within 3 months of enrollment: cerebrovascular accident / stroke; myocardial infarction; unstable angina; uncontrolled atrial fibrillation of any grade b. History of congestive heart failure (New York Heart Association Classification class ≥ II); second- or third-degree AV block (unless paced), or any AV block with a consistent PR of >220 ms; or ongoing arrhythmia of NCI-CTCAE grade ≥ 2. 11. Patient has a primary CNS tumor associated with central nervous system (CNS) metastases or progressive neurological symptoms, or requires an increased dose of corticosteroids to control CNS disease. If the patient requires corticosteroids for management of CNS disease, the dose must be stable for 2 weeks prior to C1D1. Asymptomatic leptomeningeal carcinomatosis is permitted. 12. Symptomatic spinal cord compression. 13. Patients with moderate to severe cognitive or psychiatric disorders that impair the patient's ability to comply with study requirements. 14. Evidence of active malignancy (other than a current ALK-positive solid malignancy) within the past 2 years requiring systemic therapy. Exceptions: nonmelanoma skin cancer, melanoma in situ, cervical cancer in situ, papillary thyroid cancer, intraductal carcinoma in situ of the breast, or localized and presumed cured prostate cancer. Patients on long-term antihormonal therapy for a previous malignancy are permitted as long as the malignancy has not been active within the past 2 years. 15. Concurrent use of a strong CYP3A4 inducer or a strong CYP3A4 inhibitor (within 12 days of enrollment). 16. Evidence of malabsorption due to previous gastrointestinal surgery, disease or other illness that may affect the oral absorption, distribution, metabolism or excretion of the study drug. 17. Patient is pregnant or breastfeeding. WOCBP must have a negative serum pregnancy test at screening and a negative serum or urine test prior to the first dose of study drug. 18. Actively receiving systemic treatment or direct medical intervention in another therapeutic clinical study. 19. Any evidence of current ILD or pneumonia, or a history of ILD or non-infectious pneumonia. 20. Any medical condition or laboratory abnormality that poses risk to the study patient or confounds the ability to interpret study results.

[0343] Study Drug, Dose and Route of Administration: Compound 1 is supplied as a tablet for oral administration in two strengths: 5 mg and 50 mg. Compound 1 should be taken on an empty stomach at least 1 hour before and not less than 2 hours after ingestion of food and / or beverages other than water.

[0344] Previous and Concomitant Medications and Therapies:

[0345] In certain embodiments, the concurrent use (within 12 days of enrollment) of drugs that are known strong CYP3A4 inducers (e.g., phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's Wort) is prohibited. In certain embodiments, the concurrent use (within 12 days of enrollment) of drugs that are known strong CYP3A4 inducers (e.g., phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's Wort) is permitted. In certain embodiments, the concurrent use (within 12 days of enrollment) of drugs that are known strong CYP3A4 inducers (e.g., phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's Wort) is used with caution.

[0346] In certain embodiments, the concurrent use (within 12 days of registration) of drugs that are known strong CYP3A4 inhibitors is prohibited. In certain embodiments, the concurrent use (within 12 days of registration) of drugs that are known strong CYP3A4 inhibitors is permitted. In certain embodiments, the concurrent use (within 12 days of registration) of drugs that are known strong CYP3A4 inhibitors is used with caution. In certain embodiments, the strong CYP3A4 inhibitors are clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, and grapefruit b (including juice).

[0347] In certain embodiments, the concomitant use (within 12 days of registration) or coadministration of Compound 1 with 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 is permitted. In certain embodiments, concurrent use (within 12 days of enrollment) or coadministration 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 is prohibited.

[0348] In certain embodiments, the simultaneous use (within 12 days of registration) or co-administration of gastric acid reducers with Compound 1 should be avoided. In certain embodiments, the simultaneous use (within 12 days of registration) or co-administration of gastric acid reducers with Compound 1 should be used with caution. In certain embodiments, the simultaneous use (within 12 days of registration) or co-administration of gastric acid reducers with Compound 1 is permitted.

[0349] Exemplary agents provided herein include, but are not limited to, the following: ●CYP3A4 inducers: phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's wort CYP3A4 inhibitors: clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, grapefruit (including juice) - CYP3A4 substrates (sensitive): buspirone, everolimus, lovastatin, midazolam, simvastatin, triazolam, maraviroc, conivaptan, darifenacin ●CYP2C8 substrates (sensitive): repaglinide, montelukast, pioglitazone, rosiglitazone P-gp substrates: digoxin, fexofenadine, loperamide, quinidine, talinolol, vinblastine ●BCRP substrates: daidzein, dantrolene, estrone-3-sulfate, prazosin, sulfasalazine OATP1B1 / OATP1B3 substrates: Antiviral protease inhibitors (e.g., ritonavir), clarithromycin, cyclosporine, gemfibrozil, rifampin, simepravir MATE1 substrates: metformin, tetraethylammonium (TEA), cimetidine, procainamide

[0350] Example 2: Cholangiocarcinoma MR619 model The MR619 model was derived from a patient with cholangiocarcinoma harboring the STRN-ALK fusion who progressed on alectinib treatment due to the acquisition of 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 cultured at approximately 170 mm 3 The mice were randomized into five groups of five animals with a mean initial tumor volume of 100 mg / kg QD PO 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 and was used to formulate compound 1. Lorlatinib was formulated in 2 equivalents HCl + 20% HP-β-CD in water. Alectinib was formulated in 0.02 N HCl, 10% DMSO, 10% Cremophor EL, 15% PEG-400, and 15% HP-β-CD. Tumor volumes were measured twice weekly and body weights were measured approximately five times weekly. The results confirmed that the model was resistant to alectinib, consistent with clinical observations. Lorlatinib was able to induce regression, but compound 1 at both doses induced stronger regression than lorlatinib (Figure 2). Abbreviations: QD = once daily, BID = twice daily, PO = oral, HP-β-CD = hydroxypropyl-β-cyclodextrin, DMSO = dimethyl sulfoxide, PEG = polyethylene glycol.

[0351] Example 3: Neuroblastoma Assay Biochemical assay. Several kinase inhibitors, including compound 1, were evaluated for their inhibitory activity in a biochemical PhosphoSens assay (AssayQuant Technologies, MA, USA). The compounds were premixed with AT, DTT, and fluorogenic substrate AQT0101 (AssayQuant Technologies) for 30 min at 30° C. The reaction was initiated by the addition of one of the following enzymes: 2 nM ALK F1174L (SignalChem #A19-12EG), 0.5 nM ALK F1174S (SignalChem #A19-12FG), 1 nM ALK R1275Q (SignalChem #A19-12LG), or 0.5 nM 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 MgCl 2 , 15 μM AQT0101, and the enzyme at the specified concentration. The plates were incubated at λ ex / em = 360 / 485 nm and readings were taken every 1-2 min for 240 min at 30 °C. The initial velocity of the reaction (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 50 ) was determined from the percent inhibition of the initial reaction rate and the inhibitor concentration using four-parameter logistic regression.

[0352] Cell viability assay. Kelly (ALK F1174L), SH-SY5Y (ALK F1174L), or NB-1 (ALK Ex2-3del) cells were plated at 1,000 cells / well (40 μL) in 384-well plates for one day. Test compounds (40 nL) were then added in 3-fold dilution series using a TECAN EVO200 liquid handler and incubated for 72 hours. Plates were equilibrated at room temperature for 15 minutes, followed by the addition of 40 μL of CellTiter-Glo reagent (Promega). Luminescence was measured in a plate reader. Half-maximal inhibitory concentrations (IC 50 ) was calculated from the percent inhibition and inhibitor concentration using four-parameter logistic regression.

[0353] A summary of the results from the biochemical and cell viability assays is shown in FIG.

[0354] Example 4: Anaplastic large cell lymphoma assay Cell viability assay. Karpas299 cells were plated at 1,000 cells / well (40 μL) in 384-well plates for one 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. Plates were equilibrated at room temperature for 15 minutes, followed by the addition of 40 μL of CellTiter-Glo reagent (Promega). Luminescence was measured in a plate reader. Half-maximal inhibitory concentrations (IC 50 ) was calculated from the percent inhibition and inhibitor concentration using four-parameter logistic regression.

[0355] Cellular phosphorylation assay. Test compounds (100 nL each) were added to 96-well plates in 3-fold serial dilutions 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 (Cell Signaling Technology #7020) according to the manufacturer's instructions. Half-maximal inhibitory concentrations (IC 50 ) was calculated from the percent inhibition and inhibitor concentration using four-parameter logistic regression.

[0356] A summary of the results of the cell viability and phosphorylation assays is shown in FIG.

[0357] Example 5: Soft Tissue Sarcoma (SS) Assay Cell viability assay. Aska-SS cells harboring an ALK deletion around exons 2-17 were plated at 1,000 cells / well (40 μL) in 384-well plates 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 h. Plates were equilibrated at room temperature for 15 min, followed by the addition of 40 μL of CellTiter-Glo reagent (Promega). Luminescence was measured in a plate reader. Half-maximal inhibitory concentrations (IC 50 ) was calculated from the percent inhibition and inhibitor concentration using four-parameter logistic regression.

[0358] Cellular phosphorylation assay. Test compounds (100 nL each) were added to 96-well plates in 3-fold serial dilutions 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. Half-maximal inhibitory concentrations (IC 50 ) was calculated from the percent inhibition and inhibitor concentration using four-parameter logistic regression.

[0359] A summary of the results of the cell viability and phosphorylation assays is shown in FIG.

[0360] Example 6: MR448re cell line carrying EML4-ALK v3 G1202R / T1151M mutation The MR448re cell line was established from the ascites (intraperitoneal exudate) of a patient with non-small cell lung cancer who had EML4-ALK v3 fusion and progressed on lorlatinib treatment due to the acquisition of G1202R / T1151M mutation. Ascites mononuclear cells were isolated by Ficoll centrifugation and cultured in medium (DMEM F12 Glutamax, 10% antibiotic / antimycotic, 10% FBS, hydrocortisone, adenine, RockInhibitor, and 1 / 10 cholera toxin). After obtaining stable cancer cells, the presence of EML4-ALK fusion and G1202R / T1151M compound mutation was confirmed by PCR and sequencing. MR448re cells were treated with test compounds at half-log dilutions (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 viability was measured using CellTiter-Glo reagent (Promega). 50 ) was calculated from percent inhibition and inhibitor concentration using four-parameter logistic regression. Representative data are shown in FIG.

[0361] Example 7: Mutation assessment The inhibitory activity of ALK inhibitors was evaluated in Ba / F3 cells harboring EML4-ALK fusions with various 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 harboring EML4-ALK fusions, and Ba / F3 cells harboring ETV6-TRKB or TPM3-TRKA fusions, using the following general procedure.

[0362] Cells were plated in 384-well plates. Test compounds were added in 3-fold serial dilutions using a TECAN EVO200 liquid handler and incubated for 72 hours. Plates were equilibrated at room temperature for 15 minutes followed by addition of CellTiter-Glo reagent (Promega). Luminescence was measured in a plate reader. Half-maximal inhibitory concentrations (IC 50 ) was calculated from percent inhibition and inhibitor concentration using four-parameter logistic regression. Representative data are shown in FIG.

[0363] Example 8: MR448re PDX Study The MR448re cell line was established from ascites (intraperitoneal exudate) of an NSCLC patient progressing on lorlatinib. Ascites mononuclear cells were isolated by Ficoll centrifugation and cultured in culture medium (DMEM F12 Glutamax, 10% antibiotic / antimycotic, 10% FBS, hydrocortisone, adenine, RockInhibitor, and 1 / 10 cholera toxin). After obtaining stable cancer cells, 5 million cells were injected into Swiss nude mice to obtain xenograft models. After inoculation, mice were randomized and grouped according to tumor size. Test compounds were administered orally twice daily for several days.

[0364] Example 9: Western blot analysis of PD markers Abstract: ALK gene rearrangements can induce constitutive activation of ALK kinase activity, resulting in ALK autophosphorylation (pALK) and subsequent activation of MAP kinase (MAPK), PI3K / AKT, and JAK / STAT pathways to drive 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 along with phospho-p44 / 42 MAPK ERK1 / 2 (pERK) as downstream MAPK pathway markers, phospho-AKT (pAKT) and phospho-S6 as markers of the PI3K / AKT pathway, and cleaved PARP as a marker of apoptosis.

[0365] Results. Compound 1 dose-dependently reduced pALK levels upon QD x 1 day treatment at 1 and 12 hours, with robust reductions observed at a dose of 1.5 mg / kg (the dose that induced regression, also referred to as the "regression dose," data not shown). Lorlatinib at 5 mg / kg QD x 1 day reduced pALK levels 1 and 12 hours after treatment. Over this period, compound 1 at 1.5 mg / kg and lorlatinib at 5 mg / kg modestly reduced total ALK levels (Figures 8A and 8C). Repeated administration of compound 1 and lorlatinib (BID x 5 days) produced similar results, with compound 1 dose-dependently reducing pALK levels and lorlatinib reducing pALK levels. Over the same period, compound 1 (1.5 mg / kg) and lorlatinib (5 mg / kg) modestly reduced total ALK levels, whereas ALK levels in vehicle-treated tumors were variable (Figures 8B and 8D). Reduction of pALK is consistent with direct inhibition of ALK kinase activity by compound 1 and lorlatinib.

[0366] To evaluate the effect of treatment with compound 1 on downstream signaling pathways, the levels of pERK, a phosphomarker of the MAPK pathway, and pAKT and pS6, phosphomarkers of the PI3K / AKT pathway, were monitored. Compound 1 QD x 1 day dose-dependently reduced pERK levels, with lower levels observed at 1 hour compared to 12 hours after treatment. Lorlatinib at 5 mg / kg QD x 1 day behaved similarly (Figure 9A). In contrast, compound 1 and lorlatinib reduced pAKT / AKT levels 12 hours after QD x 1 day treatment, but not at 1 hour, despite having variable responses in the vehicle group (Figure 9C). For the pS6 / S6 readout, lorlatinib moderately reduced pS6 / S6 levels 1 hour after QD x 1 day treatment, but compound 1 did not dose-dependently reduce pS6 / S6 levels (Figure 9E).

[0367] The observation of tumor regression with compound 1 prompted evaluation of a marker of apoptosis, cleaved PARP. Treatment with a single dose of compound 1 (1.5 mg / kg) significantly increased the levels of cleaved PARP at 12 hours. This was not observed with compound 1 at 0.06 mg / kg, a dose that did not induce regression. Treatment with a single dose of 5 mg / kg lorlatinib also increased cleaved PARP at 12 hours (Figure 9G).

[0368] The effect of repeated administration of compound 1 and lorlatinib (BID x 5 days) on signaling through the MAPK and AKT pathways was also evaluated. Repeated administration of compound 1 or lorlatinib did not result in a sustained reduction in pERK levels (Figure 9B). In contrast, pAKT / AKT and pS6 / S6 levels were reduced upon repeated administration (Figure 9D and Figure 9F).

[0369] Example 10: Biochemical Assays Generation of Ba / F3 stable cell line 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) at a multiplicity of infection of 1 or 10 for 1 day. Infected cells were rescued for 2 days in medium (RPMI-1640 with 10% fetal bovine serum, 1% streptomycin and penicillin) supplemented with mouse IL-3 (10 ng / mL), and stable expressing cell lines were selected by IL-3 withdrawal and puromycin (0.8 μg / mL) for 7 days. Transformation of the desired gene was confirmed by Sanger sequencing and Western blot.

[0370] Cell proliferation assay Stable cells were plated at 1,000 cells / well (40 μL) in 384-well plates for one day. Test compounds (40 nL) were then added in 3-fold serial dilutions using a TECAN EVO200 liquid handler and incubated for 72 h. Plates were equilibrated at room temperature for 15 min, followed by the addition of 40 μL of CellTiter-Glo reagent (Promega). Luminescence was measured in a plate reader. Half-maximal inhibitory concentrations (IC 50 ) was calculated from the percentage inhibition and inhibitor concentration using four-parameter logistic regression. IC 50 The data is shown in the table below. [Table 4]

[0371] Example 11: Phase 1, Open Label Study, Food Effect of Compound 1 in Healthy Subjects, Potential Impact of pH Adjustment, and Potential Drug-Drug Interactions Part A is a Phase 1, open-label, crossover study to investigate the effect of co-administration of food and lansoprazole on the PK of Compound 1 in healthy male and female subjects. Fourteen subjects will be enrolled in Part A of the study.

[0372] Part B is a Phase 1, open-label, fixed-route study to investigate the effects of multiple doses of Compound 1 versus a single oral dose of midazolam in healthy male and female subjects. Fourteen subjects will be enrolled in this portion of the study.

[0373] In CYP reaction phenotyping studies performed in human liver microsomes (HLM) and human recombinant CYP enzyme assays, compound 1 was a substrate for CYP3A4 with potential contributions from CYP2C8 and CYP2C9. Thus, the potential for drug-drug interactions (DDIs) between compound 1 and strong CYP3A4 inhibitors exists. In studies performed in HLM with midazolam, compound 1 was considered a moderate inhibitor of CYP3A4. Given the theoretical possibility that compound 1 inhibits CYP3A4-mediated metabolism, clinical drug interaction studies are warranted to determine the effect of compound 1 on the PK of midazolam, a substrate commonly used to evaluate CYP3A4 inhibition.

[0374] the purpose:

[0375] Part A: Primary Objective: To determine the effect of food on the single oral dose pharmacokinetics of Compound 1 in healthy subjects;To determine the effect of multiple oral doses of the proton pump inhibitor (PPI) lansoprazole (victim molecule) on the single oral dose pharmacokinetics of Compound 1 (victim molecule) in healthy subjects. Secondary Objective: To evaluate the safety and tolerability of Compound 1 when co-administered with lansoprazole in healthy subjects.

[0376] Part B: Primary Objective: To determine the effect of multiple oral doses of Compound 1 (the offender molecule) on the single oral dose pharmacokinetics of midazolam (the victim molecule) in healthy subjects. Secondary Objective: To evaluate the safety and tolerability of Compound 1 when co-administered with midazolam in healthy subjects.

[0377] Endpoints:

[0378] Part A: Primary endpoint: Key pharmacokinetic parameters of compound 1 determined using noncompartmental analysis: extrapolated area under the concentration-time curve from time 0 to infinity (AUC 0-∞ ), the area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC 0-tlast ), area under the concentration-time curve from time 0 to 24 hours (AUC 0-24 ), apparent terminal elimination half-life (t 1 / 2 ), apparent total clearance (CL / F), and time to maximum observed concentration (t max ), and the maximum observed concentration (C max ).

[0379] Part B: Primary endpoint: Key pharmacokinetic parameters of midazolam determined using noncompartmental analysis: extrapolated area under the concentration-time curve from time 0 to infinity (AUC 0-∞ ), the area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC 0-tlast ), area under the concentration-time curve from time 0 to 24 hours (AUC 0-24 ), apparent terminal elimination half-life (t 1 / 2 ), apparent total clearance (CL / F), and time to maximum observed concentration (t max ), and the maximum observed concentration (C max ).

[0380] For Part...

Claims

1. A pharmaceutical composition for treating solid tumors in patients, comprising compound 1: 【Chemistry 1】 The pharmaceutical composition comprising, or a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the solid tumor is a progressive solid tumor.

3. The pharmaceutical composition according to claim 2, wherein the progressive solid tumor is recurrent, refractory to, or resistant to a tyrosine kinase inhibitor (TKI) after prior treatment with a TKI.

4. The pharmaceutical composition according to claim 1, wherein the solid tumor is lung cancer.

5. The pharmaceutical composition according to claim 1, wherein the solid tumor is non-small cell lung cancer (NSCLC).

6. The pharmaceutical composition according to claim 1, wherein the solid tumor is cholangiocarcinoma, neuroblastoma, or soft tissue sarcoma.

7. The pharmaceutical composition according to claim 1, wherein the solid tumor is metastatic.

8. The pharmaceutical composition according to claim 7, wherein the solid tumor is CNS metastatic.

9. The pharmaceutical composition according to claim 1, wherein the solid tumor is ALK-positive.

10. The pharmaceutical composition according to claim 9, wherein the ALK-positive solid tumor is characterized by the presence of an ALK mutation, or the ALK-positive solid tumor is characterized by the presence of a partially deleted ALK protein.

11. The pharmaceutical composition according to claim 10, wherein the ALK mutation comprises one or more ALK rearrangements, one or more ALK point mutations, or a combination thereof, wherein the ALK mutation comprises one or more ALK fusions, or wherein the ALK mutation comprises one or more compound mutations.

12. The pharmaceutical composition according to claim 11, wherein the ALK fusion is a fusion with a fusion partner 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, MTA3, PLEKHH2, and KIF5B.

13. The pharmaceutical composition according to claim 12, wherein the ALK fusion is a fusion with NPM1, STRN, HIP1, or EML4, and is optionally EML4-ALK wt variant 1, EML4-ALK variant 2, or EML4-ALK variant 3.

14. The aforementioned ALK mutations are G1202R, F1174C, F1174L, I1171N, I1171S, I1171T, L1196M, V1180L, C1156Y, G1202del, G1202K, G1269A, G1269V, F1174S, F1174I, S1206Y, E1210K, T1151M, T1151_L1152insT, D1203N, S The pharmaceutical composition according to claim 11, comprising 1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, E1129K, S1206F, L1198H, F1245C, T1151K, I1268V, F1174V, L1198Q, S1206A, or F1245V, or a combination thereof.

15. The pharmaceutical composition according to claim 14, wherein the ALK mutation comprises G1202R, F1174S, F1174L, R1275Q, or T1151M.

16. The pharmaceutical composition according to claim 11, wherein the compound mutation is G1202R / F1174L, G1202R / T1151M, G1202R / L1196M, G1202R / G1269A, G1202R / L1198F, G1202R / F1174S, C1156Y / L1256F, C1156Y / S1206F, C1156Y / F1174V, C1156Y / F1174I, L1196M / L1198H, L1196M / I1179V, or L1196M / L1256F.

17. The pharmaceutical composition according to claim 11, wherein the ALK mutation is EML4-ALK I1171N, EML4-ALK G1202R, STRN-ALK G1202R, EML4-ALK G1202R / T1151M, EML4-ALK G1202R / L1196M, or EML4-ALK G1202R / G1269A.

18. A pharmaceutical composition according to any one of claims 1 to 17, (a) The patient is inexperienced with tyrosine kinase inhibitor (TKI) therapy, (b) The patient has been treated with one previous TKI therapy, (c) The patient has been treated with at least one previous TKI therapy, (d) The patient has been treated with at least two previous TKI therapies, where, The TKI is arbitrarily an ALK TKI, The ALK TKI may be crizotinib, ceritinib, alectinib, brigatinib, ensartinib, or lorlatinib. The aforementioned pharmaceutical composition.

19. A pharmaceutical composition according to any one of claims 1 to 17, (a) The patient has been treated with one or more prior systemic anticancer therapies, (b) The patient has never been treated with chemotherapy before, (c) The patient has previously been treated with chemotherapy, (d) The patient has been treated with up to two previous lines of chemotherapy, (e) The patient has not been treated with previous immunotherapy, (f) The patient has previously been treated with immunotherapy, (g) The patient has been treated with up to two previous lines of immunotherapy, The aforementioned pharmaceutical composition.

20. A pharmaceutical composition according to any one of claims 1 to 17, (a) The solid tumor is progressive or metastatic ALK-positive NSCLC, and the patient has been treated with at least one previous ALK TKI therapy, Optionally, at least one of the previous ALK TKI therapies was ceritinib, crizotinib, alectinib, brigatinib, or lorlatinib. (b) The solid tumor is advanced or metastatic ALK-positive NSCLC and the patient has previously been treated with one ALK TKI regimen, The previous ALK TKI therapy was optionally ceritinib, crizotinib, alectinib, brigatinib, or lorlatinib. (c) The solid tumor is advanced or metastatic ALK-positive NSCLC, and the patient has been treated with two or three previous ALK TKI therapies, The two or three previous ALK TKI therapies are optionally crizotinib, ceritinib, alectinib, brigatinib, ensartinib, and lorlatinib. The second or third prior ALK TKI therapy is optionally lorlatinib. The patient may have been treated with ≤2 previous chemotherapy and / or immunotherapy lines. The patient may optionally have previously been treated with two or more lines of chemotherapy and / or immunotherapy. (d) The solid tumor is an advanced or metastatic ALK-positive solid tumor and the patient has been treated with one or more prior systemic anticancer therapies, (e) The solid tumor is progressive or metastatic ALK-positive NSCLC, and the patient has experienced disease progression in response to previous therapy, The aforementioned pharmaceutical composition.

21. A pharmaceutical composition according to any one of claims 1 to 17, wherein compound 1 is formulated to be administered to the patient over a period of one day or more, or over at least one treatment cycle, wherein the treatment cycle is optionally at least 7 days, at least 14 days, or at least 21 days.

22. A pharmaceutical composition according to any one of claims 1 to 17, wherein compound 1 is prescribed to the patient to be administered once daily (QD) or twice daily (BID) in an amount equivalent to about 5 mg to about 400 mg, 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 by weight of free base compound 1, wherein, Optionally, the pharmaceutical composition is formulated to administer compound 1 orally to the patient. Optionally, the pharmaceutical composition is formulated to administer compound 1 to the patient in the form of one or more tablets. The tablets may optionally contain approximately 5 mg, 50 mg, 75 mg, 100 mg, 125 mg, or 150 mg of free base compound 1 per unit dose, based on weight. The aforementioned pharmaceutical composition.

23. The pharmaceutical composition according to claim 22, wherein the pharmaceutical composition is formulated to administer compound 1 to the patient once daily in an amount equivalent to about 150 mg by weight of free base compound 1.

24. A pharmaceutical composition according to claim 22, (a) The pharmaceutical composition is formulated to administer compound 1 to a patient who is hungry. (b) The pharmaceutical composition is formulated to administer compound 1 to a patient who is satiety. (c) The patient is not taking any one of the following: a potent inducer of CYP3A4, a potent inhibitor of CYP3A4, a sensitive substrate of CYP3A4 and / or CYP2C8, a substrate of P-gp / multidrug resistance protein (MDR1), a substrate of BCRP / breast cancer resistance protein (ABCG2), a substrate of OATP1B1, a substrate of OATP1B3, a substrate of MATE1, or a gastric acid reducer. (d) The patient is taking one of the following: a potent inducer of CYP3A4, a potent inhibitor of CYP3A4, a sensitive substrate of CYP3A4 and / or CYP2C8, a substrate of P-gp / multidrug resistance protein (MDR1), a substrate of BCRP / breast cancer resistance protein (ABCG2), a substrate of OATP1B1, a substrate of OATP1B3, a substrate of MATE1, or a gastric acid reducer. (e) The patient is taking either a potent inducer of CYP3A4 or a potent inhibitor of CYP3A4, (f) The patient is not taking either a potent inducer of CYP3A4 or a potent inhibitor of CYP3A4, (g) The patient is not taking any of the potent inducers of CYP3A4, The aforementioned pharmaceutical composition.

25. The pharmaceutical composition according to claim 22, wherein the patient has not taken a potent CYP3A4 inhibitor, a potent CYP3A4 inducer, a CYP3A4-sensitive substrate, and / or a CYP2C8-sensitive substrate.

26. The pharmaceutical composition according to claim 1, wherein the solid tumor is positive for leukocyte receptor tyrosine kinase (LTK).

27. The pharmaceutical composition according to any one of claims 1 to 17, which is formulated for co-administration with one or more additional therapeutic agents selected from the group consisting of EGFR inhibitors, Raf inhibitors, PIK3CA inhibitors, CDK4 inhibitors or CDK6 inhibitors, STAT3 inhibitors, taxanes, epothirone, tilvanibulin, eribulin mesylate, vinflunin, vinorelbine, narcosine, vincristine sulfate, vinblastine sulfate, colchicine, HER2-targeted therapy, anti-angiogenic agents, JNK inhibitors, proteasome inhibitors, mTOR inhibitors, YAP1 inhibitors, TOPK inhibitors, trophoblast cell surface antigen 2 (TROP2) antibody-drug conjugates (ADCs), or AXL ADCs.

28. The aforementioned compound is compound 1 free base, or The compound is the solid form of compound 1, and the solid form is characterized by an XRPD pattern including peaks at 12.4, 18.9, and 21.1°²θ (±0.2°). A pharmaceutical composition according to any one of claims 1 to 17.

29. A pharmaceutical composition according to any one of claims 1 to 17, comprising compound 1, a diluent, a disintegrant, a fluidizing agent, a binder, and a lubricant, The pharmaceutical composition wherein the diluent is optionally microcrystalline cellulose, the disintegrant is croscarmellose sodium, the fluidizer is colloidal silicon dioxide, the binder is hydroxypropyl cellulose (HPC), and the lubricant is magnesium stearate.

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