Methods for treating advanced solid tumors

Abstract

Provided herein are methods of using a compound of formula (I), or a pharmaceutically acceptable form thereof, for treating advanced solid tumors, including in combination with a VEGFR inhibitor.

Description

[Technical Field]

[0001] 1. Cross reference This application claims the benefit of priority from U.S. Provisional Application Nos. 63 / 476,604, filed December 21, 2022, 63 / 501,108, filed May 9, 2023, and 63 / 582,448, filed September 13, 2023, each of which is incorporated by reference in its entirety.

[0002] 2.Technical Field As used herein, the term "compound of formula (I): [ka]

[0010] Methods are provided for treating, preventing, or managing advanced solid tumors using a farnesyltransferase inhibitor, which is a compound of formula (I), or a pharmaceutically acceptable form thereof, in combination with a vascular endothelial growth factor receptor (VEGFR) inhibitor, such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanzarintinib, or a pharmaceutically acceptable form thereof. Also provided herein are methods for alleviating, slowing the progression of, or overcoming tyrosine kinase inhibitor (TKI) resistance in subjects with advanced solid tumors who are currently being treated or have previously been treated with a TKI, using a compound of formula (I), or a pharmaceutically acceptable form thereof. Also provided herein are methods for preventing or delaying the emergence of TKI resistance in TKI-naive subjects with advanced solid tumors, using a compound of formula (I), or a pharmaceutically acceptable form thereof.

[0003] Also provided herein are methods for treating advanced solid tumors with HRAS amplification and / or HRAS overexpression using a compound of Formula (I), or a pharmaceutically acceptable form thereof, optionally in combination with an HRAS mutation. Also provided herein are methods for treating, preventing, or managing advanced solid tumors with squamous epithelial histology, HRAS amplification, and / or HRAS expression using a compound of Formula (I), or a pharmaceutically acceptable form thereof, optionally in combination with an HRAS mutation. Also provided herein are methods for treating, preventing, or managing advanced solid tumors with HRAS amplification and / or HRAS overexpression using a compound of Formula (I), or a pharmaceutically acceptable form thereof, optionally in combination with an HRAS mutation. In some embodiments, the advanced solid tumor is (a) an advanced solid tumor with HRAS amplification, (b) HNSCC with HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with NRAS or HRAS amplification. [Background technology]

[0004] 3.Background technology Angiogenesis plays an important role in tumor progression, as new blood vessels support tumor growth, supply oxygen and nutrients to proliferating tumor cells, and promote metastasis formation. Prominent angiogenesis inhibitors target the vascular endothelial growth factor (VEGF) signaling pathway and include inhibitors of VEGF receptors (VEGF), primarily VEGFR-2. Receptor tyrosine kinases and VEGFRs mediate a series of signal transduction pathways in endothelial cells, such as the Ras / Raf, MEK / MAPK, phosphatidylinositol 3'-kinase (PI3K), Akt / PKB, and mTOR pathways, which are involved in both normal cell functions and pathological processes such as tumorigenesis, proliferation, migration, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

[0005] Inhibitors in this category have demonstrated clinical efficacy in a variety of tumor types, including renal cell carcinoma, thyroid cancer, hepatocellular carcinoma, and gastrointestinal stromal tumors (GISTs). Several VEGFR inhibitor small molecule therapeutics have been approved for such cancers, including cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanzarintinib. VEGFR inhibitors may exhibit inhibitory activity against one or more VEGFR isoforms, and may be multi-targeted kinase inhibitors active against additional receptor tyrosine kinases, such as FGFR-1, -2, -3, or -4, PDGFR-α or -β, KIT, RET, MET, AXL, ROS1, TYRO3, MER, TRKB, FLT-3, TIE-2, DDR2, TRKA, EPH2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, ABL, FGFR-1 or -3, Itk, Lck, c-Fms, or CSF-1R, or combinations thereof. The platelet-derived growth factor (PDGF) family is also involved in tumor angiogenesis. Certain anti-angiogenic kinase inhibitors are inhibitors of both VEGFR and PDGFR signaling. VEGFR inhibitors can be type 1 kinase inhibitors that recognize the active conformation of the kinase, type II inhibitors that recognize the inactive conformation of the kinase, such as sunitinib, sorafenib, or covalent inhibitors such as vandetanib.

[0006] Although antiangiogenic VEGFR inhibitors have demonstrated clinical utility, preclinical and clinical studies have revealed resistance to these drugs. Modulation of downstream signaling pathways by VEGFR inhibitors can induce resistance by promoting the development of other pathways to stimulate angiogenesis, such as AXL, MET, and PDGF / PDGFR, thereby allowing cancer cells to evade VEGF / VEGFR blockade. In some cases, initial clinical response is followed by tumor progression due to acquired drug resistance, while in other cases, tumors have intrinsic resistance to the inhibitors. Furthermore, treatment with antiangiogenic drugs can lead to significant toxicities, including severe bleeding, impaired wound healing, gastrointestinal perforation, hypertension, fatigue, and QT prolongation.

[0007] Renal cell carcinoma (RCC) is the most common type of kidney cancer, with approximately 400,000 patients diagnosed annually worldwide and causing over 180,000 deaths in 2020. Nearly one-third of new diagnoses occur in patients with unresectable advanced or metastatic disease at the time of diagnosis, and 20–30% of patients with localized tumors ultimately recur after nephrectomy. The 5-year survival rate for patients with advanced RCC is 12%. The majority of RCC diagnoses (approximately 80%) fall into the clear cell renal cell carcinoma (ccRCC) category, a highly vascularized tumor type most commonly resulting from inactivation of the von Hippel-Lindau (VHL) gene. Loss of VHL stabilizes hypoxia-inducible factor alpha protein (HIFα), driving a hypoxic transcriptional response including the induction of VEGF and PDGF2, which mediate tumor angiogenesis.

[0008] Antiangiogenic TKIs, such as sunitinib (primarily targeting VEGFR and PDGFR) and axitinib (a specific VEGFR-1, -2, and -3 inhibitor), have demonstrated therapeutic efficacy in patients with ccRCC by exploiting the tumor's dependency on the vasculature for oxygen, nutrients, and growth factors. Although sunitinib is the most commonly used TKI, only 20–30% of patients respond to initial treatment, and almost all initial responders develop resistance within two years. This antiangiogenic TKI strategy has also been successfully applied to other tumor types, such as thyroid cancer, hepatocellular carcinoma, and neuroendocrine tumors. However, as mentioned above, resistance to TKIs commonly develops, leading to disease progression.

[0009] Antiangiogenic VEGFR inhibitors have been approved for clinical use in a range of advanced solid tumors. Cabozantinib is an inhibitor of MET, VEGFR-1, -2, and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2, and is approved for the treatment of thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma. Lenvantinib is an inhibitor of VEGFR-1, -2, and -3, as well as FGFR-1, -2, -3, and -4, PDGFR-α, KIT, and RET, and is approved for the treatment of certain types of thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, and endometrial carcinoma. Axitinib is an inhibitor of VEGFR-1, -2, and -3, and is approved for the treatment of renal cell carcinoma. Regorafenib is an inhibitor of VEGFR-1, -2, and -3, RET, KIT, PDGFR-α, PDGFR-β, FGFR-1 and -2, TIE-2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, Abl, and CSF-1R, and is approved for the treatment of colorectal cancer, hepatocellular carcinoma, and GIST. Vandetanib is an inhibitor of VEGFR and EGFR family members, RET, BRK, TIE-2, and EPH receptor and Src kinase family members, and is approved for the treatment of thyroid cancer. Pazopanib is an inhibitor of VEGFR-1, -2, and -3, PDGFR-α and -β, FGFR-1 and -3, Kit, Itk, Lck, and c-Fms, and is approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Sunitinib is an inhibitor of VEGFR-1, -2, and -3, PDGFR-α and -β, KIT, FLT3, CSF-1R, and RET, and is approved for the treatment of renal cell carcinoma, GIST, and pancreatic neuroendocrine tumors. Sorafenib is an inhibitor of VEGFR-1, -2, and -3, PDGFR-β, c-CRAF, BRAF, mutant BRAF, KIT, FLT-3, RET, and RET / PTC, and is approved for the treatment of renal cell carcinoma, hepatocellular carcinoma, and thyroid carcinoma. Tivozanib is an inhibitor of VEGFR-1, -2, and -3, PDGFR-β, and c-kit, and is approved for the treatment of renal cell carcinoma.Zanzarintinib (e.g., zanzarintinib fumarate) is an inhibitor of tyrosine kinases such as MET, VEGFR, AXL, and MER. Fruquintinib (e.g., fruquintinib free base) is an inhibitor of VEGFR-1, -2, and -3 and is approved for the treatment of colorectal cancer, particularly metastatic colorectal cancer in patients who have received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, as well as anti-VEGF therapy, and, if RAS wild-type and medically appropriate, anti-EGFR therapy.

[0010] Farnesylation is important for the function of over 140 proteins. However, blocking farnesylation does not necessarily significantly affect protein function, as in the case of Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS), due to compensatory mechanisms including prenylation by type 1 geranylgeranyltransferase. However, Harvey rat sarcoma viral oncogene homolog (HRAS) cannot be geranylgeranylated, and its membrane localization and cellular functions (e.g., oncogenic signaling) were inhibited by tipifarnib, a selective nonpeptide farnesyltransferase inhibitor (FTI), in vitro and in vivo studies. HRAS-dependent tumors were shown to be highly sensitive to FTI treatment in PDX models of head and neck squamous cell carcinoma (HNSCC). Furthermore, tipifarnib demonstrated high response rates and favorable long-term outcomes in patients with HRAS-mutated HNSCC. Furthermore, tumor cell lines and mouse models bearing NRAS-dependent tumors have been shown to be responsive to tipifarnib, with inhibition of angiogenesis, cell and tumor growth, and induction of apoptosis that correlates with inhibition of farnesylated targets, including NRAS (End et al., Cancer Res. 2001, 61, 131-137).

[0011] Although mutations are key drivers of tumor biology, other factors exist that can regulate tumor growth and survival, including the overexpression of non-mutated oncogenic signaling proteins and the influence of the tumor microenvironment. For example, approximately 30% of human tumors exhibit alterations in HRAS, KRAS, and / or NRAS. The Cancer Genome Atlas (TCGA) has shown HRAS overexpression in 25%–30% of HNSCC patients, indicating a potential reliance on HRAS that may mimic HRAS as a driver oncogene for HNSCC in the broader population (cBioPortal for Cancer Genomics, 2020, https: / / www.cbioportal.org / ). A higher prevalence of oncogenic HRAS mutations and elevated levels of HRAS RNA and protein (e.g., overexpression) have been observed in multiple tumor types with squamous histology unrelated to the tumor site of origin (e.g., esophagus, head and neck, lung, etc.), although such alterations occur in non-squamous tumor types as well. NRAS alterations are observed in a variety of solid tumor types, including melanoma, colorectal cancer (carcinoma or adenocarcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, small cell lung carcinoma), breast cancer, ovarian cancer, pancreatic cancer (e.g., carcinoma or pancreatic ductal adenocarcinoma), glioma, HNSCC, and thyroid cancer, as well as other tumor types, such as leukemia and lymphoma.

[0012] There remains a need in the art for therapies and regimens for treating advanced solid tumors, including metastatic, relapsed, or refractory forms thereof. Similarly, there is a need to reduce, avoid, delay, or overcome, to the greatest extent possible, drug resistance associated with existing therapies, including those treating advanced solid tumors. The methods provided herein address one or more of the above-mentioned problems associated with the treatment of advanced solid tumors. Summary of the Invention

[0013] 4. Overview In one aspect, there is provided a method of treating an advanced solid tumor in a subject, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising same), and a VEGFR inhibitor.

[0014] In another aspect, there is provided a method of reducing, slowing the progression of, or overcoming drug resistance in an advanced solid tumor in a subject, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising same), and a VEGFR inhibitor.

[0015] In another aspect, a method for preventing or delaying the emergence of TKI drug resistance in an advanced solid tumor in a TKI-naive subject, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising same), and a VEGFR inhibitor.

[0016] In another aspect is a pharmaceutical composition comprising: (a) a compound of formula (I), or a pharmaceutically acceptable form thereof; and (b) a VEGFR inhibitor.

[0017] In another aspect is a pharmaceutical kit comprising: (a) a compound of formula (I), or a pharmaceutically acceptable form thereof; and (b) a VEGFR inhibitor.

[0018] In another aspect, provided herein are (1) a pharmaceutical composition comprising (a) a compound of Formula (I), or a pharmaceutically acceptable form thereof, and (b) a VEGFR inhibitor; or (2) a pharmaceutical composition comprising (a) a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient, or diluent, and pharmaceutical packaging comprising (b) a pharmaceutical composition comprising a VEGFR inhibitor, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0019] In another aspect, a method of treating an advanced solid tumor having HRAS amplification and / or HRAS overexpression, optionally in combination with an HRAS mutation, in a subject, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising same). In another aspect, a method of treating an advanced solid tumor having squamous histology and HRAS amplification and / or HRAS overexpression, optionally in combination with an HRAS mutation, in a subject, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising same).

[0020] In another aspect, a method of treating an advanced solid tumor in a subject having HRAS amplification and / or HRAS overexpression, optionally in combination with an HRAS mutation, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising same).

[0021] In another aspect is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable form thereof, for use in the methods described herein. 5. Brief description of the drawings [Brief explanation of the drawings]

[0022] [Figure 1] 1 is a plot of tumor volume over time upon treatment of A498 RCC CDX with the compound of formula (I), axitinib, or the combination.

[0023] [Figure 2] FIG. 1 is a plot of tumor volume over time upon treatment of KI-12-0073 RCC PDXs with the compound of formula (I), axitinib, or the combination.

[0024] [Figure 3]A-B: Combination treatment of the compound of Formula (I) and cabozantinib inhibited tumor growth in an RCC CDX model. A: 786-O CDX treated with the compound of Formula (I) (20 mg / kg, bid) and cabozantinib (20 mg / kg, QD) (lane 3) compared to treatment with the compound of Formula (I) (lane 1) or cabozantinib (lane 2) alone; B: A498 CDX treated with the compound of Formula (I) and cabozantinib (8 or 20 mg / kg, QD) (lanes 4 and 5, respectively) compared to treatment with the compound of Formula (I) alone (lane 1) or cabozantinib alone (lanes 2 and 3).

[0025] [Figure 4A] The combination of the compound of formula (I) and cabozantinib inhibited tumor growth in RCC PDX and CDX models for the compound of formula (I), cabozantinib, and the combination. Plot of tumor volume over time in the KI-12-0073 VHL-mutated ccRCC PDX model. [Figure 4B] The combination of the compound of formula (I) and cabozantinib inhibited tumor growth in RCC PDX and CDX models for the compound of formula (I), cabozantinib, and the combination. Plot of % tumor volume change in the KI-12-0073 VHL-mutated ccRCC PDX model. [Figure 4C] The combination of the compound of formula (I) and cabozantinib inhibited tumor growth in RCC PDX and CDX models for the compound of formula (I), cabozantinib, and the combination. Plot of tumor volume over time in the 786-O CDX model. [Figure 4D] The combination of the compound of formula (I) and cabozantinib inhibited tumor growth in RCC PDX and CDX models for the compound of formula (I), cabozantinib, and the combination. Plot of % tumor volume change in the 786-O CDX model. [Figure 4E]The combination of the compound of formula (I) with cabozantinib inhibited tumor growth in RCC PDX and CDX models for the compound of formula (I), cabozantinib, and the combination. Plot of tumor volume over time in the KI-0326 VHL-mutated ccRCC PDX model. [Figure 4F] The combination of the compound of formula (I) and cabozantinib inhibited tumor growth in RCC PDX and CDX models for the compound of formula (I), cabozantinib, and the combination. Plot of % tumor volume change in the KI-0326 VHL mutant ccRCC PDX model.

[0026] [Figure 5] Plot of the percent change in tumor volume at day 28 relative to day 0 in mice bearing 786-O VHL mutant CDX treated with the compound of formula (I) (20 mg / kg, BID) and cabozantinib (4, 8, 10, or 12 mg / kg, QD), alone or in combination.

[0027] [Figure 6] Plot of tumor volume over time in 786-O CDX mice treated with cabozantinib, the compound of formula (I), lenvatinib, the combination of lenvatinib and everolimus, the combination of the compound of formula (I) and cabozantinib, and the combination of the compound of formula (I) and lenvatinib.

[0028] [Figure 7] Plot of tumor volume over time in 786-O CDX mice treated with the compound of formula (I), cabozantinib, axitinib, or the combination of the compound of formula (I) and cabozantinib.

[0029] [Figure 8] Immunoblot of cell signaling markers from 786-O CDX cells after treatment with cabozantinib, a combination of Formula (I), or the combination.

[0030] [Figure 9A]Plot of cell viability (%) of HUVEC cells treated with various concentrations of a compound of formula (I) and various concentrations of cabozantinib. [Figure 9B] Plot of cell viability (%) of HUVEC cells treated with various concentrations of a compound of formula (I) and various concentrations of axitinib. [Figure 9C] Plot of % cell viability of HUVEC cells treated with various concentrations of a compound of formula (I) and various concentrations of lenvantinib (Figure 9C).

[0031] [Figure 10] A-F: Tube formation in HUVEC cells was inhibited by the combination of the compound of formula (I) and axitinib or cabozantinib. A: Vehicle; B: Axitinib; C: Cabozantinib; D: Compound of formula (I); E: Axitinib and compound of formula (I); F: Cabozantinib and compound of formula (I).

[0032] [Figure 11A] GFP imaging of the effect on tube formation in GFP-labeled HUVEC cells treated with vehicle, compound of formula (I), cabozantinib, or the combination. [Figure 11B] Plot of master segment number and total master segment length of the effect on tube formation in GFP-labeled HUVEC cells treated with vehicle, a compound of formula (I), cabozantinib, or a combination thereof.

[0033] [Figure 12] Plot of cell death over time as a percentage normalized to baseline in HUVEC cells treated with a compound of formula (I), cabozantinib, or the combination (staurosporine as control).

[0034] [Figure 13] Immunoblot of HRAS levels in SCC9 and HSC3 cells after GTP pulldown.

[0035] [Figure 14] Plot of tumor volume over time for vehicle and compound of formula (I) in the HN2594 (HRASWT-high) patient-derived xenograft model.

[0036] [Figure 15] Plot of tumor volume over time for vehicle and various doses of the compound of formula (I) in the HN2576 (HRASWT-high) HNSCC patient-derived xenograft model.

[0037] [Figure 16] Plot of tumor volume over time for vehicle and the compound of formula (I) at various doses in the HN2594 (HRASWT-high) HNSCC patient-derived xenograft model. DETAILED DESCRIPTION OF THE INVENTION

[0038] 6. MODE FOR CARRYING OUT THE INVENTION Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In the event that there are a plurality of definitions for terms herein, those in this section prevail unless stated otherwise.

[0039] As used herein, and in this specification and the appended claims, the indefinite articles "a" and "an," and the definite article "the," include plural and singular referents unless the context clearly dictates otherwise.

[0040] As used herein, unless otherwise specified, the terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, mean a dose, amount, or weight percent within 30%, within 20%, within 15%, within 10%, or within 5% of the specified dose, amount, or weight percent.

[0041] As used herein, a "pharmaceutically acceptable form" of a compound disclosed herein includes, but is not limited to, pharmaceutically acceptable salts, solvates, isomers, and isotopologues (i.e., isotopically labeled derivatives) of a compound disclosed herein, including combinations thereof (e.g., a solvate of a pharmaceutically acceptable salt, or an isomer and / or isotopologue of the compound or its solvate, salt, or solvate of a salt of the compound). In some embodiments, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, solvates, isomers (e.g., tautomers or stereoisomers), and isotopologues (i.e., isotopically labeled derivatives) of a compound of Formula (I) disclosed herein.

[0042] The term "isomer," as used herein, includes stereoisomers or tautomers as defined herein. As used herein, the term "stereoisomer" is understood to mean isomers that differ only in the way the atoms are arranged in space. As used herein, the term "isomer" includes any and all geometric and stereoisomers. For example, "isomer" includes geometric double bond cis- and trans-isomers, also known as E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof, as included within the scope of this disclosure.

[0043] As used herein, unless otherwise indicated, the term "stereoisomerically pure" refers to one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of that compound. Some embodiments include a compound of formula (II) (i.e., (R)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4A stereomerically pure compound of formula (I) (i.e., (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2,4-dicarbonitrile) is provided, the compound being substantially free of 2 ,4 4 -dicarbonitrile). Stereomerically pure compounds having two chiral centers are substantially free of other diastereomers of the compound. Typical stereomerically pure compounds contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. Compounds may have chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the embodiments provided herein.

[0044] It should be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be in either the (R) or (S) configuration, or may be a mixture thereof. It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. Thus, those skilled in the art will recognize that administration of a compound in its (R) form is equivalent to administration of a compound in its (S) form for compounds that undergo epimerization in vivo.

[0045] Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography on chiral stationary phases.

[0046] The use of stereomerically pure forms of such compounds, as well as mixtures of those forms, are encompassed by the embodiments provided herein. For example, mixtures containing equal or unequal amounts of the enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. For example, Jacques, J., et al., (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p.268(ELEliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN,1972);Todd,M.,Separation Of Enantiomers:Synthetic Methods(Wiley-VCH Verlag gmbH & Co. KGaA,Weinheim,Germany,2014);Toda,F.,Enantiomer Separation:Fundamentals and Practical Methods(Springer Science & Business Media,2007);Subramanian,G.Chiral Separation See Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0047] In certain embodiments, the pharmaceutically acceptable forms are atropisomers, which are stereoisomers resulting from hindered rotation about a single bond axis, where the rotational barrier is sufficient to allow for the isolation of rotamers.

[0048] In certain embodiments, the pharmaceutically acceptable form is a tautomer. As used herein, the term "tautomer" refers to a type of isomer that includes two or more interconvertible compounds resulting from the formal migration of at least one hydrogen atom and a change in at least one valence (e.g., from a single bond to a double bond, a triple bond to a double bond, or a triple bond to a single bond, or vice versa). "Tautomerization" includes prototropic or proton shift tautomerization, which are considered subsets of acid-base chemistry. "Prototropic tautomerization" or "proton shift tautomerization" involves the migration of a proton accompanied by a change in bond order. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. When tautomerization is possible (e.g., in solution), a chemical equilibrium of the tautomers can be reached. Tautomerization (i.e., the reaction that produces a tautomeric pair) can be catalyzed by an acid or base, or can occur without the action or presence of an external agent. The concentration of isomeric forms may vary depending on the environment in which the compound is found, for example, whether the compound is solid or in an organic or aqueous solution.Exemplary tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactim; enamine-imine; and enamine-(different) enamine tautomerizations.For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, which are referred to as tautomers of each other: [ka]

[0049] As will be readily understood by one of ordinary skill in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds are within the scope of the compounds provided herein.

[0050] In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic reactions, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. provide a detailed description of pharmaceutically acceptable salts (see J.Pharm.Sci.(1977)66:1-19). Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases, such as suitable inorganic and organic addition acids and bases.

[0051] In certain embodiments, the pharmaceutically acceptable forms of the compounds disclosed herein exclude salt forms (i.e., not salts), which may be referred to as the free form or free base form of the compounds disclosed herein. Some embodiments are solvates of such free base forms.

[0052] In certain embodiments, the compounds described herein are in the form of a solvate (e.g., a hydrate). As used herein, the term "solvate" refers to a compound that further comprises a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate may be a solvate of the disclosed compounds or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate." In some embodiments, the solvate is a hydrate. Pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 0.1, 0.25, 0.50, 0.75, or 1 solvent or water molecule, or may contain 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It will be understood that the term "compound," as used herein, encompasses the compound (or a pharmaceutically acceptable salt thereof) and solvates of the compound or a pharmaceutically acceptable salt thereof, as well as mixtures thereof.

[0053] The term "isotopologue" refers to an isotopically enriched compound identical to those listed herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Unless otherwise stated, structures represented herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Examples of isotopes that may be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphate, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 35 Cl, 36 Cl, and 37 Cl are included, each also within the scope of the present disclosure. For example, compounds having the structure of the present invention at one or more atoms in the molecule, except for the replacement or enrichment of hydrogen with deuterium or tritium, are within the scope of the present disclosure. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced or enriched with deuterium. When a compound is enriched with deuterium, the deuterium to hydrogen ratio on the deuterated atom of the molecule substantially exceeds the naturally occurring deuterium to hydrogen ratio. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced or enriched with tritium. Additionally, deuterium (i.e., 2Substitution with heavy isotopes, such as H, offers certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) due to improved metabolic stability. Isotopically labeled compounds disclosed herein can generally be prepared by substituting an isotopically enriched reagent for a non-isotopically enriched reagent. Isotopically enriched compounds can generally be prepared using procedures known to those skilled in the art by substituting an appropriate isotopically enriched reagent for a non-isotopically enriched reagent. Embodiments described herein can include isotopologue forms in which an isotopologue is substituted with one or more deuterium atoms in place of one or more hydrogen atoms on one or more atomic members of the compound. Embodiments described herein can include compounds in which a carbon atom can have 1 to 3 hydrogen atoms optionally replaced with deuterium.

[0054] As used herein, the compounds disclosed herein include, but are not limited to, the free base form or a pharmaceutically acceptable salt thereof, and solvates or hydrates thereof, and isotopologues (i.e., isotopically labeled derivatives) of such compounds. Some embodiments contemplate the free base or a pharmaceutically acceptable salt of a compound of Formula (I), or a hydrate or solvate and / or isotopologue (i.e., isotopically labeled derivative) or analogous form of a VEGFR inhibitor.

[0055] It should be noted that in the event of a discrepancy between a structure shown in the drawing and the name of that structure, emphasis is placed on the structure shown in the drawing.

[0056] As used herein, the term "pharmaceutically acceptable carrier, excipient, or diluent" means a carrier, excipient, or diluent approved by a federal or state regulatory agency for use in animals, and more specifically in humans, or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia. The term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete or incomplete)), vehicle, or vehicle with which a therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water, and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a specific carrier for pharmaceutical compositions administered intravenously. Saline and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. For example, the term pharmaceutically acceptable carrier, excipient, or diluent includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art.Except as long as any conventional media or agent is incompatible with active ingredient, its use in the pharmaceutical compositions disclosed herein is contemplated.Auxiliary active ingredients can also be incorporated into pharmaceutical compositions.The examples of excipients that can be used in the oral dosage forms provided herein include but are not limited to binders, fillers, disintegrants and lubricants.

[0057] As used herein, the term "VEGFR inhibitor" refers to an inhibitor that inhibits one or more VEGFR isoforms (e.g., VEGFR-1, VEGFR-2, VEGFR-3) with an IC500 nM or less in a biochemical or cellular assay. 50 In some embodiments, the IC 50is 250 nM, or 150 nM, or 100 nM, or 50 nM, or 30 nM, or 20 nM, or 10 nM, or 5 nM, or 1 nM or less. VEGFR inhibitors include pharmaceutically acceptable forms thereof. VEGFR inhibitors may inhibit one or more VEGFR isoforms and other targets other than VEGF receptors, such as FGFR-1, -2, -3, or -4, PDGFR-α or -β, KIT, RET, MET, AXL, ROS1, TYRO3, MER, TRKB, FLT-3, TIE-2, DDR2, TRKA, EPH2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, ABL, or CSF-1R, or a combination thereof. In some embodiments, the VEGFR inhibitor inhibits at least one VEGFR isoform and at least one of PDGFR-α and PDGFR-β. In some embodiments, the VEGFR inhibitor is a type 1 kinase inhibitor, a type II inhibitor, or a covalent inhibitor. The VEGFR inhibitor can be a type 1 kinase inhibitor that recognizes the active conformation of the kinase, a type II inhibitor that recognizes the inactive conformation of the kinase, such as sunitinib or sorafenib, or a covalent inhibitor such as vandetanib. In some embodiments, the VEGFR inhibitor is approved by the U.S. Food and Drug Administration (FDA) or a similar regulatory agency in another jurisdiction for the treatment of renal cell carcinoma, thyroid cancer, hepatocellular carcinoma, colorectal cancer, gastrointestinal stromal tumor, soft tissue sarcoma, pancreatic neuroendocrine tumor, or endometrial cancer. In some embodiments, the advanced solid tumor is squamous cell carcinoma, large cell carcinoma, or adenocarcinoma. Exemplary VEGFR inhibitors include, but are not limited to, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanzarintinib. In some embodiments, the VEGFR inhibitor is cabozantinib, lenvantinib, axitinib, pazopanib, sunitinib, sorafenib, or tivozanib. In some embodiments, the VEGFR inhibitor is zanzarintinib. In some embodiments, the VEGFR inhibitor is fruquintinib.In some embodiments, the VEGFR inhibitor is cabozantinib, axitinib, sunitinib, or sorafenib. In some embodiments, the VEGFR inhibitor is cabozantinib. As used herein, a reference to a VEGFR inhibitor or its generic name includes a reference to its pharmaceutically acceptable form. In some embodiments, the pharmaceutically acceptable form of the VEGFR inhibitor is cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanzarintinib fumarate.

[0058] As used herein, the term "advanced solid tumor" has its general meaning in the art and refers to an abnormal mass of tissue that does not contain cysts or liquid areas, especially a disease of tissue with uncontrolled cell growth, which in some cases leads to metastasis. Advanced solid tumors can be benign or malignant and can arise in the muscles, bones, or organs of the body. In some embodiments, the advanced solid tumor is renal cell carcinoma (RCC) (such as clear cell RCC, papillary RCC, chromophobe RCC, advanced or unclassified RCC, and relapsed or refractory RCC, and post-nephrectomy RCC), thyroid cancer (including medullary thyroid carcinoma, differentiated thyroid carcinoma, including locally advanced, metastatic, symptomatic, progressive, and / or radioactive iodine-refractory forms), hepatocellular carcinoma (including unresectable forms), colorectal cancer (such as metastatic colorectal cancer), gastrointestinal stromal tumor (GIST; including locally advanced, unresectable, or metastatic GIST, and progressing / intolerant to imatinib, e.g., imatinib mesylate), soft tissue sarcoma (including advanced soft tissue sarcoma), pancreatic neuroendocrine tumor (including advanced, differentiated, locally advanced, and metastatic forms), or endometrial carcinoma. In some embodiments, the advanced solid tumor is squamous cell carcinoma, large cell carcinoma, or adenocarcinoma. In some embodiments, the advanced solid tumor is thyroid cancer, thyroid carcinoma, head and neck cancer, head and neck squamous cell carcinoma, urothelial carcinoma, salivary gland cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, brain cancer, gastric cancer, prostate cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, colon cancer, rectal cancer, colorectal cancer, skin cancer, melanoma, liver cancer, pancreatic cancer, or pancreatic ductal cell carcinoma. In some embodiments, the advanced solid tumor is melanoma, colorectal cancer (carcinoma or adenocarcinoma), lung cancer (e.g., non-small cell lung cancer, lung squamous cell carcinoma, small cell lung cancer), breast cancer, ovarian cancer, pancreatic cancer (e.g., carcinoma or ductal adenocarcinoma), glioma, HNSCC, or thyroid cancer.

[0059] In some embodiments, the advanced solid tumor with HRAS amplification and / or HRAS overexpression, optionally in combination with an HRAS mutation, is HNSCC. In some embodiments, the advanced solid tumor has HRAS amplification. In some embodiments, the advanced solid tumor overexpresses HRAS. In some embodiments, the advanced solid tumor has squamous histology. In some embodiments, the advanced solid tumor has NRAS amplification and / or NRAS overexpression. In some aspects, the advanced solid tumor is (a) an advanced solid tumor with HRAS amplification, (b) HNSCC with HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with NRAS or HRAS amplification. In some embodiments, the advanced solid tumor is metastatic, advanced, relapsed, unresectable, recurrent, or refractory, or a combination thereof.

[0060] As used herein, the term "HNSCC" refers to head and neck squamous cell carcinoma (HNSCC). Head and neck squamous cell carcinoma (HNSCC) is the seventh most common invasive cancer worldwide, with approximately 830,000 new cases diagnosed annually worldwide, 200,000 deaths annually worldwide, and approximately 54,000 new cases annually in the United States. HNSCC is also the most common cancer in Central Asia. HNSCC has two distinct etiologies and corresponding tumor types. The first subtype is associated with smoking and alcohol use and is unrelated to human papillomavirus (HPV- or HPV-negative). The second subtype is associated with high-risk HPV infection (HPV+ or HPV-positive). This second subtype is primarily limited to oropharyngeal cancer. HPV+ tumors are a distinct entity with a favorable prognosis and may require different treatments. A significant proportion of HNSCC, particularly oropharyngeal cancer, is caused by HPV infection. High-risk HPV subtype 16 accounts for 85% of all HPV+ tumors in HNSCC. P16 can be used as a surrogate marker for HPV infection in HNSCC, particularly in the oropharynx. More accurate HPV tests are available, which are based on E6 / E7 detection (Liang C, et al. Cancer Res. 2012;72:5004-5013).

[0061] As used herein, unless otherwise specified, the term "dysregulated HRAS" or "HRAS dysregulation" refers to tumors that are dependent on HRAS due to oncogenic alterations in the RAS pathway, including, but not limited to, oncogenic HRAS mutations, oncogenic amplifications of the HRAS gene, and oncogenic copy gains of the HRAS gene, or combinations thereof.

[0062] As used herein, unless otherwise specified, the term "HRAS altered" refers to tumors that depend on an altered HRAS gene, such as a mutated or amplified HRAS gene.

[0063] As used herein, the term "overexpression" refers to a tumor with an increased copy number of a protein compared to a reference level. In some embodiments, the overexpressed protein is a wild-type protein. In some embodiments, the overexpressed protein is a mutant protein.

[0064] As used herein, the term "amplification" refers to an increase in the copy number of a gene compared to a reference level. In some embodiments, the amplified gene is a wild-type gene. In some embodiments, the amplified gene is a mutant gene.

[0065] As used herein, unless otherwise specified, the term "copy gain" refers to the amplification of a gene between diploid (n=2) and a specified cutoff for "amplification" of a particular gene (e.g., n=4, 5, or 6). For example, the specified cutoff for an amplified HRAS or NRAS gene may be n=4, 5, or 6, and thus the copy gain of the HRAS or NRAS gene would cover n=2 to n=4, 5, or 6, respectively.

[0066] The term "HRAS mutation" or "H-Ras mutation," as used herein, refers to an activating mutation in the HRAS gene or H-Ras protein. An H-Ras mutation can refer to either a genetic change in the DNA sequence of the HRAS gene that results in activation of the corresponding H-Ras protein, or a change in the amino acid sequence of the H-Ras protein that results in activation of the H-Ras protein. Therefore, as used herein, the term "HRAS mutation" or "H-Ras mutation" does not include a change in the HRAS gene that does not result in activation of the H-Ras protein, or a change in the H-Ras protein sequence that does not induce its activation. Therefore, a sample or subject that does not have any "H-Ras mutations" as used herein may still have a mutation in the HRAS gene that does not affect the activity of the H-Ras protein or a mutation that impairs the activity of the H-Ras protein, or a mutation in the H-Ras protein that does not affect the activity of the H-Ras protein or a mutation that impairs the activity of the H-Ras protein. A sample or subject may have multiple copies of the HRAS gene. A sample or subject may also have both a wild-type H-Ras protein and a mutant H-Ras protein. As used herein, a sample or subject with an H-Ras mutation may also have a copy of a wild-type HRAS gene and / or a wild-type H-Ras protein. As used herein, a sample or subject determined to have a "wild-type H-Ras" refers to a sample or subject that has only a wild-type HRAS gene and a wild-type H-Ras protein, but does not have an H-Ras mutation. In some embodiments, the mutant HRAS gene encodes a mutant H-Ras protein, and the HRAS gene mutation is or includes an alteration in a codon encoding an amino acid substitution at a specific position selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and any combination thereof, of the corresponding mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in a codon encoding an amino acid substitution at the G12 position of the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is in a codon that encodes a G12R substitution in the mutant H-Ras protein.The HRAS gene mutation can be a mutation in a codon encoding a G12C, G12D, G12A, G12V, G12S, G12F, G12R, or G12N substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in a codon encoding a G12V substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in a codon encoding an amino acid substitution at the G13 position in the mutant H-Ras protein. The HRAS gene mutation can be a mutation in a codon encoding a G13A, G13C, G13V, G13D, G13R, G13S, G13N, or G13V substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in a codon encoding a G13C substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in a codon encoding a G13R substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in a codon encoding an amino acid substitution at position Q61 of the mutant H-Ras protein. The HRAS gene mutation can be a mutation in a codon encoding a Q61E, Q61K, Q61H, Q61L, Q61P, or Q61R substitution of the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in a codon encoding a Q61L substitution of the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in a codon encoding a Q61R substitution of the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in a codon encoding an amino acid substitution at position Q22 of the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in a codon encoding a Q22K or Q22T substitution of the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in a codon encoding an amino acid substitution at position K117 of the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in a codon that encodes a K117N or K117L substitution in the mutant H-Ras protein.In some embodiments, the HRAS gene mutation is a mutation in a codon that encodes an amino acid substitution at the A146 position of the mutant H-Ras protein.The HRAS gene mutation can be a mutation in a codon that encodes an A146V, A146T, or A146P substitution of the mutant H-Ras protein.In some embodiments, the HRAS gene mutation is a mutation in a codon that encodes an A146P substitution of the mutant H-Ras protein.In some embodiments, the mutation can be a mutation in another codon that results in activation of the H-Ras protein.

[0067] As used herein, unless otherwise specified, the term "dysregulated NRAS" or "NRAS dysregulation" refers to tumors that are dependent on NRAS due to oncogenic alterations in the RAS pathway, including, but not limited to, oncogenic NRAS mutations, oncogenic amplifications of the NRAS gene, and oncogenic copy gains of the NRAS gene, or combinations thereof.

[0068] As used herein, unless otherwise specified, the term "NRAS altered" refers to tumors that depend on an altered NRAS gene, such as a mutated or amplified NRAS gene.

[0069] As used herein, the terms "NRAS mutation" or "N-Ras mutation" refer to an activating mutation in the NRAS gene or N-Ras protein, respectively. An N-Ras mutation can refer to either a genetic change in the DNA sequence of the NRAS gene that results in the activation of the corresponding N-Ras protein, or a change in the amino acid sequence of the N-Ras protein that results in the activation of the N-Ras protein. Therefore, as used herein, the terms "NRAS mutation" or "N-Ras mutation" do not include a change in the NRAS gene that does not result in the activation of the N-Ras protein, or a change in the N-Ras protein sequence that does not induce its activation. Therefore, a sample or subject that does not have any "N-Ras mutations" as used herein may still have a mutation in the NRAS gene that does not affect the activity of the N-Ras protein or a mutation that impairs the activity of the N-Ras protein, or a mutation in the N-Ras protein that does not affect the activity of the N-Ras protein or a mutation that impairs the activity of the N-Ras protein. A sample or subject may have multiple copies of the NRAS gene. A sample or subject may also have both wild-type and mutant N-Ras proteins. As used herein, a sample or subject with an N-Ras mutation may also have a copy of a wild-type NRAS gene and / or wild-type N-Ras protein. As used herein, a sample or subject determined to have a "wild-type N-Ras" refers to a sample or subject that has only a wild-type NRAS gene and wild-type N-Ras protein, but does not have an N-Ras mutation. In some embodiments, the mutant NRAS gene encodes a mutant N-Ras protein, and the NRAS gene mutation is or includes an alteration in a codon encoding an amino acid substitution at a specific position selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and any combination thereof, of the corresponding mutant H-Ras protein. In some embodiments, the modification is a G12C, G12D, G12S, G12V, G12R, Q61H, Q61K, Q61L, Q61R, or A146T substitution.

[0070] Advanced solid tumors can be classified using the tumor-node-metastasis (TNM) staging system. See Spira, J. & Ettinger, DS, N. Engl. J. Med., 350:382-(2004); Greene et al. (eds). AJCC Cancer Staging Manual. 6 th edition. New York: Springer-Verlag,2002:167-77;Sobin,LH& CHWittekind(eds). International Union Against Cancer. TNM classification of malignant tumors.6 th See, e.g., J. Med. 1999, ed. New York: Wiley-Liss (2002). Thus, in some embodiments, advanced solid tumors may be stratified into stages (e.g., latent, stage 0, stage IA, stage IB, stage IIA, stage IIB, stage IIIA, stage IIIB, or stage IV).

[0071] As used herein, unless otherwise specified, the term "relapsed" or "recurrent" refers to a disorder, disease, or condition that has progressed after responding to treatment (e.g., achieving a partial or complete response). The treatment may include one or more lines of therapy. For example, "relapsed" HNSCC or "recurrent" HNSCC may refer to an HNSCC that has been previously treated with one or more lines of therapy. In one embodiment, the relapsed HNSCC (or recurrent HNSCC) is an HNSCC that has been previously treated with one, two, three, or four lines of therapy. In one embodiment, the relapsed HNSCC (or recurrent HNSCC) is an HNSCC that has been previously treated with two or more lines of therapy. In another example, the advanced solid tumor may have been treated with one or more TKIs prior to treatment. For example, the disorder, disease, or condition is RCC. In some embodiments, the RCC has been previously treated with one TKI, two TKIs, or three TKIs, or at least one TKI.

[0072] As used herein, unless otherwise indicated, the term "refractory" refers to a disorder, disease, or condition that has not responded to prior treatment, which may include one or more lines of therapy. In some embodiments, the disorder, disease, or condition has previously received first-, second-, third-, or fourth-line treatment. In some embodiments, the disorder, disease, or condition has previously been treated with two or more lines of therapy and has had less than a complete response (CR) to the most recent systemic therapy, including the regimen. For example, the disorder, disease, or condition is HNSCC. For example, the disorder, disease, or condition is RCC. In some embodiments, the RCC has previously been treated with one TKI, two TKIs, or three TKIs, or at least one TKI.

[0073] As used herein, the terms "prevention" and "preventing" refer to obtaining beneficial or desired results, including, but not limited to, a preventative effect. For a preventative effect, the compounds and pharmaceutical compositions disclosed herein can be administered in accordance with the treatment methods provided herein to patients at risk of developing an advanced solid tumor, patients who have not been diagnosed with an advanced solid tumor but who have reported one or more physiological symptoms of an advanced solid tumor, or patients who are in remission from an advanced solid tumor. In some cases, a preventative effect can reduce the risk of recurrence of a solid tumor after prior therapy, for example, the risk of recurrent RCC after nephrectomy.

[0074] As used herein, unless otherwise indicated, the term "effective amount" with respect to a compound means an amount capable of treating, preventing, or managing a disorder, disease, or condition disclosed herein, or a symptom thereof. In some embodiments, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable form thereof, an effective amount of a VEGFR inhibitor, and / or a combination thereof may provide one or more benefits in accordance with the treatment methods provided herein. For example, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable form thereof, an effective amount of a VEGFR inhibitor, and / or a combination thereof may prevent, treat, and / or ameliorate one or more symptoms associated with an advanced solid tumor; prevent or delay the emergence of drug resistance in an advanced solid tumor; reduce, slow, or overcome drug resistance in an advanced solid tumor; inhibit disease progression or tumor growth, reduce the primary tumor (in size, volume, or extent of metastasis), alleviate tumor-related symptoms, and / or improve tumor secretion. The therapeutic effect of the compound may be to inhibit a factor, delay the appearance of primary or secondary tumors, reduce the onset of primary or secondary tumors, delay or reduce the severity of secondary effects of the disease, halt tumor growth, cause tumor regression, prolong time to progression (TTP), prolong progression-free survival (PFS), prolong overall survival (OS), increase overall response rate (ORR, e.g., complete response (CR) and partial response (PR) as determined by the patient's best tumor response), increase CR rate, increase duration of response (DoR), or decrease time to response (TTR), or a combination thereof. CR, PR, DoR, and PFS may be evaluated according to RECIST v. 1.1 guidelines. In some cases, drug resistance is TKI resistance or VEGFR inhibitor resistance, or resistance to one or more specific VEGFR inhibitors.

[0075] In some embodiments, when a compound in the form of a pharmaceutically acceptable salt and / or solvate is described as a dosage, daily dose, or amount listed in a pharmaceutical composition, pharmaceutical kit, or pharmaceutical packaging, the amount is expressed as the mass of the compound in free form (e.g., free base) equivalent (i.e., the form of the compound excluding salts and non-solvates). This amount is referred to as the "free form equivalent" or "free base equivalent."

[0076] As used herein, the terms "continuous dosing" and "continuous dosing schedule," or "continuous" and "sequentially," in the context of administration, refer to daily administration of a compound of Formula (I) or a pharmaceutically acceptable form thereof, or a VEGFR inhibitor disclosed herein, such as once daily (QD), twice daily (BID), three times daily (TID), or four times daily (QID), or a combination thereof.

[0077] As used herein, the terms "concurrently" or "concurrent" in the context of administration refer to the simultaneous administration of two or more agents, such as a compound of Formula (I) or a pharmaceutically acceptable form thereof and a VEGFR inhibitor, to a subject within a time proximity of each other within the same day. For example, in certain embodiments, the simultaneous administration of two or more agents to a subject occurs within 3 hours, 2 hours, 1 hour, 30 minutes of each other within the same day, or simultaneously.

[0078] As used herein, in the context of administration, the term "sequentially" or "sequentially" refers to the simultaneous administration of two or more agents, such as a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a VEGFR inhibitor, to a subject in a specific order, e.g., a predetermined order, within a single day. For example, in certain embodiments, the simultaneous administration of two agents, e.g., a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a VEGFR inhibitor, to a subject is accomplished by administering one agent to the subject first, followed by administering a second agent to the subject on the same day, unless a specific time limit within the same day is otherwise specified.

[0079] As used herein, the terms "interval dosing" and "interval dosing schedule" refer to a schedule in which a drug is administered on certain days and not on other days during a treatment cycle, e.g., a 28-day treatment cycle. For example, interval dosing of a drug, such as a compound of Formula (I) or a pharmaceutically acceptable form thereof and a VEGFR inhibitor, includes a scheduled period of dosing of the drug followed by a scheduled period of rest during a treatment cycle, e.g., a 28-day treatment cycle. For example, interval dosing of a drug includes, but is not limited to, administering the drug only every other day during a 28-day treatment cycle, or a treatment cycle in which the drug is administered for 4 consecutive weeks during a 6-week treatment cycle; administering the drug continuously only every other week (e.g., one week on and one week off, e.g., one week on and one week off, e.g., one week on days 1-7 and 15-21 of a 28-day treatment cycle, or one week on days 8-14 and 22-28 of a 28-day treatment cycle, or vice versa); administering the drug continuously; These include, but are not limited to, administering the agent for only two consecutive weeks (e.g., two weeks on and two weeks off, e.g., consecutively administering on days 1-14 of a 28-day treatment cycle, days 7-21 of a 28-day treatment cycle, or days 15-28 of a 28-day treatment cycle, or vice versa), or administering the agent for only three consecutive weeks (e.g., three weeks on and one week off, e.g., consecutively administering on days 1-21 of a 28-day treatment cycle, or days 7-28 of a 28-day treatment cycle, or vice versa). For example, in certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable form thereof and / or the VEGFR inhibitor disclosed herein may each independently be administered only every other day, continuously every other week, or continuously only during week 1, week 2, or week 3 during the course of a treatment cycle, such as during a 28-day treatment cycle.

[0080] As understood herein, a "treatment cycle" is a given period during which one or more treatments are administered to a subject in need thereof. In some embodiments, the treatment cycle is a 28-day treatment cycle.

[0081] As used herein, the terms "delayed dosing," "delayed dosing period," and "delayed dosing schedule" refer to the period between administering a first dose of a VEGFR inhibitor according to the methods described herein and subsequently administering a first dose of a compound of Formula (I) or a pharmaceutically acceptable form thereof to a subject. In some embodiments, the subject is a VEGFR inhibitor-naive subject. In some embodiments, the subject has a relapsed or refractory advanced solid tumor. In some embodiments, the subject has a relapsed or refractory advanced solid tumor and was previously treated with a VEGFR inhibitor, where the treatment was terminated prior to administration of the first dose of the VEGFR inhibitor. For example, the delayed dosing period can be about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1.25 years, about 1.5 years, about 1.75 years, about 2 years, about 2.25 years, about 2.5 years, about 2.75 years, or about 3 years. For example, in certain embodiments, the delayed dosing period is about 12 months, about 9 months, about 6 months, about 3 months, about 2 months, about 8 weeks, about 6 weeks, about 5 weeks, about 1 month, about 4 weeks, about 3 weeks, about 2 weeks, or within about 1 week. In some embodiments, the delayed dosing schedule comprises administering the compound of formula (I) or a pharmaceutically acceptable form thereof on a spaced dosing schedule after the delayed dosing period.

[0082] As used herein, the terms "dose escalation," "dose escalation interval," "escalation dose," "escalation dosing period," and "escalation dosing schedule" refer to an incremental increase in the amount of a drug, such as the compound of Formula (I) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor, administered to a subject over a period of time (sometimes referred to herein as a dose escalation period). In certain embodiments, the escalation is an increase in the dosage of the drug administered to the subject. In certain embodiments, the escalation is an increase in the daily dose of the drug administered to the subject. In certain embodiments, the period over which the completion of the escalation occurs (the dose escalation period) is 2 days, 3 days, 7 days (1 week), 10 days, 2 weeks, 3 weeks, or 4 weeks. In certain embodiments, during the dose escalation period, an escalation in the amount of the drug occurs (or is scheduled to occur) every 1 day, 2 days, 3 days, 7 days (1 week), 10 days, or 2 weeks. In certain embodiments, an increase, such as an incremental or total increase, in the amount of a drug administered to a subject is a 10% to 99%, e.g., 10%, 25%, 30%, 33%, 50%, 66%, 75%, 90%, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, or 4-fold increase in the amount of drug administered to a subject compared to the initial amount of drug administered to the subject at the start of the dose titration period or compared to a previous incremental increase in the amount of drug administered to a subject during the dose titration period. In certain embodiments, the final amount of drug administered at the end of the dose titration period is an effective amount of drug, e.g., an effective amount of drug administered during a treatment cycle, such as a 28-day treatment cycle. In certain embodiments, the amount of only one drug in a combination of drugs administered to a subject is increased incrementally over the course of the dose titration period, while the amounts of the remaining drugs in the combination are held constant. For example, in certain embodiments, the amount of the compound of Formula (I) or a pharmaceutically acceptable form thereof administered to the subject is increased over the course of a dose escalation period while the amount of the VEGFR inhibitor administered to the subject remains constant. In certain embodiments, the amount of a first agent, such as the compound of Formula (I) or a pharmaceutically acceptable form thereof, and the amount of a second agent, such as a VEGFR inhibitor, of a combination of drugs administered to the subject are each independently increased in a stepwise manner over the course of the dose escalation period.

[0083] As used herein, the terms "dose reduction," "dose reduction interval," "reduced dose administration," "dose reduction period," and "dose reduction schedule" refer to a gradual reduction in the amount of a drug, such as the compound of Formula (I) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor, administered to a subject over a period of time (sometimes referred to herein as a dose reduction period). In certain embodiments, the gradual reduction is a reduction in the dosage of the drug administered to the subject. In certain embodiments, the gradual reduction is a reduction in the daily dose of the drug administered to the subject. In certain embodiments, the period over which the completion of the gradual reduction occurs (the dose reduction period) is 2 days, 3 days, 7 days (1 week), 10 days, 2 weeks, 3 weeks, or 4 weeks. In certain embodiments, during the dose reduction period, the gradual reduction in the amount of the drug occurs (or is scheduled to occur) every 1 day, 2 days, 3 days, 7 days (1 week), 10 days, or 2 weeks. In certain embodiments, the reduction, such as a stepwise or total reduction, in the amount of drug administered to a subject is a 10% to 99%, e.g., 10%, 25%, 30%, 33%, 50%, 66%, 75%, 90%, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, or 4-fold reduction in the amount of drug administered to a subject compared to the initial amount of drug administered to the subject at the start of the dose reduction period or compared to a previous stepwise reduction in the amount of drug administered to a subject during a dose reduction period. In certain embodiments, the final amount of drug administered at the end of the dose reduction period is an effective amount of drug, e.g., an effective amount of drug administered during a treatment cycle, such as a 28-day treatment cycle. In certain embodiments, the amount of only one drug in a combination of drugs administered to a subject is stepwise reduced over the course of the dose reduction period, while the amounts of the remaining drugs in the combination remain constant. For example, in certain embodiments, the amount of the compound of Formula (I) or a pharmaceutically acceptable form thereof administered to the subject is decreased over the course of a dose reduction period while the amount of the VEGFR inhibitor administered to the subject remains constant. In certain embodiments, the amount of a first agent, such as the compound of Formula (I) or a pharmaceutically acceptable form thereof, and the amount of a second agent, such as a VEGFR inhibitor, of a combination of drugs administered to the subject are each independently decreased in a stepwise manner over the course of the dose reduction period.

[0084] As used herein, the term "loading dosing cycle" refers to administering a drug, such as a compound of Formula (I) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor, at a dose (sometimes referred to herein as a loading dose) that is higher than the maintenance dose (e.g., the dose administered during a treatment cycle). In certain embodiments, the loading dosing cycle continues until a therapeutic steady-state concentration of the drug is achieved. In certain embodiments, the loading dose of a drug, such as a compound of Formula (I) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor, may be in the range of about 1.1 to about 10 times the dose of the drug administered during a treatment cycle. In certain embodiments, the daily loading dose of a drug, such as a compound of Formula (I) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor, may be in the range of about 1.1 to about 10 times the daily dose of the drug administered during a treatment cycle.

[0085] As used herein, the term "first-line therapy" refers to the treatment of advanced solid tumors with platinum-based chemotherapy (e.g., cisplatin, carboplatin, or oxaliplatin, and combinations such as cisplatin / 5-FU or carboplatin / paclitaxel), optionally in combination with anti-EGFR antibody therapy (e.g., cetuximab, panitumumab, afatinib) for HNSCC or other advanced solid tumors. In some embodiments, first-line treatment options can be surgery, chemotherapy and radiation therapy following surgery, or systemic therapy such as pembrolizumab monotherapy, VEGFR monotherapy such as pazopanib or sunitinib monotherapy, a combination of pembrolizumab and platinum-based chemotherapy, axitinib or lenvatinib, a combination of nivolumab and cabozantinib or ipilimumab, axitinib and avelumab, or a combination of a TKI and an immune checkpoint inhibitor. In some embodiments, primary therapy is in the context of patients with recurrent or metastatic HNSCC, or HNSCC patients who have only received therapy for localized or locoregional disease. Primary treatment for advanced solid tumors is the first treatment a patient receives after recurrence or diagnosis of unresectable or metastatic disease.

[0086] As used herein, the term "second-line therapy" refers to a therapy for treating a recurrent, unresectable, or metastatic advanced solid tumor, or a therapy when at least one prior therapy has not alleviated or reduced the severity of at least one symptom associated with the advanced solid tumor. For example, second-line therapy may include the use of taxanes, methotrexate, and / or cetuximab for HNSCC. Second-line therapy for advanced solid tumors is a therapy administered to patients who have progressed during or after first-line therapy.

[0087] As used herein, unless otherwise indicated, the term "subject" to which administration is contemplated can be an animal, including, but not limited to, humans (i.e., male or female of any age group, e.g., adult or juvenile); primates (e.g., cynomolgus monkeys, rhesus monkeys), and / or other animals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, dogs, rabbits, rodents, and / or birds (e.g., commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys). In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a juvenile human. In some embodiments, the subject is an adult. In some embodiments, the subject is a patient, e.g., a human patient. In some embodiments, the subject is a smoker. In some embodiments, the subject is a non-smoker. In some embodiments, the subject is a non-smoker who was a former smoker.

[0088] In some embodiments, the subject has, is suffering from, has symptoms associated with, or has been diagnosed with an advanced solid tumor. In some embodiments, the subject has or is suffering from an advanced solid tumor. In some embodiments, the subject has symptoms associated with an advanced solid tumor. In some embodiments, the subject is diagnosed with an advanced solid tumor. In some embodiments, the subject can be diagnosed with an advanced solid tumor by one of skill in the art, e.g., a physician such as an oncologist. In some embodiments, the subject can be diagnosed with an advanced solid tumor by analysis of plasma or tissue biopsy from the subject, such as a tumor tissue biopsy. In some embodiments, the subject can be diagnosed with an advanced solid tumor by one or more imaging tests (e.g., MRI, CT, PET, PET-CT, nuclear scan, ultrasound), optionally in combination with analysis of plasma or tumor tissue biopsy. In some embodiments, the subject can be diagnosed with an advanced solid tumor by blood analysis. In some embodiments, the analysis includes circulating tumor DNA (ctDNA) analysis. In some embodiments, the subject is a previously treated advanced solid tumor subject. In some embodiments, the subject has previously received one treatment for an advanced solid tumor, and the current method comprises "second-line" treatment. In some embodiments, the subject has previously received one treatment and relapsed or is refractory to that treatment, and therefore receives second-line treatment, and therefore the current method comprises "third-line" treatment. In some embodiments, the subject is a VEGR inhibitor-naive subject. In some embodiments, the subject is a subject naive to treatment with one or more of cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanzarintinib. In some embodiments, the subject has previously been treated with a TKI, such as one TKI, two TKIs, or three TKIs in a previous line of treatment. In some embodiments, the subject has previously been treated with a VEGFR inhibitor, for example, the subject has previously been treated with a VEGFR inhibitor but is not currently being treated with a VEGFR inhibitor.In some embodiments, the subject has previously been treated with one or more of cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanzarintinib, and optionally, the subject is not currently being treated with the same agents. In some embodiments, the subject has been treated with chemotherapy (such as platinum chemotherapy, oxaliplatin chemotherapy, or irinotecan chemotherapy), or radioactive iodine (for thyroid cancer), imitanib (for GIST), systemic therapy, anti-VEGF therapy, anti-EGFR therapy, surgery (e.g., resection, nephrectomy), or radiation therapy, or is, in some cases, intolerant to other therapies. In some embodiments, the subject is currently being treated with a VEGFR inhibitor, for example, currently being treated with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib. In some embodiments, the advanced solid tumor is a drug-resistant advanced solid tumor, such as a TKI-resistant or VEGFR inhibitor-resistant advanced solid tumor. In some embodiments, the subject is a subject with an advanced solid tumor in remission. In some embodiments, the advanced solid tumor subject has a metastatic advanced solid tumor, a recurrent advanced solid tumor, or a refractory advanced solid tumor. In some embodiments, the subject has a metastatic advanced solid tumor. In some embodiments, the subject has a recurrent advanced solid tumor or a refractory advanced solid tumor.

[0089] As used herein, unless otherwise indicated, "treat," "treating," "treatment," and "ameliorating" are used interchangeably herein and mean to alleviate, in whole or in part, a disorder, disease, or condition, such as an advanced solid tumor, or to slow or halt one or more symptoms associated with a disorder, disease, or condition, such as an advanced solid tumor, or the further progression or worsening of those symptoms, or to alleviate or eradicate the cause(s) of the disorder, disease, or condition itself. In some embodiments, these terms refer to an approach for obtaining a beneficial or desired result, including, but not limited to, a therapeutic effect or a prophylactic benefit. Therapeutic effects resulting from the methods of treatment provided herein include eradication or amelioration of the underlying disease, such as an advanced solid tumor, being treated, and eradication or amelioration of one or more physiological signs or symptoms associated with the underlying disease (e.g., an advanced solid tumor), where improvement is observed in the patient, even though the patient may still be afflicted with the underlying disease or disorder (e.g., an advanced solid tumor). For example, when used in reference to a patient with an advanced solid tumor, a therapeutic effect refers to an effect that reduces the severity of or delays or slows the progression of an advanced solid tumor, including (a) inhibiting the growth of or halting the development of an advanced solid tumor, and (b) causing regression of an advanced solid tumor or delaying or minimizing one or more symptoms associated with the presence of an advanced solid tumor. A prophylactic effect resulting from the therapeutic methods provided herein includes a delay or elimination of the appearance of a disease or disorder (e.g., an advanced solid tumor), a delay or elimination of the onset of symptoms of a disease or disorder (e.g., an advanced solid tumor), a slowing, halting, or reversing the progression of a disease or disorder (e.g., an advanced solid tumor), or any combination thereof.

[0090] For advanced solid tumors, treatment can be evaluated by, among other things, inhibition of disease progression, inhibition of tumor growth, reduction in primary tumors, alleviation of tumor-related symptoms, inhibition of tumor-secreted factors, delay in the appearance of primary or secondary tumors, delay in the time to the appearance of drug resistance, delay in the development of primary or secondary tumors, reduction in the appearance of primary or secondary tumors, delay or reduction in the severity of secondary effects of the disease, arrest of tumor growth and tumor regression, prolongation of time to progression (TTP), prolongation of progression-free survival (PFS), and prolongation of overall survival (OS). OS, as used herein, refers to the time from the start of treatment to death from any cause. TTP, as used herein, refers to the time from the start of treatment to tumor progression; TTP does not include death. In some embodiments, PFS refers to the time from the start of treatment to tumor progression or death. In some embodiments, PFS refers to the time from the first dose of the compound to the first occurrence of disease progression or death from any cause. In some embodiments, the PFS rate will be calculated using the Kaplan-Meier estimator. Event-free survival (EFS) means the time from initiation of treatment to any form of treatment failure, treatment discontinuation for any reason, including disease progression, or death. In some embodiments, overall response rate (ORR) means the proportion of patients who achieve a response. In some embodiments, ORR means the combined proportion of patients who achieve a complete response (CR) and a partial response (PR). In some embodiments, ORR means the proportion of patients whose best response is a partial response (PR) or better. In some embodiments, duration of response (DoR) is the time from response to relapse or disease progression. In some embodiments, DoR is the time from a response of partial response (PR) or better to relapse or disease progression. In some embodiments, DoR is the time from first documentation of a response to first documentation of progressive disease or death. In some embodiments, DoR is the time from first documentation of a response of partial response (PR) or better to first documentation of progressive disease or death.In some embodiments, time to response (TTR) refers to the time from the first dose of a compound or combination of compounds (e.g., a compound of Formula (I) or a pharmaceutically acceptable form thereof and / or a VEGFR inhibitor) to the first documentation of a response. In some embodiments, TTR refers to the time from the first dose of a compound or combination of compounds to the first documentation of a response of at least a partial response (PR). In some embodiments, efficacy outcomes of the methods disclosed herein are determined according to applicable RECIST criteria (e.g., RECIST v.1.1). For example, in some embodiments, the RECIST criteria apply to an assessment of one or more target lesions (TL), including a quantitative assessment (sum of lesion diameters), an assessment of one or more non-target lesions (NTL), including a qualitative assessment (present, absent, or definite progression), and an assessment of the presence or absence of new lesions. In some embodiments, the efficacy outcomes of the methods disclosed herein are measured in comparison to treatment of an advanced solid tumor with a VEGFR inhibitor monotherapy, e.g., compared to a VEGFR inhibitor monotherapy that ultimately relapses and / or becomes resistant in an advanced solid tumor subject, e.g., compared to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zalintinib. In some embodiments, the efficacy outcomes of the methods disclosed herein are measured in comparison to standard of care advanced solid tumor treatments, including, but not limited to, surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or a combination thereof. In some embodiments, the efficacy outcomes of the methods disclosed herein are measured in comparison to untreated advanced solid tumors.

[0091] 6.1 Compounds In some embodiments, the methods of treatment provided herein comprise administering to a subject (a) a compound of Formula (I) or a pharmaceutically acceptable form thereof, and (b) a VEGFR inhibitor. The compound of Formula (I) or a pharmaceutically acceptable form thereof is a farnesyltransferase inhibitor and has high potency (lower IC) compared to the level of inhibition of geranylgeranyltransferase type 1. 50 It is a selective farnesyltransferase inhibitor that selectively inhibits farnesyltransferase at a concentration of 1000kJ / kg / day (value).

[0092] Some embodiments include (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile and has the following structure: [ka]

[0093] Some embodiments include (R)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile and has the following structure: [ka]

[0094] Some embodiments include (3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile and has the following structure: [ka] Compounds that are useful as described herein include compounds of formulas (I), (II), and (III), and pharmaceutically acceptable forms thereof.

[0095] The synthesis and specific uses, inhibitory activity, and metabolic stability of the compounds of Formula (I), (II), and (III), and pharmaceutically acceptable forms thereof, provided herein are described in International Patent Application No. PCT / US2022 / 80565, which is incorporated herein by reference in its entirety, and are illustrated in Example 1 disclosed herein. In some embodiments, the compound for use in the methods of treatment provided herein is a compound of Formula (I), or a pharmaceutically acceptable form thereof. Throughout this application, any disclosure involving the use of a compound of Formula (I), or a pharmaceutically acceptable form thereof, applies equally to a compound of Formula (II), or a pharmaceutically acceptable form thereof, or a compound of Formula (III), or a pharmaceutically acceptable form thereof.

[0096] In certain embodiments, the use of farnesyltransferase inhibitors, particularly compounds of Formula (I), (II), or (III), and pharmaceutically acceptable forms thereof, is applicable to the farnesyltransferase inhibitor tipiparnib.

[0097] In some embodiments, the VEGFR inhibitor used as provided herein is cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, including pharmaceutically acceptable forms thereof. In some embodiments, the VEGFR inhibitor used as provided herein is cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanzarintinib fumarate. In some embodiments, the VEGFR inhibitors used herein are pharmacologically active metabolites of the VEGFR inhibitors described herein, including, for example, the M-2 and M-5 metabolites of regorafenib and the desmethyl metabolite of vandetanib.

[0098] 6.2 Pharmaceutical Compositions, Kits and Packaging In some embodiments, provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, provided herein are pharmaceutical compositions comprising a VEGFR inhibitor such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, or a pharmaceutically acceptable form thereof, such as cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanzarintinib fumarate, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable form thereof, a VEGFR inhibitor such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, or cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanzarintinib fumarate, and a pharmaceutically acceptable carrier, diluent, or excipient.For example, the pharmaceutical composition comprises a compound of formula (I), or a pharmaceutically acceptable form thereof, and cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, or cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanzarintinib fumarate, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0099] In some embodiments, provided herein is a pharmaceutical kit comprising (a) a compound of Formula (I), or a pharmaceutically acceptable form thereof, and (b) a VEGFR inhibitor. In some embodiments, the pharmaceutical kit further comprises instructions detailing a dosing regimen for administering each compound over one or more treatment cycles. In some embodiments, the pharmaceutical kit further comprises a color-coding system detailing a dosing regimen for administering each compound independently over one or more treatment cycles. In some embodiments, the pharmaceutical kit is a pharmaceutical package.

[0100] In some embodiments, the pharmaceutical kit or packaging further includes instructions for administering the contents of the kit to a subject with an advanced solid tumor. For example, in some embodiments, the instructions may detail a dosing regimen for administering the compound of Formula (I), or a pharmaceutically acceptable form thereof, e.g., once or twice daily, or, e.g., once or twice daily on days 1-7, 1-7, and 15-21, 1-21 of a 28-day treatment cycle, or each day of a 28-day treatment cycle; and a dosing regimen for administering the VEGFR inhibitor, e.g., once or twice daily, or, e.g., once or twice daily on each day of a treatment cycle, such as a 28-day treatment cycle, or once or twice daily on weeks 1-4 of a 6-week treatment cycle. In some embodiments, the instructions for administering each agent may be color-coded with a different color for the instructions for each agent. In some embodiments, the instructions may include details of an ascending dosing period, a descending dosing period, or a loading dosing period, optionally color-coded, for administering the compound of Formula (I) or a pharmaceutically acceptable form thereof. For example, in some embodiments, the instructions may be color-coded and may detail an ascending dosing period or a descending dosing period for administering a VEGFR inhibitor.

[0101] In some embodiments, the pharmaceutical composition, or pharmaceutical kit or pharmaceutical package containing same, comprises an effective amount of a compound of formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. For example, in some embodiments, the pharmaceutical composition, or pharmaceutical kit or pharmaceutical package containing same, may contain, for example, 0.5 to 2.5 mg, 0.5 to 5 mg, 0.5 to 10 mg, 0.5 to 25 mg, 0.5 to 50 mg, 0.5 to 75 mg, 0.5 to 100 mg, 0.5 to 300 mg, 0.5 to 600 mg, 0.5 to 1200 mg, 1 to 5 mg, 1 to 10 mg, 1 to 25 mg, 1 to 50 mg, 1 to 75 mg, 1 to 100 mg, 1 to 300 mg, 1 to 600 mg, 1 to 1200 mg, 1 to 2400 mg, 20 to 100 mg, 40 to 75 mg, 50 to 75 mg, 50 to 100 mg, 50 to 150 mg, 75 to 100 mg, 100 to 2400 mg, and 2000-2400 mg, or 0.5-2400 mg of the compound of formula (I), or a pharmaceutically acceptable form thereof, in an amount selected from the group consisting of 00 mg, 125-200 mg, 150-300 mg, 200-250 mg, 200-400 mg, 300-600 mg, 250-500 mg, 400-600 mg, 500-750 mg, 600-900 mg, 700-100 mg, 650-1000 mg, 800-1200 mg, 900 mg-1500 mg, 1000-1600 mg, 1000-2000 mg, 1200-1600 mg, 1500-2000 mg, 1500-2400 mg, 1800-2400 mg, and 2000-2400 mg.In some embodiments, the pharmaceutical composition, or pharmaceutical kit or pharmaceutical package comprising same, is at least about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, and 2.0 mg, about 2.5 mg, about 3.0 mg, about 5 mg, about 10 mg, about 15 mg, About 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 9 5mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, about 250mg, about 275mg, about 300mg, about 325mg, about 350mg, about 375mg, about 400m g, about 425mg, about 450mg, about 475mg, about 500mg, about 525mg, about 550mg, about 575mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg , about 900mg, about 950mg, about 1000mg, about 1050mg, about 1100mg, about 1150mg, about 1200mg, about 1250mg, about 1300mg, about 1350mg, about 1400mg, about 1450m g, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, and about 2400 mg of a compound of formula (I), or a pharmaceutically acceptable form thereof.

[0102] In some embodiments, the pharmaceutical composition, or pharmaceutical kit or pharmaceutical package comprising the same, comprises 0.2 to 1500 mg of a VEGFR inhibitor, e.g., an amount selected from 0.5 to 10 mg, 2 to 15 mg, 10 to 30 mg, 10 to 40 mg, 10 to 240 mg, 20 to 50 mg, 20 to 240 mg, 30 to 50 mg, 35 to 70 mg, 40 to 80 mg, 60 to 100 mg, 80 to 120 mg, 80 to 160 mg, 80 to 240 mg, 160 to 250 mg, 160 to 300 mg, 100 to 600 mg, or 200 to 1000 mg of a VEGFR inhibitor. In some embodiments, the pharmaceutical composition, or pharmaceutical kit or pharmaceutical package comprising same, is at least one of the following: 0.89 mg, 1 mg, 1.34 mg, 4 mg, 5 mg, 8 mg, 10 mg, 12 mg, 12.5 mg, 14 mg, 15 mg, 18 mg, 20 mg, 24 mg, 25 mg, 30 mg, 35 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 375 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, In some embodiments, the VEGFR inhibitor is in the form of a salt and / or solvate, in which case the amount of VEGFR inhibitor is expressed as the equivalent amount of free base.

[0103] In some embodiments, the pharmaceutical composition, kit, or package comprises (Table 1): [Table 1] TIFF2025542187000008.tif145165

[0104] In some embodiments, a pharmaceutical composition comprising a VEGFR inhibitor, such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, or a pharmaceutical kit or pharmaceutical package comprising the same, is formulated as an oral dosage form, such as a tablet or capsule. In some embodiments, the pharmaceutical composition comprising a VEGFR inhibitor further comprises an excipient. In some embodiments, the excipient is selected from the group consisting of mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate, lactose anhydrous, lactose monohydrate, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, calcium carbonate, mannitol, talc, povidone, calcium hydrogen phosphate dihydrate, crospovidone, cornstarch, and sodium starch glycolate. In some embodiments, the tablet comprises a film coating, and the capsule comprises a capsule shell. In some embodiments, the VEGFR inhibitor is formulated with an excipient selected from (Table 2): [Table 2]

[0105] In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof, and methods for combination with a VEGFR inhibitor, such as: (a) treatment of advanced solid tumors with a VEGFR inhibitor monotherapy, compared to treatment of advanced solid tumors with a VEGFR inhibitor monotherapy that ultimately leads to recurrence and / or resistance in subjects with advanced solid tumors, e.g., cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or treatment of the advanced solid tumor with zanzarintinib; (b) compared to standard treatments for the advanced solid tumor, including but not limited to surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or a combination thereof; or (c) compared to untreated advanced solid tumors, the VEGFR inhibitor contained in the pharmaceutical composition, pharmaceutical kit, or pharmaceutical packaging provided herein is effective in reducing or ameliorating one or more symptoms of the advanced solid tumor, or is effective in treating, delaying progression of, or delaying the time to the development of drug resistance to the advanced solid tumor.In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof, or a VEGFR inhibitor when in combination with a VEGFR inhibitor, or a combination thereof, is: (a) for combination methods with a VEGFR inhibitor, such as treatment of an advanced solid tumor with a VEGFR inhibitor monotherapy, compared to treatment of an advanced solid tumor with a VEGFR inhibitor monotherapy that ultimately leads to recurrence and / or resistance in a subject with an advanced solid tumor, e.g., cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sonoprost, sucralose ... (b) compared to treatment of advanced solid tumors with rafenib, tivozanib, fruquintinib, or zanzarintinib; (b) compared to standard treatments for advanced solid tumors, including but not limited to surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or a combination thereof; or (c) compared to untreated advanced solid tumors, including an amount effective to: reduce or delay the risk of recurrence of an advanced solid tumor, prolong PFS and / or OS, prolong PFS, prolong OS, increase ORR, increase CR, prolong TTP, prolong PFS, prolong EFS, or prolong DoS, or a combination thereof. In some embodiments, the effective amount of the compound of Formula (I), or a pharmaceutically acceptable form thereof, and / or VEGFR inhibitor in a pharmaceutical composition, or in a pharmaceutical kit or pharmaceutical package comprising the same, depends on the absorption, tissue distribution, metabolism, excretion rate of the active compound, the administration schedule, the dose, the particular formulation, and other factors known to those skilled in the art. Effective amounts can be empirically determined by testing the compounds in the in vitro and in vivo systems described herein and then extrapolating therefrom to dosages for humans.

[0106] In some embodiments, pharmaceutical compositions are provided for administration to a subject in unit dosage forms, such as tablets, capsules, microcapsules, pills, powders, granules, troches, suppositories, injections, syrups, patches, creams, lotions, ointments, gels, sprays, sterile parenteral solutions or suspensions, and oral solutions or suspensions, as well as oil-water emulsions containing a suitable amount of a compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions provided herein are in the form of tablets. In some embodiments, the pharmaceutical compositions provided herein are in the form of capsules. In some embodiments, the capsules contain a compound provided herein but do not contain additional carriers, excipients, or vehicles. Typically, the compounds disclosed herein are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999). In some embodiments, the pharmaceutical compositions are formulated and administered in unit dosage forms or multi-dosage forms. Such dosage forms contain a predetermined amount of the active ingredient and can be prepared by pharmaceutical methods well known to those skilled in the art. As used herein, a unit dose form refers to a physically discrete unit suitable for human and animal subjects and individually packaged as known in the art. Each unit dose contains a predetermined amount of a therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle, or diluent. Examples of unit dose forms include ampoules and syringes, and individually packaged tablets or capsules. A unit dose form may be administered in fractions or multiples thereof. A multiple dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in separate unit dose forms. Examples of multiple dose forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Thus, a multiple dose form is a plurality of unit doses that are not separated within the package.

[0107] The compounds and pharmaceutical compositions provided herein can be administered at once, or can be divided into several smaller doses and administered at intervals of time. It is understood that the exact dosage and duration of treatment can depend on the disease being treated (e.g., advanced solid tumors) and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It should be noted that concentrations and dosage values ​​can also vary depending on the severity of the condition to be alleviated. For any particular subject, specific dosage regimens can be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions, and it should be further understood that the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed pharmaceutical compositions.

[0108] The compounds and pharmaceutical compositions are intended to be administered by any suitable route, including, but not limited to, oral, parenteral, rectal, topical, and local administration. For oral administration, capsules and tablets may be formulated. Pharmaceutical compositions may be in liquid, semi-liquid, or solid form and are formulated in a manner suitable for each administration route. In one embodiment, when administered orally, the compounds provided herein are administered with food and water. In another embodiment, the compounds provided herein are dispersed in water or juice (e.g., apple juice or orange juice) and orally administered as a solution or suspension. In one embodiment, the compounds provided herein are administered while the subject is eating. In one embodiment, the compounds provided herein are administered while the subject is being fed a high-fat and / or high-calorie food. In one embodiment, the compounds provided herein are administered while the subject is being fed an FDA-standard high-fat, high-calorie meal. In one embodiment, the compounds provided herein are administered while the subject is fasting. In one embodiment, the compounds provided herein are administered after the subject has fasted overnight for at least 8 hours. In one embodiment, the compounds provided herein are administered with or without food.

[0109] The compounds and pharmaceutical compositions provided herein may also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, intramucosally, by inhalation, or topically to the ear, nose, eye, or skin. The method of administration is left to the discretion of the medical practitioner and may depend, in part, on the site of the medical condition. Depending on the disease being treated and the condition of the subject, the compounds may be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation, nasal, vaginal, rectal, sublingual, or topically (e.g., transdermally or topically). The compound of Formula (I), or a pharmaceutically acceptable form thereof, and / or a VEGFR inhibitor, may be formulated alone or in suitable dosage units with pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each administration route.

[0110] In some embodiments, the pharmaceutical compositions provided herein may provide delayed or prolonged pharmacokinetics through appropriate formulation. For example, in some embodiments, the pharmaceutical compositions provided herein delay or prolong the dissolution of the compound of Formula (I), or a pharmaceutically acceptable form thereof, or the VEGFR inhibitor, or a combination thereof. For example, slowly dissolving pellets of the compounds provided herein can be prepared and incorporated into tablets or capsules, or as sustained-release implantable devices. This technique also includes producing pellets with several different dissolution rates and filling capsules with a mixture of these pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Parenteral formulations of the compounds provided herein can be prolonged by dissolving or suspending them in an oily or emulsified medium, allowing the compounds to gradually disperse in the serum.

[0111] 6.3 Methods, Dosing Regimen and Schedule 6.3.1 Treatment method In some embodiments, provided herein are methods of treating an advanced solid tumor in a subject, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising same), and a VEGFR inhibitor. In some embodiments, provided herein are methods of treating an advanced solid tumor in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising same), and an effective amount of a VEGFR inhibitor.

[0112] In another aspect, a method of alleviating, slowing progression, or overcoming drug resistance in an advanced solid tumor in a subject comprises administering to the subject a compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising same), and a VEGFR inhibitor. Another aspect comprises a method of alleviating, slowing progression, or overcoming drug resistance in an advanced solid tumor in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising same), and an effective amount of a VEGFR inhibitor. In some embodiments, the drug resistance is TKI resistance. In some embodiments, the drug resistance is TKI resistance in an advanced solid tumor subject currently or previously treated with a TKI. In some embodiments, the drug resistance is VEGFR inhibitor resistance, for example, in a TKI-resistant or VEGFR inhibitor-resistant advanced solid tumor where the subject is currently being treated or previously treated with a TKI or VEGFR inhibitor.

[0113] In some embodiments, provided herein are methods for preventing or delaying the emergence of TKI resistance in advanced solid tumors in TKI-naive subjects, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a VEGFR inhibitor. In some embodiments, provided herein are methods for preventing or delaying the emergence of TKI resistance in advanced solid tumors in TKI-naive subjects, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof, and an effective amount of a VEGFR inhibitor. In some embodiments, the TKI resistance is TKI resistance in TKI-naive or VEGFR inhibitor-naive advanced solid tumors.

[0114] In some embodiments, provided herein are methods of treating an advanced solid tumor in a subject having HRAS amplification and / or HRAS overexpression, optionally in combination with an HRAS mutation, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable form thereof. In some embodiments, provided herein are methods of treating an advanced solid tumor in a subject having squamous histology and HRAS amplification and / or HRAS overexpression, optionally in combination with an HRAS mutation, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable form thereof. In some embodiments, provided herein are methods of treating an advanced solid tumor in a subject having squamous histology and HRAS amplification and / or HRAS overexpression, optionally in combination with an HRAS mutation, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof. In some embodiments, such methods comprise administering a compound of Formula (I), or a pharmaceutically acceptable form thereof, as the only anti-tumor agent in a treatment regimen, e.g., as monotherapy. In some embodiments, the advanced solid tumor is (a) an advanced solid tumor with HRAS amplification, (b) HNSCC with HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with HRAS amplification.

[0115] In some embodiments, provided herein are methods of treating an advanced solid tumor in a subject with squamous histology and NRAS amplification and / or NRAS overexpression, optionally in combination with an NRAS mutation, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable form thereof. In some embodiments, provided herein are methods of treating an advanced solid tumor in a subject with squamous histology and NRAS amplification and / or NRAS overexpression, optionally in combination with an NRAS mutation, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof. In some embodiments, such methods comprise administering a compound of Formula (I), or a pharmaceutically acceptable form thereof, as the only anti-tumor agent in a treatment regimen, e.g., as monotherapy. In some aspects, the advanced solid tumor is non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with NRAS amplification.

[0116] In some embodiments, the subject treated according to the treatment methods provided herein has, is suffering from, has symptoms related to, or is diagnosed with, an advanced solid tumor. In some embodiments, the subject is a TKI-naive subject or a VEGFR inhibitor-naive subject. In some embodiments, the subject is a relapsed or refractory advanced solid tumor subject who has previously been treated with a TKI or VEGFR inhibitor but is not currently being treated.

[0117] In some embodiments, the subject to whom a compound is administered in the methods provided herein has, is suffering from, has symptoms associated with, or is diagnosed with an advanced solid tumor. In some embodiments, the subject has or is suffering from an advanced solid tumor. In some embodiments, the subject has symptoms associated with an advanced solid tumor. In some embodiments, the subject is diagnosed with an advanced solid tumor. In some embodiments, the subject is a subject with a previously treated advanced solid tumor. In some embodiments, the subject is a TKI-naive subject or a VEGFR inhibitor-naive subject. In some embodiments, the subject is naive to treatment with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanzarintinib. In some embodiments, the subject has been previously treated with a TKI, or a VEGFR inhibitor, or with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib. In some embodiments, the subject has been previously treated with cabozantinib. In some embodiments, the subject is a subject with an advanced solid tumor who is in remission. In some embodiments, the advanced solid tumor subject is a TKI-resistant advanced solid tumor subject, such as a VEGFR inhibitor-resistant advanced solid tumor subject. In some embodiments, the subject is a mammal, for example, a human, such as a human who has, is suffering from, has symptoms related to, or has been diagnosed with an advanced solid tumor.

[0118] In some embodiments, the VEGFR inhibitor is cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib. In some embodiments, the VEGFR inhibitor is in the form of cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanzarintinib fumarate. In some embodiments, the VEGFR inhibitor is cabozantinib, axitinib, sunitinib, or sorafenib. In some embodiments, the VEGFR inhibitor is cabozantinib, such as cabozantinib (S)-malate. In some embodiments, the VEGFR inhibitor is zanzarintinib, such as zanzarintinib fumarate. In some embodiments, the VEGFR inhibitor is fruquintinib, such as fruquintinib free base.

[0119] In some embodiments, the progressive solid tumor is a metastatic solid tumor, a recurrent solid tumor, an unresectable solid tumor, a recurrent solid tumor, or a refractory solid tumor. In some embodiments, the metastatic solid tumor is. In some embodiments, the progressive solid tumor is an unresectable solid tumor. In some embodiments, the progressive solid tumor is a recurrent solid tumor. In some embodiments, the progressive solid tumor is a refractory solid tumor.

[0120] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, administered in accordance with the methods provided herein inhibits protein farnesylation, e.g., inhibits farnesylation of a farnesylation-dependent protein. Without being bound by any one theory, in some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, administered in accordance with the methods provided herein inhibits farnesylation of one or more farnesylation-dependent proteins selected from RhoB, RhoE, and lamin B, or a combination thereof. In some embodiments, the farnesylation-dependent protein is a dysregulated farnesylation-dependent protein.

[0121] In some embodiments, inhibition of farnesylation of farnesylation-dependent proteins by the methods of treatment provided herein occurs in a cell, such as a cell of a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. Without being bound by any one theory, in some embodiments, inhibiting farnesylation of farnesylation-dependent proteins by administering a compound of Formula (I), or a pharmaceutically acceptable form thereof, in combination with a VEGFR inhibitor provides a subject with: (a) a significant reduction in the farnesylation of farnesyl-dependent proteins compared to treatment of advanced solid tumors with TKI monotherapy or VEGFR inhibitor therapy, e.g., with respect to the combination with a VEGFR inhibitor, that ultimately leads to relapse and / or resistance in the subject with the advanced solid tumor; (b) compared to treatment of advanced solid tumors with inhibitor therapy, for example, compared to treatment of advanced solid tumors with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib; (b) compared to standard treatments for advanced solid tumors, including, but not limited to, surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or a combination thereof; or (c) resulting in a therapeutic effect, such as a synergistic benefit, compared to untreated advanced solid tumors.For example, in some embodiments, therapeutic effects, such as synergistic benefits, provided by administering a compound of Formula (I), or a pharmaceutically acceptable form thereof, according to the methods provided herein include improving efficacy (e.g., inhibiting tumor growth and inducing tumor regression); increasing PFS by 10-99%, e.g., 10%, 25%, 50%, 80%, 90%, 95%, or 99%, 2-fold, 3-fold, or 4-fold; or increasing OS by 10-99%, e.g., 10%, 25%, 50%, 80%, 90%, 95%, or 99%. increasing PFS and / or OS, such as by 95%, 95%, or 99%, or by a factor of 2, 3, or 4; in combination with a VEGFR inhibitor, reducing the effective dose of the TKI or VEGFR inhibitor, reducing the severity, incidence, or risk of toxicity selected from severe bleeding, impaired wound healing, gastrointestinal perforation, hypertension, fatigue, arterial and venous thromboembolic events, bleeding, cardiovascular events, heart failure, hepatotoxicity, and QT prolongation, or a combination thereof. reducing toxicant-associated toxicity; or, for example, compared to treatment of advanced solid tumors with TKI monotherapy or VEGFR inhibitor monotherapy that ultimately leads to relapse and / or resistance in subjects with advanced solid tumors, compared to treatment of advanced solid tumors with TKI monotherapy or VEGFR inhibitor monotherapy, e.g., compared to treatment of advanced solid tumors with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib; for all methods, compared to standard of care advanced solid tumor treatments, including, but not limited to, surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or a combination thereof; or, for all methods, compared to untreated advanced solid tumors, delaying the emergence of TKI or VEGFR inhibitor resistance, e.g., delaying the emergence of TKI or VEGFR inhibitor resistance unexpectedly. In some embodiments, efficacy outcomes are determined according to applicable RECIST criteria (eg, RECIST v.1.1).In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable form thereof, in combination with a VEGFR inhibitor according to the methods disclosed herein may provide therapeutic efficacy, including synergistic benefit, in a treated subject, e.g., compared to treatment of advanced solid tumors with TKI monotherapy or VEGFR inhibitor monotherapy that ultimately leads to relapse and / or resistance in subjects with advanced solid tumors, compared to treatment of advanced solid tumors with TKI monotherapy or VEGFR inhibitor monotherapy, e.g., treatment of advanced solid tumors with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib. In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable form thereof, according to the methods disclosed herein may provide a therapeutic effect, including a synergistic benefit, in a treated subject compared to standard advanced solid tumor treatments, including, but not limited to, surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or a combination thereof. In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable form thereof, according to the methods disclosed herein may provide a therapeutic effect, including a synergistic benefit, in a treated subject compared to untreated advanced solid tumors. In some embodiments, inhibition of farnesyltransferase present in cells occurs in a subject afflicted with an advanced solid tumor.

[0122] In some embodiments, the methods provided herein provide one or more therapeutic benefits in a subject: (a) in combination with a VEGFR inhibitor, compared to treatment of an advanced solid tumor with a TKI or VEGFR inhibitor monotherapy, e.g., compared to treatment of an advanced solid tumor with a TKI monotherapy or VEGFR inhibitor therapy that ultimately leads to relapse and / or resistance in a subject with an advanced solid tumor, e.g., compared to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib; (b) compared to standard of care advanced solid tumor treatments, including, but not limited to, surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or a combination thereof; or (c) compared to untreated advanced solid tumors. For example, in some embodiments, the one or more therapeutic effects provided by the methods disclosed herein include a delay in the time to the emergence or progression of drug resistance, e.g., TKI drug resistance or VEGFR inhibitor resistance, and in some embodiments, the delay is unexpected. In some embodiments, the one or more therapeutic effects provided by the methods disclosed herein include delaying, halting, or preventing the progression of an advanced solid tumor. In some embodiments, the one or more therapeutic effects provided by the methods disclosed herein include delaying, halting, or preventing the growth of an advanced solid tumor. In some embodiments, the one or more therapeutic effects provided by the methods disclosed herein include a reduction in primary advanced solid tumor size, e.g., a reduction in the size, volume, or appearance of a primary advanced solid tumor, or a reduction in the extent of metastasis from a primary advanced solid tumor. In some embodiments, the one or more therapeutic effects provided by the methods disclosed herein include alleviating symptoms associated with an advanced solid tumor. In some embodiments, the one or more therapeutic effects provided by the methods disclosed herein include inhibiting an advanced solid tumor-secreted factor.In some embodiments, the one or more therapeutic effects provided by the methods disclosed herein include delaying the appearance of primary or secondary solid tumors. In some embodiments, the one or more therapeutic effects provided by the methods disclosed herein include delaying the onset of primary or secondary solid tumors, e.g., delaying the onset of a solid tumor to an advanced stage. For example, in certain embodiments, the one or more therapeutic effects provided by the methods disclosed herein include delaying the progression of an advanced solid tumor and / or a primary or secondary solid tumor to metastasis. In some embodiments, the one or more therapeutic effects provided by the methods disclosed herein include reducing the appearance of primary or secondary solid tumors. In some embodiments, the one or more therapeutic effects provided by the methods disclosed herein include delaying or reducing the severity of secondary effects associated with an advanced solid tumor. In some embodiments, the one or more therapeutic effects provided by the methods disclosed herein include slowing, halting (halting), or reducing the growth of an advanced solid tumor and / or reducing the solid tumor. For example, in some embodiments, the methods provided herein reduce the volume of a solid tumor or reduce the size of a solid tumor. In some embodiments, the one or more therapeutic effects provided by the methods disclosed herein include an increase in time to progression (TTP), progression-free survival (PFS), event-free survival (EFS), overall survival (OS), overall response rate (ORR), complete response rate (CR rate), or duration of response (DoR), or a combination thereof. In some embodiments, the one or more therapeutic effects provided by the methods disclosed herein include a decrease in time to response (TTR).In certain embodiments, the one or more therapeutic effects provided to a subject are compared to treatment of an advanced solid tumor with TKI or VEGFR monotherapy, e.g., compared to treatment of an advanced solid tumor with TKI monotherapy or VEGFR inhibitor therapy that ultimately leads to relapse and / or resistance in a subject with an advanced solid tumor, e.g., compared to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, in combination with a VEGFR inhibitor. In certain embodiments, the one or more therapeutic effects provided to a subject are associated with standard-of-care treatment of an advanced solid tumor, including, but not limited to, surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or a combination thereof. In certain embodiments, the one or more therapeutic effects provided to a subject are associated with untreated advanced solid tumors.

[0123] In some embodiments, the methods provided herein can be for second line, third line, more than second line, or more than third line treatment. In such cases, the subject may have received prior treatment selected from chemotherapy, TKI, or VEGFR inhibitor, and the method provides the subject with one or more therapeutic benefits, such as: (a) in combination with a VEGFR inhibitor, compared to treatment of advanced solid tumors with TKI or VEGFR inhibitor monotherapy, for example, compared to treatment of advanced solid tumors with TKI monotherapy or VEGFR inhibitor therapy that ultimately leads to recurrence and / or resistance in subjects with advanced solid tumors, for example, compared to treatment of advanced solid tumors with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib; (b) compared to standard treatment of advanced solid tumors, including but not limited to surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or a combination thereof; or (c) compared to untreated advanced solid tumors. In some embodiments, the method provided herein includes one or more prior treatments according to the NCCN guidelines.

[0124] In some embodiments, the method of using a combination of a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a VEGFR inhibitor comprises administering a combination of one or more of the following embodiments (Table 3): [Table 3] TIFF2025542187000011.tif214165TIFF2025542187000012.tif227165TIFF2025542187000013.tif211165TIFF2025542187000014.tif203165

[0125] In some embodiments, the method comprises administering to the subject (a) a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, and (b) a pharmaceutical composition comprising a VEGFR inhibitor and a pharmaceutically acceptable carrier, diluent, or excipient. For example, in some embodiments, the method comprises administering to the subject (a) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, and (b) a pharmaceutical composition comprising an effective amount of a VEGFR inhibitor and a pharmaceutically acceptable carrier, diluent, or excipient.

[0126] In some embodiments, the methods provided herein comprise administering to a subject a pharmaceutical kit or pharmaceutical package containing (a) a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, and (b) a pharmaceutical composition comprising a VEGFR inhibitor, such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, and a pharmaceutically acceptable carrier, diluent, or excipient. For example, in some embodiments, the methods provided herein comprise administering to a subject such a pharmaceutical kit or packaging containing (a) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, and (b) a pharmaceutical composition comprising an effective amount of a VEGFR inhibitor, such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical kit or packaging contains instructions detailing the dosing regimen for each agent, and optionally, one or more treatment cycles.

[0127] In some embodiments of the methods related to advanced solid tumors with squamous histology and HRAS amplification and / or overexpression, and optionally HRAS mutations, the methods provided herein comprise administering to a subject a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments of the methods related to advanced solid tumors with HRAS amplification and / or overexpression, and optionally HRAS mutations, the methods provided herein comprise administering to a subject a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the advanced solid tumor has squamous histology. In some embodiments, the advanced solid tumor is (a) an advanced solid tumor with HRAS amplification, (b) HNSCC with HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with HRAS amplification.

[0128] In some embodiments of the methods related to advanced solid tumors with NRAS amplification and / or overexpression, and optionally NRAS mutation, the methods provided herein comprise administering to a subject a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments of the methods related to advanced solid tumors with NRAS amplification and / or overexpression, and optionally NRAS mutation, the methods provided herein comprise administering to a subject a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some aspects, the advanced solid tumor is (a) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with NRAS amplification.

[0129] 6.3.2 Dosage and Regimen In some embodiments, the methods provided herein comprise administering to a subject (a) a compound of Formula (I), or a pharmaceutically acceptable form thereof, and (b) a VEGFR inhibitor, such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or a zanzarintinib, such as cabozantinib. For example, in some embodiments, the methods provided herein comprise administering to a subject (a) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof, and (b) a VEGFR inhibitor, such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or a zanzarintinib, such as cabozantinib. In some embodiments, the method comprises administering to the subject a pharmaceutical composition of each of the agents described herein. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising an effective amount of each of the agents described herein.

[0130] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable form thereof, is administered to a subject according to the methods provided herein at a dose of 1 to 2400 mg per day. In some embodiments, the dose of the compound of Formula (I), or a pharmaceutically acceptable form thereof, is 0.5 to 2.5 mg, 0.5 to 5 mg, 0.5 to 10 mg, 0.5 to 25 mg, 0.5 to 50 mg, 0.5 to 75 mg, 0.5 to 100 mg, 0.5 to 300 mg, 0.5 to 600 mg, 0.5 to 1200 mg, 1 to 5 mg, 1 to 10 mg, 1 to 25 mg, 1 to 50 mg, 1 to 75 mg, 1 to 100 mg, 1 to 300 mg, 1 to 600 mg, 1 to 1200 mg, 1 to 2400 mg, 20 to 100 mg, 40 to 75 mg, 50 to 75 mg, 50 to 100 mg, 50 to 600 mg, 1 to 1200 mg, 1 to 2400 mg, 20 to 100 mg, 40 to 75 mg, 50 to 75 mg, 50 to 100 mg, 50 to 1500 mg, 150 to 2 ... The dosage is selected from 150 mg, 75 to 100 mg, 100 to 200 mg, 125 to 200 mg, 150 to 300 mg, 200 to 250 mg, 200 to 400 mg, 300 to 600 mg, 250 to 500 mg, 400 to 600 mg, 500 to 750 mg, 600 mg to 900 mg, 700 to 100 mg, 650 to 1000 mg, 800 to 1200 mg, 900 to 1500 mg, 1000 to 1600 mg, 1000 to 2000 mg, 1200 to 1600 mg, 1500 to 2000 mg, 1500 to 2400 mg, 1800 mg to 2400 mg, and 2000 to 2400 mg.In some embodiments, the dose of the compound of Formula (I), or a pharmaceutically acceptable form thereof, is about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, and 2.0 mg, about 2.5 mg, about 3.0 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 ... mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85 mg, about 90mg, about 95mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, about 250mg, about 275mg, about 300mg, about 325mg, about 350mg , about 375mg, about 400mg, about 425mg, about 450mg, about 475mg, about 500mg, about 525mg, about 550mg, about 575mg, about 600mg, about 650mg, about 700mg, about 750m g, about 800mg, about 850mg, about 900mg, about 950mg, about 1000mg, about 1050mg, about 1100mg, about 1150mg, about 1200mg, about 1250mg, about 1300mg, about 135 In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered 1, 2, 3, or 4 times per day. In some embodiments, the daily dosage of the compound of formula (I), or a pharmaceutically acceptable form thereof, is divided into 2, 3, or 4 doses, for example, 2, 3, or 4 equal doses, particularly 2 doses or 2 equal doses, and is administered to the subject according to the methods provided herein. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable form thereof, is administered once or twice a day, or once a day, or twice a day.

[0131] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered to a subject according to the methods provided herein at a dose of 0.01 to 50 mg per kg of body weight per day. In some embodiments, the dose of a compound of Formula (I), or a pharmaceutically acceptable form thereof, is selected from 0.01 to 1 mg / kg, 0.01 to 2.5 mg / kg, 0.01 to 5 mg / kg, 0.1 to 5 mg / kg, 0.1 to 10 mg / kg, 0.1 to 20 mg / kg, 1 to 30 mg / kg, 1 to 40 mg / kg, 5 to 50 mg / kg, 10 to 50 mg / kg, 15 to 50 mg / kg, 20 to 50 mg / kg, 25 to 50 mg / kg, 30 to 50 mg / kg, 40 to 50 mg / kg, 20 to 40 mg / kg, and 25 to 25 mg / kg per kg of body weight per day. In some embodiments, the dose of the compound of Formula (I), or a pharmaceutically acceptable form thereof, is selected from the group consisting of about 0.01 mg / kg, about 0.02 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, and about 50 mg / kg of body weight per day. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable form thereof, is administered 1, 2, 3, or 4 times a day, for example, once or twice a day, or once or twice a day. In some embodiments, the daily dose of the compound of formula (I), or a pharmaceutically acceptable form thereof, is divided into 2, 3, or 4 doses, for example, as 2, 3, or 4 equal doses, particularly 2 doses or 2 equal doses, and administered to the subject according to the methods provided herein.

[0132] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered to a subject monthly, weekly, or daily according to the methods provided herein. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered to a subject 1, 2, 3, or 4 times daily for one or more treatment cycles. In some embodiments, the daily dose of the compound of Formula (I), or a pharmaceutically acceptable form thereof, is divided into two doses, e.g., two equal doses, and administered to the subject on specific days or daily for one or more treatment cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered once or twice daily for one or more treatment cycles, e.g., twice daily for one or more treatment cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered to a subject 1, 2, 3, or 4 times daily consecutively, or until remission is achieved in the subject. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered to a subject once daily (sometimes referred to as QD) for one or more treatment cycles, e.g., for two or more treatment cycles, three or more treatment cycles, or four or more treatment cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered to a subject twice daily (sometimes referred to as BID) for one or more treatment cycles, e.g., for two or more treatment cycles, three or more treatment cycles, or four or more treatment cycles. In some embodiments, the treatment cycle is 1 day, 7 days, or 28 days. In some embodiments, the treatment cycle is 1 day. In some embodiments, the treatment cycle is 7 days. In some embodiments, the treatment cycle is 28 days. In some embodiments, the treatment cycle is a 28-day treatment cycle. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered to a subject twice daily for one or more 28-day treatment cycles.In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered to the subject twice daily for one or more 28-day treatment cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered to the subject once or twice daily every other week during the 28-day treatment cycle.

[0133] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable form thereof, is administered to a subject according to the methods provided herein one, two, three, or four times daily on days 1-7, days 8-14, days 15-21, days 22-28, days 1-7 and days 15-21, days 8-14 and days 21-28, days 1-14, days 1-21, or each day (i.e., days 1-28) of a 28-day treatment cycle, for one of multiple treatment cycles. For example, in some embodiments, the compound of formula (I), or a pharmaceutically acceptable form thereof, is administered QD to a subject on days 1-7, days 8-14, days 15-21, days 22-28, days 1-7 and days 15-21, days 8-14 and days 21-28, days 1-14, days 1-21, or each day (i.e., days 1-28) of a 28-day treatment cycle for one of multiple treatment cycles. For example, in some embodiments, the compound of formula (I), or a pharmaceutically acceptable form thereof, is administered BID to a subject on days 1-7, days 8-14, days 15-21, days 22-28, days 1-7 and days 15-21, days 8-14 and days 21-28, days 1-14, days 1-21, or each day (i.e., days 1-28) of a 28-day treatment cycle for one or more treatment cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered QD to a subject on days 1-7 of a 28-day treatment cycle for one or more treatment cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered BID to a subject on days 1-7 of a 28-day treatment cycle for one or more treatment cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered QD to a subject on days 1-7 and days 15-21 of a 28-day treatment cycle for one or more treatment cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered BID to a subject on days 1-7 and days 15-21 of a 28-day treatment cycle for one or more treatment cycles.In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered QD to a subject on days 1-21 of a 28-day treatment cycle for one or more treatment cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered BID to a subject on days 1-21 of a 28-day treatment cycle for one or more treatment cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered QD to a subject on each day (i.e., days 1-28) of a 28-day treatment cycle for one or more treatment cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered BID to a subject on each day (i.e., days 1-28) of a 28-day treatment cycle for one or more treatment cycles.

[0134] In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib is administered to a subject in accordance with the methods of treatment provided herein at a dose of 0.2 to 1500 mg per day. In some embodiments, the dose of the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib administered to a subject is selected from 0.5 to 10 mg, 2 to 15 mg, 10 to 30 mg, 10 to 40 mg, 10 to 240 mg, 20 to 50 mg, 20 to 240 mg, 30 to 50 mg, 35 to 70 mg, 40 to 80 mg, 60 to 100 mg, 80 to 120 mg, 80 to 160 mg, 80 to 240 mg, 160 to 250 mg, 160 to 300 mg, 100 to 600 mg, or 200 to 1000 mg per day.In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib is administered at a dose of about 0.89 mg, 1 mg, 1.34 mg, 4 mg, 5 mg, 8 mg, 10 mg, 12 mg, 12.5 mg, 14 mg, 15 mg, 18 mg, 20 mg, 24 mg, 25 mg, 30 mg, 35 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg per day. g, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 800 mg. In some embodiments, the dose of the VEGFR inhibitor cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib administered to the subject is selected from (Table 4): [Table 4]

[0135] In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, is administered 1, 2, 3, or 4 times daily. In some embodiments, the daily dose of the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, is divided into two doses, for example, two equal doses, administered to the subject according to the methods provided herein. In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib is administered to the subject once or twice daily, for example, once daily.

[0136] In some embodiments, the dose of VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib is administered to a subject daily for one or more treatment cycles according to the methods provided herein.For example, in some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib is administered 1, 2, 3, or 4 times a day for one or more treatment cycles. In some embodiments, the daily dose of the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, is divided into two doses, such as two equal doses, administered to the subject according to the methods provided herein. In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, is administered to the subject once or twice daily for one or more treatment cycles, for example, once daily for one or more treatment cycles. In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, is administered to the subject 1, 2, 3, or 4 times daily, continuously or until remission is achieved. In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, is administered to the subject once daily (sometimes referred to as QD) for one or more treatment cycles, for example, for two or more treatment cycles, three or more treatment cycles, or four or more treatment cycles.For example, in some embodiments, the VEGFR inhibitor cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib is administered to a subject twice daily (sometimes referred to as BID) for one or more treatment cycles, for example, two or more treatment cycles, three or more treatment cycles, or four or more treatment cycles. In some embodiments, the treatment cycle is 1 day, 7 days, or 28 days. In some embodiments, the treatment cycle is 1 day. In some embodiments, the treatment cycle is 7 days. In some embodiments, the treatment cycle is 28 days. In some embodiments, a dose of the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, is administered to a subject once daily for one or more 28-day treatment cycles. In some embodiments, a dose of the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, is administered to a subject twice daily for one or more 28-day treatment cycles. In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, is administered to a subject once or twice daily every other week during a 28-day treatment cycle. In some embodiments, the VEGFR inhibitor, such as fruquintinib, is administered during the first 21 days of each 28-day cycle.

[0137] In some embodiments, the methods provided herein include (1) an ascending administration cycle followed by (2) one or more treatment cycles. In some embodiments, the methods provided herein include (1) an ascending administration cycle comprising administering (a) ascending doses of a compound of Formula (I), or a pharmaceutically acceptable form thereof, and (b) an effective amount of a VEGFR inhibitor, followed by (2) one or more treatment cycles comprising administering (a) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof, and (b) an effective amount of a VEGFR inhibitor. In some embodiments, the ascending administration cycle lasts for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, or 28 days. For example, the ascending administration cycle can include a stepwise increase in the amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof, administered to a subject while maintaining the amount of a VEGFR inhibitor administered to the subject. For example, an ascending administration cycle may include administering a first dose of the compound of Formula (I), or a pharmaceutically acceptable form thereof, to the subject at the beginning of the ascending administration cycle, and administering a second ascending dose (or a final ascending dose) of the compound of Formula (I), or a pharmaceutically acceptable form thereof, to the subject at the end of the ascending administration cycle, optionally while maintaining the amount of the VEGFR inhibitor administered to the subject. For example, an ascending administration cycle may include gradually increasing the amount of the VEGFR inhibitor administered to the subject while maintaining the amount of the compound of Formula (I), or a pharmaceutically acceptable form thereof, administered to the subject. In certain embodiments, the final ascending dose is an effective amount of the compound of Formula (I), or a pharmaceutically acceptable form thereof, or the VEGFR inhibitor administered to the subject during one or more treatment cycles. In some embodiments, the inclusion of an ascending administration cycle provides a synergistic benefit or therapeutic effect to the subject, including, but not limited to, identifying an effective dose for the subject, improving efficacy, reducing or avoiding toxicity, adverse events or adverse symptoms (e.g., reducing the severity, incidence, or risk of such effects), or a combination thereof, associated with the compound of Formula (I), or a pharmaceutically acceptable form thereof, or associated with a VEGFR inhibitor.

[0138] In some embodiments, the methods provided herein include (1) a loading dose cycle followed by (2) one or more treatment cycles. In some embodiments, the methods provided herein include (1) a loading dose cycle comprising administering (a) a loading dose of a compound of Formula (I), or a pharmaceutically acceptable form thereof, and (b) an effective amount of a VEGFR inhibitor, followed by (2) one or more treatment cycles comprising administering (a) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof, and (b) an effective amount of a VEGFR inhibitor. In some embodiments, the loading dose (sometimes referred to as an ascending dose or bolus dose) of the compound of Formula (I), or a pharmaceutically acceptable form thereof, is 1.1 to 10 times the dose administered during the one or more treatment cycles. For example, in some embodiments, the loading dose is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times the dose administered during one or more treatment cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered 1, 2, 3, or 4 times daily during the loading administration cycle. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered once daily during the loading administration cycle. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered twice daily during the loading administration cycle. In some embodiments, the loading administration cycle is 1, 2, 3, 4, 5, 6, 7, 14, 21, or 28 days long. In some embodiments, including a loading cycle prior to one or more treatment cycles provides a subject with a synergistic benefit or therapeutic effect, including, but not limited to, reducing or avoiding toxicity, adverse events or adverse symptoms (e.g., reducing the severity, incidence, or risk of such effects) associated with the compound of Formula (I), or a pharmaceutically acceptable form thereof, or associated with a VEGFR inhibitor, or a combination thereof.

[0139] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, and the VEGFR inhibitor are administered to a subject on an interval dosing schedule, or on a continuous dosing schedule, such as 1, 2, 3, or 4 times daily. In some embodiments, the interval dosing schedule involves administering the agent on some days of a treatment cycle and not administering the agent on other days, for example, administering the agent only every other week, or only every other week (e.g., 1 week on, 1 week off, or vice versa), or only for 2 consecutive weeks (e.g., 2 weeks on, 2 weeks off, or vice versa), or only for 3 consecutive weeks (e.g., 3 weeks on, 1 week off, or vice versa) during a 28-day treatment cycle. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered on an interval dosing schedule. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered on an interval dosing schedule, and the VEGFR inhibitor is administered on a continuous dosing schedule. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered QD or BID to a subject on days 1-7, days 1-7 and 15-21, days 1-21, or every day of a 28 day treatment cycle, and a VEGFR inhibitor is administered QD or BID every day of the 28 day treatment cycle. For example, in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered QD to a subject on days 1-7, days 1-7 and 15-21, days 1-21, or every day of a 28 day treatment cycle, and a VEGFR inhibitor is administered QD every day of the 28 day treatment cycle. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered BID to a subject on days 1-7, days 1-7 and 15-21, days 1-21, or every day of a 28 day treatment cycle, and a VEGFR inhibitor is administered QD every day of the 28 day treatment cycle. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable form thereof, is administered to a subject QD on days 1-7, days 1-7 and days 15-21, days 1-21, or every day of a 28 day treatment cycle, and the VEGFR inhibitor is administered BID every day of a 28 day treatment cycle.In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered to a subject BID on days 1-7, days 1-7 and days 15-21, days 1-21, or every day of a 28-day treatment cycle, and a VEGFR inhibitor is administered BID every day of the 28-day treatment cycle. In some embodiments, in each regimen, the VEGFR inhibitor is administered for the first 21 days of each 28-day cycle rather than every day. In some embodiments, the two agents are administered at approximately the same time of day, in which case the two agents can be administered simultaneously or sequentially. For example, if a compound of Formula (I), or a pharmaceutically acceptable form thereof, is administered QD in the morning or BID in the morning and evening, and a VEGFR inhibitor is administered QD in the morning, the two morning administrations can be administered simultaneously or sequentially.

[0140] In some embodiments, the methods provided herein include (1) an initial administration cycle, followed by (2) one or more treatment cycles. In some embodiments, the methods provided herein include (1) an initial administration cycle comprising administering (a) an effective amount of a VEGFR inhibitor, followed by (2) one or more treatment cycles comprising administering (a) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof, and (b) an effective amount of a VEGFR inhibitor. In some embodiments, the methods provided herein include (1) a delayed administration schedule, followed by (2) one or more treatment cycles. In some embodiments, the methods provided herein include (1) a delayed administration schedule comprising one or more initial administration cycles, the one or more initial administration cycles comprising administering (a) an effective amount of a VEGFR inhibitor, followed by one or more treatment cycles comprising administering (2) (a) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable form thereof, and (b) an effective amount of a VEGFR inhibitor. In some embodiments, the initial administration cycle is 1 day to about 56 days, or 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the initial administration cycle is 28 days. In some embodiments, the initial administration cycle is 6 weeks or less. In some embodiments, the subject is a VEGFR inhibitor naive subject. In some embodiments, the subject is a subject with a relapsed or refractory advanced solid tumor who was previously treated with a VEGFR inhibitor but is not currently being treated.

[0141] In some embodiments, the methods provided herein provide a therapeutic effect, such as a synergistic benefit, to a subject (a) in combination with a VEGFR inhibitor, compared to treatment of an advanced solid tumor with a TKI or VEGFR inhibitor monotherapy, e.g., compared to treatment of an advanced solid tumor with a TKI or VEGFR inhibitor monotherapy that ultimately leads to recurrence and / or resistance in the subject, e.g., compared to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib; (b) compared to standard treatments for advanced solid tumors, including, but not limited to, surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or a combination thereof; or (c) compared to untreated advanced solid tumors. For example, in some embodiments, the methods provided herein improve efficacy (e.g., inhibit tumor growth and induce tumor regression). In some embodiments, the methods provided herein provide unexpected synergistic effects compared to either agent alone, e.g., the methods increase PFS and / or OS. In some embodiments, the increased PFS is 10-99%, e.g., 10%, 25%, 50%, 80%, 90%, 95%, or 99%, 2-fold, 3-fold, or 4-fold. In some embodiments, the increased OS is 10-99%, e.g., 10%, 25%, 50%, 80%, 90%, 95%, or 99%, 2-fold, 3-fold, or 4-fold. In some embodiments, the effective amount of the VEGFR inhibitor for the combination is less than the effective amount for VEGFR inhibitor monotherapy. In some embodiments, the methods provided herein reduce VEGFR inhibitor-associated toxicity (e.g., the severity, incidence, or risk of such toxicity). In some embodiments, reduced toxicity comprises or consists of a reduction in the severity, incidence, or risk of severe bleeding, impaired wound healing, gastrointestinal perforation, hypertension, fatigue, arterial and venous thromboembolic events, bleeding, cardiovascular events, heart failure, hepatotoxicity, and QT prolongation, or a combination thereof.In some embodiments, the methods provided herein delay the onset of drug resistance, such as TKI resistance or VEGFR inhibitor resistance, and optionally the delay is an unexpected delay. In some embodiments, the delay in the onset of resistance comprises weeks, months, or years. In some embodiments, the efficacy outcomes described above are determined according to applicable RECIST criteria (e.g., RECIST v.1.1). In some embodiments, the efficacy outcomes are as follows: (a) in combination with a VEGFR inhibitor, compared to treatment of advanced solid tumors with TKI or VEGFR inhibitor monotherapy, e.g., compared to treatment of advanced solid tumors with TKI monotherapy or VEGFR inhibitor therapy that ultimately leads to relapse and / or resistance in a subject with an advanced solid tumor, e.g., compared to treatment of advanced solid tumors with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib; (b) compared to standard of care advanced solid tumor treatment, including, but not limited to, surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or a combination thereof; or (c) compared to untreated advanced solid tumors. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable form thereof, and the VEGFR inhibitor act unexpectedly synergistically according to the methods provided herein. [Example]

[0142] 7. Working Example Abbreviations: ACN: acetonitrile; AIBN: azobisisobutyronitrile; BTEAC: benzyltriethylammonium chloride; Cu(OAc)2: copper acetate; DCE: 1,2-dichloroethane; DCM: dichloromethane; DEA: diethylamine; DEAD: diethyl azodicarboxylate; DIAD: diisopropyl azodicarboxylate; DIBAL-H: diisobutylaluminum hydride; DIPEA: N,N-diisopropylethylamine; DIPEA: N,N-diisopropylethylamine; DMA: dimethylacetamide; DMF: dimethylformamide; DMI: 1,3-dimethyl-2-imidazolidinone; DMSO: dimethyl sulfoxide; DPPF: 1,1'-bis(diphenylphosphino)ferrocene; Et3SiCl: chlorotriethylsilane; EtOAc: ethyl acetate; EtOH: ethanol; HATU: 1-[bis(dimethylamino )methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; MeOH: methanol; NaOMe: sodium methoxide; NBS: N-bromosuccinimide; n-BuLi: n-butyllithium; PCC: pyridinium chlorochromate; Pd(Ph3)4: tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0); PPh3: triphenylphosphine; SFC: supercritical fluid chromatography; T3P: propanephosphonic anhydride; TBAF: tetra-n-butylammonium fluoride; t-BuOK: potassium tert-butoxide; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TIPSCl: triisopropylsilyl chloride; TMEDA: tetramethylethylenediamine

[0143] LCMS conditions

[0144] Each LCMS condition was performed using ESI ionization mass spectrometry on a SHIMADZU LC20-MS2020 instrument at an oven temperature of 50°C, with monitoring at wavelengths of 220 nm and 254 nm. The molecular formulas listed with the ESI calculations are understood to be the molecular formulas of the detected ions (e.g., [M+H]+ For example, the molecular formula of compound 1A-1 is C 17 H 12 BrNO (i.e., [M]), while the molecular formula listed with the ESI calculation is the molecular formula of the detected ion, C 17 H 13 BrNO (i.e., [M+H] + )

[0145] Acidic LCMS methods are referred to with the notation "AB." Each acidic LCMS method used an Xtimate C18 2.1x30 mm (3 μm particle size) column (except where noted), mobile phase A (water (4 L) and TFA (1.5 mL)), and mobile phase B (ACN (4 L) and TFA (0.75 mL)) (except where noted). Conditions for each of the acidic LCMS methods used included the following: 1.5-minute method 5-95AB refers to a Merck, RP-18e, 25x2 mm column with a gradient starting at 5% B and ending at 95% B over a total of 1.5 minutes, run at a flow rate of 1.5 mL / min.

[0146] The basic LCMS methods are referred to by the notation "CD." Each basic LCMS method used a Titank C18 2.1 x 50 mm (5 μm particle size) column, mobile phase A (water (4 L) and ammonium hydroxide (0.8 mL)), and mobile phase B (ACN). Conditions for each basic LCMS method used included the following: 3.0 min method 10-80 CD refers to a gradient starting at 10% B and ending at 80% B over a total of 3 min, with a flow rate of 1.0 mL / min.

[0147] SFC chiral HPLC conditions:

[0148] Each SFC chiral HPLC method was performed on either (1) a Waters UPCC equipped with a PDA and QDa detector, or (2) an Agilent 1260 equipped with a DAD detector.

[0149] "AD_ETOH_DEA_5_40_4ML_4MIN_5CM" refers to the use of a Chiralpak AD-3 chiral column (5 cm column length) with ethanol with CO2 (mobile phase A) and 0.05% diethylamine (v / v) (mobile phase B), and a gradient from 5% B to 40% B for a total of 4 min at a flow rate of 4 mL / min.

[0150] The following examples are offered by way of illustration and not by way of limitation.

[0151] Example 1: Preparation of Compounds of Formulas (I), (II), and (III)

[0152] Reference to a compound disclosed herein having one or more stereocenters without specifying a particular chirality (e.g., R- or S-enantiomer) will be understood to refer to the compound as a racemic mixture (or mixture of diastereomers), while inclusion of the R- or S- designation is understood to refer to the enantiomeric (or diastereomeric) form of the compound, e.g., an enantiomerically (or diastereomerically) enriched form of the compound, or the enantiomeric excess of the specified enantiomeric form of the compound, in accordance with the above discussion regarding enantiomeric enrichment and enantiomeric excess. Reference to a compound with an R- or S- designation will be understood to include the specified enantiomer of the compound in an enantiomerically enriched or enantiomeric excess, not limited to only 100% of a single specified enantiomer of the compound. For example, reference to a compound of formula (III) is to the compound prepared in Example 1 and its racemic form: (rac)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4Similarly, reference to a compound of formula (I) is understood to refer to the compound prepared in Example 1 and its single stereoisomer (S) form: (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -dicarbonitrile.

[0153] [ka] Scheme 1, Step 1: Preparation of (1-1). A mixture of 4-bromo-3-methylbenzoic acid (200 g, 930.04 mmol), NBS (248.29 g, 1.40 mol), and AIBN (30.54 g, 186.01 mmol) in CCl (1600 mL) was degassed and purged with N three times, after which the mixture was stirred under N at 85 °C for 12 h. The reaction mixture was filtered. The crude product was triturated with CHCN (500 mL) to give a mixture of 1-1 and the corresponding dibromomethyl compound (215 g, 731.44 mmol, 78.65% yield) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ = 13.36 (br s, 1H), 8.17 (s, 1H) 7.78-7.82 (m, 2H), 4.82 (s, 2H).

[0154] Scheme 1, Step 2: Preparation of (1-2). To a solution of 1-1 and the dibromomethyl compound (160 g, 544.33 mmol) in HO (1500 mL) was added NaCO (230.77 g, 2.18 mol). The mixture was stirred at 75 °C for 12 hours. The reaction mixture was adjusted with HCl (4 M in HO) to give a white solid. The solvent was removed from the white solid. To the above product in MeOH (1000 mL) under N was added NaBH (24.00 g, 634.42 mmol), and the mixture was then stirred under N at 15 °C for 1 hour. The reaction mixture was quenched with HO (400 mL) and acidified to pH = 2 with HCl (1 M in HO). The mixture was placed under reduced pressure to remove the solvent and then filtered. The white filter cake was placed under vacuum to remove excess solvent to give 1-2 (120 g, 519.38 mmol, 95.42% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ=8.08-8.15(m,1H), 7.66-7.76(m,2H), 4.53(s,2H).

[0155] Scheme 1, Step 3: Preparation of (1-3). To a solution of 1-2 (100 g, 432.90 mmol), N,O-dimethylhydroxylamine (57.97 g, 594.31 mmol, HCl), and DIPEA (223.76 g, 1.73 mol, 301.56 mL) in DCM (1000 mL) was added T3P (275.43 g, 865.64 mmol, 257.41 mL). The mixture was stirred at 15 °C for 5 min. Water (200 mL) was added to the reaction mixture, which was then extracted with DCM (500 mL × 2). The organic layer was separated, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in petroleum ether = 0% to 35%) to give 1-3 (83 g, 302.80 mmol, 69.95% yield) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ=7.92(s,1H), 7.72-7.76(m,1H),7.64(d,J=8.4Hz,1H) , 7.41(dd,J=8.4,2.0Hz,1H), 4.53(d,J=5.6Hz,2H),3.54(s,3H),3.26(s,3H).

[0156] Scheme 1, Step 4: Preparation of 4-bromo-N-methoxy-N-methyl-3-(((triisopropylsilyl)oxy)methyl)benzamide (1-4). A solution of 1-3 (83 g, 302.80 mmol), TIPSCl (58.5 g, 303.42 mmol, 64.93 mL), and imidazole (51.54 g, 756.99 mmol) in DCM (800 mL) was stirred at 15 °C for 16 h. The reaction mixture was diluted with HO (500 mL) and extracted with DCM (600 mL × 2). The combined organic layers were washed with brine (400 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude oil was purified by flash chromatography on silica gel (0-10% EtOAc in petroleum ether) to give 1-4 (104 g, 241.60 mmol, 79.79% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ=7.81(d,J=2.0Hz,1H), 7.67(d,J=8.4Hz,1H), 7.46(dd,J=8.4,2.4H z,1H), 4.80(s,2H), 3.51(s,3H), 3.23-3.29(m,3H), 1.12-1.23(m,3H), 1.03-1.08(m,18H).

[0157] [ka] Scheme 2, Step 1: Preparation of 2-1. To a mixture of (2-amino-5-bromophenyl)(3-methoxyphenyl)methanone (500 g, 1.63 mol) in toluene (3000 mL) was added AcO (333.46 g, 3.27 mol, 305.93 mL), and the mixture was stirred at 110 °C for 14 h. The reaction mixture was concentrated under reduced pressure to give 2-1 (528 g, 1.52 mol, 92.85% yield) as a brown solid. LC-MS: Method: 5-95AB, R t =0.88 min, C 16 H 15 BrNO3[M+H] + Calculated M / Z value is 350.0, actual value is 349.9.

[0158] Scheme 2, Step 2: Preparation of 2-2. To a solution of 2-1 (528 g, 1.52 mol) in DME (2000 mL) under ice water, t-BuOK (340.31 g, 3.03 mol) was added in small portions while maintaining the temperature at 20 °C under N2. The resulting mixture was stirred at 20 °C for 12 h, after which the reaction was quenched with water (200 mL). The mixture was concentrated under reduced pressure to remove DME. The residue was triturated with water (2000 mL, 2 times) and then stirred with EtOAc (1000 mL) at 25 °C for 1 h to give 2-2 (487 g, 1.47 mol, 97.27% yield) as a yellow solid. 1 NMR (400MHz, DMSO-d6) δ = 7.73-7.64 (m, 1H), 7.50-7.34 (m, 3H), 7.15-6.93 (m, 3H), 6.46 (s, 1H), 3.81 (s, 3H).

[0159] Scheme 2, Step 3: Preparation of 2-3. To a solution of 2-2 (50 g, 143.42 mmol) in DCM (500 mL) was added BBr (53.90 g, 215.13 mmol, 20.73 mL) at −40° C. under N. The mixture was stirred at 25° C. for 4 h. The reaction mixture was poured into water (500 mL). The pH was adjusted to 7 with saturated NaHCO solution. The aqueous layer was extracted with DCM (300 mL × 2). The combined organic phases were washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was triturated with petroleum ether (300 mL) at 25° C. for 30 min and CHCN (200 mL) at 25° C. for 30 min to give 2-3 (42 g, 125.53 mmol, 87.52% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 9.92 (br s, 1H), 8.03-7.91 (m, 3H), 7.56 (s, 1H), 7.43-7.37 (m, 1H), 6.99-6.91 (m, 3H).

[0160] Scheme 2, Step 4: Preparation of 2-4. To a solution of 2-3 (170 g, 508.08 mmol) in MeOH (800 mL) and THF (800 mL), CHONa (54.89 g, 1.02 mol) was added, and the mixture was stirred at 80 °C for 12 h. The solvent was removed under reduced pressure. The mixture was poured into water (1000 mL), stirred for 30 min, and then filtered. The filtrate was concentrated under reduced pressure. The crude product was triturated with CHCN (500 mL) at 25 °C for 30 min to give 2-4 (130 g, 393.73 mmol, 67.98% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ=7.79(s,3H), 7.43-7.29(m,1H), 6.99-6.84(m,4H), 4.01(s,3H), 3.64(s,1H).

[0161] Scheme 2, Step 4: Preparation of 6-bromo-2-methoxy-4-(3-((triisopropylsilyl)oxy)phenyl)-quinoline (2-5). To a solution of 2-4 (130 g, 393.73 mmol) in DCM (1500 mL) was added imidazole (58.97 g, 866.21 mmol) at 0 °C under N. The mixture was stirred until a clear solution appeared, and TIPSCl (75.91 g, 393.73 mmol, 84.25 mL) was added dropwise. The mixture was stirred at 0 °C for 1 h. After that, the ice bath was removed and the mixture was stirred at 25 °C for 12 h. The residue was poured into water (1000 mL) and then extracted with DCM (1000 mL x 3). The combined organic phase was washed with brine (1000 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude oil was purified by flash chromatography on silica gel (0-5% EtOAc in petroleum ether) and then triturated with MeOH (300 mL) at 25 °C for 30 min to give 2-5 (160 g, 328.87 mmol, 83.52% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ=7.88(d,J=2.0Hz,1H), 7.79-7.73(m,1H), 7.67(dd,J=2.4Hz,J=9.2Hz,1H), 7.35(t,J=8.0 Hz,1H), 7.03-6.97(m,2H), 6.96-6.93(m,1H), 6.83(s,1H), 4.07(s,3H), 1.32-1.23(m,3H), 1.13-1.09(m,18H).

[0162] [ka] Scheme 3, Step 1: Preparation of (3-1). To a solution of 6-bromo-2-methoxy-4-(3-((triisopropylsilyl)oxy)phenyl)quinoline (10 g, 20.55 mmol) in THF (100 mL) was added n-BuLi (2.5 M in n-hexane, 22.61 mmol, 9.04 mL), and the mixture was stirred at −70° C. under N for 0.5 h. A solution of 1-4 (9.00 g, 20.91 mmol) in THF (10 mL) was added to the above solution, and the mixture was stirred at −70° C. for 0.5 h. Water (150 mL) was added to the mixture, and the mixture was extracted with EtOAc (150 mL). The organic phase was washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated. The mixture was combined with another batch prepared from 18 g of 6-bromo-2-methoxy-4-(3-((triisopropylsilyl)oxy)phenyl)quinoline. The crude oil was purified by flash chromatography on silica gel (0–5% EtOAc in petroleum ether) to give 3-1 (40 g, 51.48 mmol, 83.50% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ=8.28(s,1H), 8.09-7.95(m,3H), 7.62-7.54(m,2H), 7.35-7.29(m,1H), 7.09-7.04(m,1H), 7.00-6.95( m,2H), 6.92(s,1H), 4.85(s,2H), 4.16(s,3H), 1.28-1.21(m,3H), 1.16-1.13(m,3H), 1.11-1.07(m,18H), 1.04-1.01(m,18H).

[0163] Scheme 3, Step 2: Preparation of (3-2). To a solution of 1-methyl-1H-imidazole (1.16 g, 14.16 mmol, 1.13 mL) in THF (50 mL) was added n-BuLi (2.5 M in n-hexane, 14.16 mmol, 5.66 mL), and the mixture was stirred at −70° C. under N for 20 minutes. Next, EtSiCl (2.13 g, 14.16 mmol, 2.41 mL) in THF (10 mL) was added to the mixture, and the mixture was stirred at −70° C. for 20 minutes. Next, n-BuLi (2.5 M in n-hexane, 14.16 mmol, 5.66 mL) was added to the mixture, and the mixture was stirred at −70° C. for 20 minutes. Next, 3-1 (10 g, 12.87 mmol) in THF (40 mL) was added to the above mixture, and the mixture was stirred at −70° C. for 20 min. Water (500 mL) was added to the mixture, and the mixture was extracted with EtOAc (500 mL). The organic phase was washed with brine (250 mL), dried over anhydrous NaSO, filtered, and concentrated. The mixture was combined with another batch prepared from 30 g of 3-1. The crude oil was purified by flash chromatography on silica gel (MeOH in DCM = 0–10%) to give 3-2 (34 g, 39.58 mmol, 76.88% yield) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ=7.70-7.63(m,2H), 7.36-7.32(m,1H), 7.30-7.25(m,2H), 7.11-7.04(m,3H), 6.81-6.76(m,2H), 6.75-6.71(m,1H), 6.69(s ,1H), 6.14(s,1H), 4.63-4.54(m,2H), 3.96(s,3H), 3.18(s,3H)), 1.13- 1.06(m,3H), 0.96-0.92(m,18H), 0.89-0.84(m,3H), 0.80-0.77(m,18H).

[0164] Scheme 3, Step 3: Preparation of (3-3). A mixture of 3-2 (26.5 g, 30.85 mmol) and TBAF (1 M in THF, 46.27 mmol, 46.27 mL) in THF (250 mL) was stirred at 25 °C for 20 min. Water (500 mL) was added to the mixture, and the mixture was extracted with EtOAc (500 mL). The organic phase was washed with brine (500 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude oil was purified by trituration with 1:5 EtOAc:petroleum ether (150 mL) to give 3-3 (16 g, 29.28 mmol, 94.93% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=9.69(s,1H), 7.81(d,J=8.8Hz,1H), 7.74-7.68(m,1H), 7.64-7.54(m,2H), 7.53-7.44(m,2H), 7.29-7.21(m,1H), 7 .04-6.96(m,1H), 6.91-6.84(m,3H), 6.83-6.75(m,2H), 6.05(s,1H), 5.42-5.35(m,1H), 4.52-4.41(m,2H), 4.03-3.98(m,3H), 3.35(s,3H). LCMS R t = 0.80 min during 1.5 min of chromatography, 5-95aB, C 28 H 25 BrN3O4[M+H] - The calculated ESI value was 546.1, and the measured value was 545.9.

[0165] Scheme 3, Step 4: Preparation of (3-4). To a solution of 3-3 (5.7 g, 10.43 mmol) in DMF (85 mL), SOCl (2.48 g, 20.86 mmol, 1.51 mL) was added, and the mixture was stirred at 25 °C for 1 h. CsCO (50.96 g, 156.41 mmol) was added, and the mixture was stirred at 70 °C for 0.5 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. The crude product was combined with another batch prepared from 10.15 g of 3-3, triturated from water (150 mL), and filtered. The solid was redissolved in toluene (100 mL x 2) and concentrated to give 3-4 (13 g, 24.60 mmol, 84.84% yield) as a pale yellow solid.1 H NMR(400MHz,DMSO-d6)δ=8.09-8.01(m,1H), 7.92-7.87(m,1H), 7.69-7.53(m,4H), 7.38-7.34(m,1H), 7.2 6(s,1H), 7.19-7.10(m,3H), 7.07-7.00(m,2H), 6.29(s,1H), 5.49-5.37(m,2H), 4.05(s,3H), 3.50(s,3H). LCMS R t = 2.00 min during 3.0 min chromatography, 10-80 cD, C 28 H 23 BrN3O3[M+H] + Calculated ESI value: 530.1, measured value: 530.1.

[0166] Scheme 3, Step 5: Preparation of (3-5). A mixture of 3-4 (12 g, 22.71 mmol), Zn(CN) (27.23 g, 231.89 mmol, 14.72 mL), Pd(dba) (3.12 g, 3.41 mmol), dppf (3.78 g, 6.81 mmol), and Zn (891.01 mg, 13.63 mmol) in DMA (300 mL) was stirred at 120 °C under N for 2 h. The mixture was filtered through Celite. The solid was washed with EtOAc (100 mL x 2). The combined organic phase was concentrated in vacuo. The crude oil was purified by flash chromatography on silica gel (50% to 100% EtOAc in petroleum ether) and then triturated with MeOH (50 mL) to give 3-5 (6.55 g, 13.80 mmol, 60.78% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=8.05-8.01(m,1H), 7.95-7.90(m,1H), 7.85-7.78(m,2H), 7.63-7.44(m,2H), 7.40-7.3 2(m,2H), 7.18(s,1H), 7.12(d,J=7.6Hz,1H), 7.07-(m,3H), 6.94(s,1H), 5.52(s,2H), 4.06(s,3H), 3.62(s,3H). LCMS R t = 1.77 min during 3.0 min of chromatography, 10-80 cD, C 29 H 23 N4O3[M+H]+ Calculated ESI value: 475.2, measured value: 475.2.

[0167] Scheme 3, Step 6: Preparation of (3-6). To a solution of 3-5 (0.12 g, 251.82 μmol) in THF (10 mL) was added HCl (4 M in HO, 2.20 mL). The reaction mixture was stirred at 70 °C for 16 h. The mixture was cooled to 20 °C and added to water (20 mL). Saturated NaHCO solution was added to adjust the pH to 8. The aqueous phase was extracted with DCM (30 mL x 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 3-6 (0.115 g, 249.74 μmol, 99.17% yield) as a colorless oil. 50 mg (108.58 μmol) of 3-6 was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 x 40 mm x 3 μm; mobile phase: [water (10 mM NHHCO)-ACN]; B%: 26%-56%, 7.8 min) to give 3-6 (12.4 mg, 26.93 μmol, 24.80% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=11.71(br s,1H), 7.89(dd,J=2.0,8.4Hz,1H), 7.81(d,J=7.8Hz,1H), (s,1H), 7.57(s,1H), 7.45(d,J=8.8Hz,2H), 7.38-7.3 1(m,1H), 7.10-7.02(m,3H), 6.75(s,1H), 6.65(s,1H), 6.52(s,1H), 6.34(s,1H), 5.55-5.46(m,2H), 3.49(s,3H). LCMS R t = 1.34 min during 3 min of chromatography, 10-80 cD, C 28 H 21 N4O3[M+H] + ESI calculated value 461.2, observed value 461.1. HPLC R t = 2.22 min of 8 min chromatography, 220 nm, 100% purity.

[0168] Scheme 3, Step 7: Preparation of (3-7). Compound 3-6 (1.2 g, 2.61 mmol) was mixed with POCl (19.80 g, 129.13 mmol, 12.00 mL) at 25 °C. The mixture was stirred at 100 °C for 1 h. The mixture was concentrated. To the residue, NaOH (1 M in H O, 100 mL) was added. The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na SO , filtered, and the filter cake was washed with EtOAc (20 mL). The combined filtrate was concentrated. The crude product was combined with another batch prepared from 0.5 g of 3-6. The crude product was purified by flash chromatography on silica gel (MeOH in DCM = 0-10%) to give 3-7 (1.3 g, 2.71 mmol, 73.35% yield) as a yellow solid. LCMS R t = 1.79 min during 3.0 min of chromatography, 10-80 CD, C 28 H 20 ClN4O2[M+H] + Calculated ESI value: 479.1, measured value: 479.1.

[0169] Scheme 3, Step 8: Preparation of (3-8). To a solution of 3-7 (1.2 g, 2.51 mmol) in DMF (10 mL) was added Zn(CN) (2.69 g, 22.91 mmol, 1.45 mL) and Pd(PPh) (579.07 mg, 501.12 μmol) in a three-necked bottom flask under N at 25 °C. The mixture was stirred at 100 °C for 2 h. The mixture was cooled to 25 °C and added to water (50 mL). The aqueous phase was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (MeOH in DCM = 0-3%) to give 3-8 (900 mg, 1.92 mmol, 76.51% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ=8.33-8.22(m,2H), 8.10(s,1H), 7.94-7.76(m,2H), 7.69(s ,1H), 7.52-7.39(m,2H), 7.28-7.02(m,5H), 6.36(s,1H), 5.54(s,2H), 3.56(s,3H).

[0170] Scheme 3, Step 9: (rac)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 Preparation of 3-8 (800 mg, 1.70 mmol) in DMI (8 mL) was added SOCl (1.01 g, 8.52 mmol, 618.05 μL). The mixture was stirred at 40 °C for 1 h. The above mixture was added to NH in MeOH (7 M, 100 mL) at −10 °C. The mixture was stirred at 25 °C for 30 min. The reaction mixture was poured into H O (100 mL). The aqueous layer was extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na SO , and the filter cake was washed with EtOAc (20 mL). The combined filtrate was concentrated. The crude product was purified by flash chromatography on silica gel (0–8% MeOH in DCM) to give compound 3 (550 mg, 1.17 mmol, 68.89% yield) as a yellow solid. LCMS R t = 1.71 min during 3.0 min of chromatography, 10-80 cD, C 29 H 21 NO [M+H] + Calculated ESI value: 469.2, measured value: 469.2.

[0171] Scheme 2, Step 10: (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4-dicarbonitrile (compound of formula (I)) and (R)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2 2 ,4 4 -Preparation of dicarbonitriles (compounds of formula (II)).

[0172] The compound of formula (III) (500 mg, 1.07 mmol) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); mobile phase: [0.1% NH3HO EtOH]; B%: 45%-45%) to give the target compound (229.5 mg, 489.85 μmol, yield 45.90%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=8.37(d,J=8.4Hz,1H), 8.23(d,J=9.2Hz,1H), 8.08(s,1H), 7.95(s,1H), 7.83(d,J=8.0Hz, 1H), 7.58(s,1H), 7.48-7.19(m,4H), 7.18-7.04(m,2H), 6.44(s,1H), 5.64-5.45(m,2H), 3.48(s,3H), 3.18(s,2H). LCMS R t = 1.68 min during 3.0 min of chromatography, 10-80 CD, C 29 H 21 NO [M+H] + ESI calculated value 469.2, observed value 469.2. HPLC R t = 3.03 min of 8 min chromatography, 220 nm, 100% purity. Chiral HPLC (S)-1:R t =2.44 minutes out of 4 minutes (ee 99.54%)(AD_ETOH_DEA_5_40_4ML_4MIN_5CM), ((R)-2:R t =1.93 min (ee 99.44%)).

[0173] Example 2: Combination testing of cell line-derived xenografts (CDX) and patient-derived xenografts (PDX) in an in vivo model

[0174] The combination of the compound of formula (I), or a pharmaceutically acceptable form thereof, and an antiangiogenic TKI may produce deeper and more durable responses in VHL-mutated 786-O RCC CDX and RCC PDX models compared to administration of either agent alone. While an antiangiogenic TKI or the compound of formula (I), or a pharmaceutically acceptable form thereof, may slow or sometimes halt tumor growth alone, the drug combination may induce greater halting of tumor growth or even tumor regression in treated animals.

[0175] VHL-mutated 786-O tumor cells were maintained in vitro in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS). VHL-mutated A498 tumor cells were maintained in vitro in Eagle's minimum essential medium supplemented with 10% FBS. Cells were grown at 37°C in an atmosphere of 5% CO2 in air. Cells were harvested during exponential growth phase and quantified using a cell counter prior to tumor inoculation. For the VHL-mutated KI-0326 and KI-12-0073 ccRCC PDX models, fresh tumor tissue was harvested from mice bearing established primary human cancer tissue and cut into small pieces (approximately 2-3 mm in diameter). For each female BALB / c mouse, 5 × 10 cells were inoculated per mouse in 0.1 mL of phosphate-buffered saline (PBS). 6 Tumor cells (CDX model) were inoculated subcutaneously into the right upper flank or surgically (approximately 30 mm 3 The tumors were grown in slices (PDX model) and the average tumor size was approximately 250-300 mm. 3Randomization began when the tumor size reached 100 mg / kg. Animals were randomly assigned to study groups using the "Matched distribution" method / "Stratified" method (StudyDirector™ software, version 3.1.399.19) / randomized block design, with 5 to 6 animals per study group, depending on the study design. Test substance administration began on the same day as randomization. Compound of Formula (I) was administered twice daily at 20 mg / kg, cabozantinib was administered orally once daily at 8, 15, or 20 mg / kg, and axitinib was administered orally once daily at 36 mg / kg. Animals were monitored daily after tumor inoculation for morbidity and mortality. During regular monitoring, animals were monitored for effects on tumor growth, behavior, including mobility, food and water consumption, and physical characteristics, including weight gain / loss, eye / hair matting, and other abnormalities. Mortality and observed clinical signs were recorded for each animal. After randomization, body weight and tumor volume were measured twice weekly. Tumor volume was measured in two dimensions using calipers and expressed in mm using the formula: V = (L x W x W) / 2, where V is tumor volume, L is tumor length (the longest tumor dimension), and W is tumor width (the longest tumor dimension perpendicular to L). 3 The doses were recorded in a lab. Dosing and tumor and body weight measurements were performed in a clean bench. Body weight and tumor volume were measured using StudyDirector™ software, version 3.1.399.19. At the end of the study, tumors were harvested by taking sections for formalin-fixed and paraffin-embedded (FFPE) and flash-freezing the remainder. FFPE was performed using standard procedures.

[0176] As shown in Figure 1, A498 CDX cells treated continuously with the compound of formula (I) (20 mg / kg, BID) and axitinib (36 mg / kg, QD) showed increased tumor regression compared to treatment with either agent alone. Error bars represent the standard error of the mean (n=5).

[0177] As shown in Figure 2, for KI-12-0073 PDX, sequential treatment with the compound of Formula (I) (20 mg / kg, BID) and axitinib (36 mg / kg, QD) increased tumor growth inhibition compared to treatment with either agent alone. Error bars represent standard error of the mean (n=8).

[0178] As shown in Figure 3, 786-O CDX (Figure 3A) treated continuously with the compound of Formula (I) (20 mg / kg, bid) and cabozantinib (20 mg / kg, QD) (lane 3) showed increased tumor growth inhibition (%TGI) compared to the compound of Formula (I) (lane 1) or cabozantinib (lane 2) alone. A498 CDX (Figure 3B) treated continuously with the compound of Formula (I) (20 mg / kg, bid) and cabozantinib (8 or 20 mg / kg, QD) (lanes 4 and 5, respectively) showed increased %TGI compared to the compound of Formula (I) alone (20 mg / kg, bid) (lane 1) or cabozantinib alone (8 and 20 mg / kg, QD) (lanes 2 and 3, respectively). Error bars represent the standard error of the mean (786-O, n = 6, %TGI calculated 16 days after the start of treatment; A498, n = 5, %TGI calculated 14 days after the start of treatment). %TGI was calculated using the following formula: [1 - (mean volume of treated tumors) / (mean volume of control tumors)] × 100%.

[0179] As shown in Figure 4, mice bearing KI-12-0073 VHL mutant PDX, 786-O VHL mutant CDX, and KI-0326 VHL mutant PDX treated sequentially with the compound of Formula (I) (20 mg / kg, bid) and cabozantinib (8, 15, and 20 mg / kg, qd, respectively) showed reduced tumor growth compared to either compound alone (Figures 4A, 4C, and 4E). Error bars represent standard error of the mean. Figures 4B, 4D, and 4F show graphs of the percent change in tumor volume at endpoint compared to day 0 in the KI-12-0073, 786-O, and KI-0326 models, respectively, to demonstrate the variability in response to cabozantinib compared to the combination of the compound of Formula (I) and cabozantinib, which resulted in regression of all but one tumor.

[0180] As shown in Figure 5, mice bearing 786-O VHL mutant CDX were continuously treated with the compound of Formula (I) (20 mg / kg, BID) and various doses of cabozantinib (4, 8, 10, and 12 mg / kg, QD), and showed dose-dependent tumor growth inhibition compared to each single agent, such as cabozantinib or the compound of Formula (I). The percent change in tumor volume was calculated using the endpoint tumor volume value (day 28) compared to day 0.

[0181] Mice bearing 786-O CDX were continuously treated with cabozantinib (15 mg / kg, QD), the compound of Formula (I) (20 mg / kg, BID), lenvatinib (10 mg / kg, QD), lenvatinib and everolimus (2 mg / kg, QD), the compound of Formula (I) and cabozantinib, and the compound of Formula (I) and lenvatinib. As shown in Figure 6, the combination of the compound of Formula (I) (20 mg / kg, BID) with either cabozantinib or lenvatinib reduced tumor growth more than either agent alone and compared favorably with treatment with lenvatinib (10 mg / kg, QD) and everolimus (a kinase / mTOR inhibitor; 2 mg / kg, QD), a combination approved by the FDA for second-line treatment of RCC. Error bars represent the standard error of the mean.

[0182] Mice bearing 786-O CDX tumors were treated continuously with axitinib (36 mg / kg, QD) for 14 days. Starting on day 15, animals were administered one of the following: a) vehicle; b) compound of Formula (I) (20 mg / kg, bid); (c) cabozantinib (15 mg / kg, QD); (d) axitinib (36 mg / kg, QD); or (e) a combination of compound of Formula (I) and cabozantinib. As shown in Figure 7, 786-O CDX tumors treated with axitinib for 14 days and then continuously administered compound of Formula (I) and cabozantinib showed reduced tumor growth over the subsequent 18 days compared to either of the other groups. Similar results may be obtained with a total of 3–4 weeks of treatment after axitinib pretreatment. Error bars represent the standard error of the mean.

[0183] Example 3: Mechanistic studies

[0184] Test 1. To investigate the mechanism of action of the results of Example 2, VHL-mutated RCC cell lines were subjected to hypoxia (1% O2) in vitro, mimicking the hypoxic conditions induced by antiangiogenic TKIs in vivo. Treatment with the compound of formula (I) allowed the effects on signaling pathways in cells exposed to hypoxia to be evaluated. In this test, hypoxia can initially reduce mTOR signaling, but this can be reversed after 24 hours, indicating that reactivation of the mTOR pathway is a potential mechanism of resistance to TKIs. Addition of the compound of formula (I), or a pharmaceutically acceptable form thereof, can block hypoxia-induced mTOR reactivation. Mechanistically, the compound of formula (I) potently inhibits the farnesylation and thus the activity of the essential farnesylated protein RHEB, a positive regulator of mTOR, suggesting that a synergistic effect may occur in this model via RHEB inhibition. Mechanistic data in cell lines suggests that the ability of compounds of formula (I), or pharmaceutically acceptable forms thereof, to inhibit mTOR reactivation observed in ccRCC cell lines under hypoxic stress may contribute to the improved durability of treatment in vivo.

[0185] Study 2.786-O CDX were flash-frozen after 14 days of treatment with vehicle, cabozantinib (15 mg / kg, QD), compound of Formula (I) (20 mg / kg, BID), or their combination. Tumors were thawed in 1X RIPA buffer (Thermo Scientific Catalog No. PI89901) supplemented with 1X HALT protease and phosphatase inhibitor cocktail (Thermo Scientific Catalog No. PI78446) and then homogenized at 4.5 m / s for 30 seconds using a bead mill homogenizer. Lysates were clarified by centrifugation at 12k x g for 10 minutes and quantified by BCA assay (Pierce). For SDS-PAGE and immunoblotting, 20-50 μg of lysate was loaded onto a 4-12% Bis-Tris gel (Invitrogen NuPAGE) and transferred to a nitrocellulose membrane. The membrane was probed with the following antibodies: anti-phospho-ERK1 / 2 (CST Catalog No. 4695); anti-phospho-AKT (CST Catalog No. 4060); anti-phospho-S6 (Ser235 / 236) (CST Catalog No. 2211); anti-phospho-S6 (Ser240 / 244) (CST Catalog No. 2215); anti-total S6 (CST Catalog No. 2217); anti-phospho-RB (CST Catalog No. 8516); anti-cyclin D1 (CST Catalog No. 55506); anti-RHEB (CST Catalog No. 13879), and anti-HSP90 (CST Catalog No. 4877). As shown in Figure 8, the combination treatment reduced the phosphorylation of two growth-promoting signaling proteins, AKT and S6, and reduced phosphorylated RB, a cell cycle arrest marker, compared with either drug alone. A slight shift of RHEB was detected with the combination treatment, indicating defarnesylation by the compound of formula (I). HSP90 served as a loading control.

[0186] Study 3. All immunohistochemistry (IHC) staining was performed at Histowiz, Inc. (Brooklyn, NY) using a Leica BOND RX automated stainer (Leica Microsystems). Slides were dewaxed using xylene and an alcohol-based dewaxing solution. Epitope retrieval was performed by heat-induced epitope retrieval (HIER) of formalin-fixed, paraffin-embedded tissues in a citrate-based pH 6 solution at 95°C for 20 minutes. Tissues were first incubated in peroxide blocking buffer (Leica Microsystems), followed by incubation with a 1:100 dilution of primary antibody for 30 minutes, followed by DAB mouse secondary reagent: polymer, DAB refine, and hematoxylin (Leica Microsystems). Slides were dried, coverslipped, and visualized using a Leica Aperio AT2 slide scanner (Leica Microsystems). The following primary antibodies were used: anti-CD31 antibody (Sigma, 131M-94) and anti-VEGFR2 antibody (Cell Signaling Technology 9698).

[0187] As shown in Table 5, consistent with the antiangiogenic activity of cabozantinib, 786-O CDX treated with cabozantinib (15 mg / kg, QD) for 14 days resulted in a decrease in angiogenesis, manifested as a decrease in CD31 and VEGFR2 expression compared to vehicle. However, the combination of the compound of formula (I) (20 mg / kg, BID) with cabozantinib (15 mg / kg, QD) led to a significant decrease in CD31 and VEGFR2 expression compared to cabozantinib alone. [Table 5]

[0188] As shown in Table 6, KI-0326 PDXs treated with cabozantinib (20 mg / kg, QD) for 14 days had reduced tumor angiogenesis compared to vehicle, as measured by CD31 immunohistochemistry. However, the combination of cabozantinib with the compound of Formula (I) (20 mg / kg, BID) did not result in a greater reduction in CD31 expression. This suggests that the additive effect of the two drugs on tumor growth inhibition is not solely driven by the inhibition of angiogenesis. [Table 6]

[0189] Test 4. Early passage (<passage 6) human umbilical vein endothelial cells (HUVECs) were seeded at 1,000 cells per well in 96-well plates in endothelial cell medium containing 0.2% fetal bovine serum (FBS) and left overnight. The next day, the medium was replaced with fresh endothelial cell medium containing 5% fetal bovine serum (FBS), 100 ng / mL recombinant VEGF-A, and endothelial cell growth factor (ECGS) and the test substance (DMSO as vehicle, various concentrations of axitinib with or without 100 nM of the compound of formula (I), or various concentrations of cabozantinib with or without 100 nM of the compound of formula (I)). On day 5, cell viability was assayed using Cell Titer-Glo 2 reagent (Promega) according to the manufacturer's instructions, and luminescence was recorded on a Tecan plate reader.

[0190] As shown in Table 7, the addition of 100 nM of the compound of formula (I) to axitinib or cabozantinib resulted in a more potent inhibition of HUVEC proliferation compared to axitinib or cabozantinib alone, resulting in an IC 50 The concentration decreased. [Table 7]

[0191] Test 5. Early passage (<passage 6) human umbilical vein endothelial cells (HUVECs) were seeded at 1,000 cells per well in a 96-well plate in complete endothelial cell medium containing 5% fetal bovine serum (FBS) and endothelial cell growth factor (ECGS) and left overnight. The next day, test substances (DMSO as vehicle, various concentrations of cabozantinib, axitinib, or lenvatinib, and various concentrations of the compound of formula (I)) were added. Seven days after addition of the test substances, cell viability was assayed using Cell Titer-Glo 2 reagent (Promega) according to the manufacturer's instructions, and luminescence was recorded on a Tecan plate reader.

[0192] As shown in Figure 9, the addition of increasing doses of the compound of formula (I) to cabozantinib (Figure 9A), axitinib (Figure 9B), or lenvatinib (Figure 9C) resulted in more potent inhibition of HUVEC viability compared to each TKI agent alone. Furthermore, the compound of formula (I) inhibited HUVEC viability in vitro as a single agent, demonstrating IC 50 was 223.4±84.02nM.

[0193] Test 6. Early passage (<passage 6) HUVEC cells or GFP-labeled HUVEC cells were serum-starved overnight and the next day plated at 6 x 10 cells per well onto a 48-well plate pre-coated with a layer of growth factor-reduced basement membrane extract (BME). 4 Plates were seeded with cells. At the time of plating, cells were treated with DMSO (vehicle), 100 nM axitinib, 10 nM cabozantinib, 300 nM or 1 mM of a compound of formula (I), 100 nM axitinib and 1 mM of a compound of formula (I), or 10 nM cabozantinib and 300 nM or 1 mM of a compound of formula (I). Each treatment group had two technical replicates. Plates were incubated in an Incucyte at 37°C under a 5% CO2 atmosphere in air. Tube formation was monitored by imaging every 30 minutes for 18 hours.

[0194] As shown in Figure 10, treatment of primary endothelial cells with 100 nM axitinib or 10 nM cabozantinib, with or without 1 μM compound of Formula (I), impaired the ability of the cells to form tubular structures on matrix proteins in vitro. (A—vehicle; B—axitinib; C—cabozantinib; D—compound of Formula (I); E—axitinib and compound of Formula (I); F—cabozantinib and compound of Formula (I).) Figure 11 shows that treatment with 10 nM cabozantinib, but not 300 nM compound of Formula (I), inhibited in vitro tube formation of GFP-labeled primary endothelial cells (Figure 11A, GFP imaging; Figure 11B, plots of master segment number and total master segment length). The combination of cabozantinib and the compound of formula (I) did not further reduce tube formation compared to cabozantinib alone, demonstrating that the compound of formula (I) does not affect this particular endothelial cell function.

[0195] Test 7. Early passage (<passage 6) human umbilical vein endothelial cells (HUVECs) were seeded at 2,000 cells per well in a Nunc 96-well flat-bottom plate in endothelial cell medium (ECM) supplemented with endothelial cell growth factor containing 5% fetal bovine serum (FBS) and left overnight. The following day, the medium was removed and replaced with Incucyte Annexin V Orange dye (Sartorius) diluted 1:200 in complete ECM medium. The following test substances were added directly to the Annexin V-conditioned medium: DMSO as vehicle, 1000 nM staurosporine as a positive control, 100 nM compound of formula (I), 100 nM cabozantinib, or the combination of compound of formula (I) and cabozantinib. Live cell imaging and analysis were performed over 4 days using an Incucyte SX5 system.

[0196] As shown in Figure 12, treatment of primary endothelial cells with the compound of formula (I) and cabozantinib induced more apoptosis than either agent alone, as plotted by Annexin V signal over time. Staurosporine was included as a positive control.

[0197] Example 4: FTI activity in a HRAS-high cell line tumor spheroid growth model

[0198] Cell lines were obtained from ATCC (SCC9) or Sigma (HSC3) and maintained at 37°C in a humidified atmosphere with 5% CO2. They were cultured in DMEM (HSC3) or DMEM / F12 (SCC9) supplemented with 10% FBS and penicillin / streptomycin. All lines tested negative for mycoplasma. Matrigel matrix was purchased from Corning and diluted in the appropriate medium before plating. Anti-GTPase HRAS antibody was purchased from Abcam. An Active GTPase Pull-Down Kit was purchased from ThermoFisher. Cells were plated in 10 cm dishes and lysed. Lysates were collected and pulled down according to the pull-down kit protocol. 500 μg of protein was loaded for pull-down, with 10 μg of protein input as a control. HRAS activity levels in each cell line were analyzed by blotting using an HRAS-specific antibody (ab32417). Cells were resuspended in 4% Matrigel and seeded at a density of 1,000–2,000 cells / well in 96-well ultra-low attachment plates. The following day, spheroids were treated with the compound of Formula (I) and DMSO as a control for normalization. Spheroids were incubated with the test compounds for 7 days, and luminescence was read using 3D Cell Titer Glo reagent (Promega). Results: The sensitivity of the compound of Formula (I) to head and neck squamous cell carcinoma (HNSCC) cell lines based on HRAS activity levels was evaluated. SCC9 and HSC3 cell lines were identified based on HRAS activity levels assayed by a GTP pulldown kit. As shown by immunoblotting, SCC9 was characterized as a high HRAS expresser, while HSC3 was characterized as a low HRAS expresser (Figure 13). The cell lines were then cultured as 3D tumor spheroids and treated with the compound of Formula (I) and DMSO for 7 days. Cell viability was calculated by normalizing compound-treated cells to DMSO-treated cells. As shown in Table 7, the compound of formula (I) was more effective in the high HRAS activity cell line (SCC9) than in the low HRAS level cell line (HSC3) based on the percentage of cell viability. [Table 8]

[0199] Example 5: Activity of compounds of formula (I) in an HRAS-modified patient-derived xenograft model

[0200] Female NOD / SCID mice were cultured with tumor fragments from a human primary tumor xenograft model (human head and neck tumor, HN2594 (HRAS)) harvested from stock mice. WT-high , Crown Bioscience, Beijing; diameter 2-3 mm) were inoculated subcutaneously into the right upper flank to allow tumor formation. All animals were randomly assigned to four test groups, each containing five mice. The average tumor size was approximately 220 mm. 3 Randomization began when the tumor density reached 100%. Randomization was performed based on the "Matched distribution" method (StudyDirector™ software, version 3.1.399.19). Dosing began on the day of randomization (day 0). Mice were orally administered control vehicle, QD, or 20 mg / kg BID of a compound of Formula (I) for 35 days. After tumor inoculation, animals were checked daily for morbidity and mortality. During regular monitoring, animals were checked for the effects of tumor growth and treatment on behaviors such as mobility, food and water consumption, weight gain / loss (weight was measured three times a week / daily after randomization), eye / hair matting, and other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal. After randomization, tumor volumes were measured three times weekly using calipers in two dimensions and expressed in mm using the formula: V = (L x W x W) / 2, where V is tumor volume, L is tumor length (longest tumor dimension), and W is tumor width (longest tumor dimension perpendicular to L). 3 The tumor volume was expressed as 0.05 mg / kg body weight. Dosing and tumor and body weight measurements were performed in a clean bench. Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19). As shown in Figure 14, the compound of formula (I) caused tumor regression in this model.

[0201] Example 6: Activity of compounds of formula (I) in an HRAS-modified patient-derived xenograft model

[0202] Human head and neck squamous cell carcinoma patient-derived xenograft (PDX) models HN2576 and HN2594 (HRAS) in female NOD / SCID mice WT-high PDXs (Crown Bioscience, Beijing) were used in this study. Fresh tumor tissues were collected from mice with established primary human cancer tissues and cut into small pieces (approximately 2-3 mm in diameter). Each mouse was subcutaneously inoculated with a specific PDX tumor fragment (3 x 3 x 3 mm) into the right anterior flank, allowing tumor formation. The average tumor size was approximately 250 mm. 3 Randomization began when tumor density reached 100 μg / kg. All animals were randomly assigned to five test groups, each containing five mice. Randomization was performed based on the "Matched distribution" method (StudyDirector™ software, version 3.1.399.19). The day of randomization was designated as day 0. Dosing began on the same day as randomization (day 0) according to the study design. HN2576 and HN2594 xenografts were orally treated with vehicle control, BID; or a compound of Formula (I), 10 mg / kg, 20 mg / kg, or 40 mg / kg, BID. After tumor inoculation, animals were monitored daily for morbidity and mortality. During regular monitoring, animals were monitored for the effects of tumor growth and treatment on behaviors such as mobility, food and water consumption, weight gain / loss (weight was measured three times a week / daily after randomization), eye / hair matting, and other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal. After randomization, tumor volumes were measured three times weekly using calipers in two dimensions and expressed in mm using the formula: V = (L x W x W) / 2, where V is tumor volume, L is tumor length (longest tumor dimension), and W is tumor width (longest tumor dimension perpendicular to L). 3The tumor growth rate was expressed as 10 mg / kg, and the tumor and body weight measurements were performed in a clean bench. Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19). In these two wild-type HRAS overexpressing xenograft models, HN2576 and HN2594, compound of formula (I) alone had a significant antitumor effect compared to vehicle control. Single-agent treatment with compound of formula (I) at increasing doses of 10 mg / kg, 20 mg / kg, and 40 mg / kg resulted in tumor growth inhibition in the HN2576 PDX model (Figure 15). In the HN2594 PDX model, increasing doses of compound of formula (I) resulted in a dose-dependent decrease in tumor growth (Figure 16). These results suggest that compound of formula (I) has single-agent activity that results in antitumor effects in HRAS-amplified head and neck squamous cell carcinoma (HNSCC) xenograft models.

[0203] Example 6: Clinical Trials

[0204] This study is designed to evaluate the safety, tolerability, and preliminary efficacy of the compound of Formula (I), or a pharmaceutically acceptable form thereof, in patients with advanced solid tumors. Eligible patients for Part 1a dose escalation (including relevant pharmacodynamic cohorts) have histologically or cytologically confirmed advanced solid tumors with confirmed HRAS mutation and / or amplification or HRAS overexpression (e.g., in the case of HNSCC), or confirmed NRAS mutation and / or NRAS amplification, e.g., NSCLC, CRC, or PDAC, and have progressed on or are refractory to standard therapy, or are not suitable for or have no standard therapy. Eligible patients for Part 1b combination dose escalation (including relevant pharmacodynamic cohorts) and Part 2 combination dose expansion have histologically or cytologically confirmed locally advanced or metastatic RCC, predominantly of the clear cell subtype (e.g., ccRCC), and optionally have received at least one prior line of systemic therapy for such carcinoma. Patients must have at least one measurable lesion per RECIST v.1.1 confirmed by radiological evaluation. Additional eligibility criteria may apply.

[0205] Dosing Regimen. During the Part 1a Dose Escalation Phase, the daily doses and regimens tested may include those listed in Table 8. The amounts listed are free base equivalent amounts. [Table 9]

[0206] The compound of formula (I) or a pharmaceutically acceptable form thereof is administered on days 1-7 and days 15-21 of a 28-day treatment cycle. Optionally, the compound is administered at, for example, 40 mg QD, with or without food.

[0207] Part 1b, the dose-escalation phase, will test the combination of the compound of Formula (I) or a pharmaceutically acceptable form thereof and cabozantinib. Cabozantinib will be administered in the form of cabozantinib (S)-malate, and the amounts listed below are the free base equivalent amount. Doses and regimens tested may include those listed in Tables 9 and 10. [Table 10] [Table 11]

[0208] In the combination dose expansion phase of Part 2, one or more dosing regimens from the dose escalation phase of Part 1b may be selected for continued evaluation of safety, tolerability, and preliminary efficacy.

[0209] Safety Assessment. DLTs will be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0) and will be evaluated at Cycle 1 (day 28) for all patients in the dose-escalation phase. Patients are DLT-evaluable if they experience a DLT or receive at least 75% of the planned dose during the DLT evaluation period.

[0210] Efficacy Assessment. Efficacy assessments will be conducted throughout Cycle 1 (28 days). Objective response rates (complete response (CR) and partial response (PR)), as determined by the patient's best tumor response, DoR, and PFS, will be assessed using RECIST v1.1 by investigator assessment. Tumor response assessments will continue until disease progression, initiation of new anticancer therapy, or withdrawal from the study. Overall survival will also be documented.

[0211] Radiographic assessment of tumor lesions will be performed at screening, at least approximately every 8 weeks (± 5 days) for the remainder of the first 12 months of study intervention (up to and including Cycle 13), and approximately every 12 weeks (± 5 days) from the second year of study intervention onward. Additional tumor assessments may be performed.

[0212] Lesions included in tumor assessment should adhere to RECIST v1.1. Computed tomography (CT) scans with contrast are the preferred imaging method, and the same technique should be used at screening and post-treatment assessments. The extent of the CT scan at screening should include scans of the chest and abdomen (including the liver and adrenal glands), as well as the pelvis. Other areas of disease involvement should be scanned based on the patient's signs and symptoms.

[0213] Pharmacokinetics and Pharmacodynamics. To assess the pharmacokinetics of the combination, blood samples were collected at various time points and analyzed for the area under the concentration-time curve (AUC), maximum plasma concentration, time to maximum observed concentration, terminal elimination rate constant, terminal half-life, apparent clearance, and apparent volume of distribution for each drug. Plasma concentrations were analyzed using noncompartmental pharmacokinetic analysis (NCA).

[0214] Pharmacodynamic biomarkers and ctDNA will be assessed during prescreening and testing. Biomarker analyses may include, but are not limited to, HRAS overexpression, HRAS mutations (including G12D / N / S / V; G13C / D / R / V; Q22T; A59T; Q61R / K / L; K117N; A146T), HRAS amplification, NRAS mutations (including G12C / D / S, G13V / R, Q61H / K / L / R, A146T), NRAS amplification, farnesylated target proteins, farnesyltransferase enzyme activity, serum tumor markers, and ctDNA. These assessments will be performed using a combination of biochemical, genomic, transcriptomic, and proteomic techniques, which may include profiling of mutations, amplifications, and / or other somatic genetic alterations at the DNA, RNA, or protein level in tumor tissue.

[0215] Biomarkers in tumor tissue and blood are examined for potential correlations between efficacy and / or treatment resistance and underlying biological factors (e.g., farnesylation status of target proteins, clearance rate).

[0216] 6.1 Exemplary Embodiments One or more (eg, including all) of the following exemplary embodiments may include each of the other embodiments, or portions thereof.

[0217] A1. A method of treating an advanced solid tumor in a subject, comprising administering to the subject a compound of formula (I): [ka] or a pharmaceutically acceptable form thereof; and This involves administering a VEGFR inhibitor.

[0218] A2. A method of reducing, slowing the progression of, or overcoming drug resistance in an advanced solid tumor in a subject, comprising administering to the subject a compound of formula (I): [ka] or a pharmaceutically acceptable form thereof; and This involves administering a VEGFR inhibitor.

[0219] A3. A method of preventing or delaying the emergence of drug resistance in advanced solid tumors in a TKI-naive subject, comprising administering to said subject a compound of formula (I): [ka] or a pharmaceutically acceptable form thereof; and This involves administering a VEGFR inhibitor.

[0220] A4. The method of any one of embodiments A1-A3, wherein the subject has an advanced solid tumor, is afflicted with an advanced solid tumor, has symptoms associated with an advanced solid tumor, is diagnosed with an advanced solid tumor, or is an advanced solid tumor subject in remission.

[0221] A5. The method of any one of embodiments A1-A4, wherein the advanced solid tumor is metastatic, recurrent, unresectable, relapsed, or refractory, or a combination thereof.

[0222] A6. The method of any one of embodiments A1-A5, wherein the advanced solid tumor is selected from renal cell carcinoma (RCC) (optionally, the RCC is clear cell RCC, papillary RCC, chromophobe RCC, unclassified RCC, or post-nephrectomy RCC), thyroid cancer (optionally, the thyroid cancer is medullary thyroid carcinoma, differentiated thyroid carcinoma, or radioactive iodine refractory), hepatocellular carcinoma, colorectal cancer, gastrointestinal stromal tumor (GIST) (optionally, the GIST is advanced or intolerant to imatinib), soft tissue sarcoma, pancreatic neuroendocrine tumor (optionally, the pancreatic neuroendocrine tumor is advanced, differentiated, locally advanced, or metastatic), or endometrial carcinoma, and wherein the advanced solid tumor is RCC or clear cell RCC.

[0223] A7. The method of any one of embodiments A1-A6 comprising administering to the subject a VEGFR inhibitor orally, optionally once or twice daily, optionally for one or more treatment cycles.

[0224] A8. The VEGFR inhibitor is selected from cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, and optionally, said VEGFR inhibitor is selected from cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib. The method of any one of embodiments A1-A7, wherein the VEGFR inhibitor is selected from zopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanzarintinib fumarate, and optionally the VEGFR inhibitor is cabozantinib, axitinib, sunitinib, or sorafenib, and optionally the VEGFR inhibitor is cabozantinib. In some embodiments, the VEGFR inhibitor is zanzarintinib. In some embodiments, the VEGFR inhibitor is fruquintinib.

[0225] A9. The method of any one of embodiments A1-A8, wherein the method reduces or alleviates toxicity associated with a VEGFR inhibitor, improves the efficacy of the VEGFR inhibitor, delays, halts, or prevents the progression of an advanced solid tumor, or increases the time to progression (TTP), progression-free survival (PFS), event-free survival (EFS), overall survival (OS), overall response rate (ORR), complete response rate (CR rate), or duration of response (DoR), or a combination of two or more thereof, compared to a comparator therapy, optionally wherein the VEGFR inhibitor is cabozantinib, and optionally wherein the advanced solid tumor is renal cell carcinoma or clear cell RCC.

[0226] A10. A method of treating an advanced solid tumor with HRAS amplification and / or HRAS overexpression, optionally in combination with an HRAS mutation, and optionally with squamous histology, in a subject, comprising administering to the subject a compound of formula (I): [ka] or a pharmaceutically acceptable form thereof.

[0227] A11. The method of embodiment A10, wherein the advanced solid tumor is HNSCC.

[0228] A12. The method of embodiment A10 or A11, wherein the advanced solid tumor has squamous histology.

[0229] A13. The method of any one of embodiments A10-A12, wherein the advanced solid tumor has HRAS amplification.

[0230] A14. The method of any one of embodiments A10-A13, wherein the advanced solid tumor overexpresses HRAS.

[0231] A15. The method of any one of embodiments A10-A14, wherein the advanced solid tumor has an HRAS mutation.

[0232] A16. The method according to any one of embodiments A10 to A15, wherein the HRAS mutation is a mutation in the HRAS gene that encodes a mutant H-Ras protein.

[0233] A17. The method of embodiment A16, wherein the HRAS gene mutation is or comprises a modification of a codon encoding an amino acid substitution at a specific position selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and any combination thereof, and optionally, in the corresponding mutant H-Ras protein, the modification is G12C, G12D, G12A, G12V, G12S, G12F, G12R, G12N, G13A, G13C, G13V, G13D, G13R, G13S, G13N, G13V Q61E, Q61K, Q61H, Q61L, Q61P, Q61R, Q22K, Q22T, K117N, K117L, A146V, A146T, or A146P.

[0234] A18. A method of treating an advanced solid tumor with HRAS amplification and / or HRAS overexpression, optionally in combination with an HRAS mutation, in a subject, comprising administering to the subject a compound of formula (I): [ka] or a pharmaceutically acceptable form thereof.

[0235] A19. The method of embodiment A18, wherein the advanced solid tumor has NRAS amplification.

[0236] A20. The method of embodiment A18 or A19, wherein the advanced solid tumor overexpresses NRAS.

[0237] A21. The method of any one of embodiments A18-A20, wherein the advanced solid tumor has an NRAS mutation.

[0238] A22. The method according to any one of embodiments A18 to A21, wherein the NRAS mutation is a mutation in the NRAS gene that encodes a mutant N-Ras protein.

[0239] A23. The method of embodiment A22, wherein the NRAS gene mutation is or comprises a modification in a codon encoding an amino acid substitution at a specific position selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and any combination thereof, and optionally, in the corresponding mutant N-Ras protein, the modification is a G12C, G12D, G12S, G12V, G12R, Q61H, Q61K, Q61L, Q61R, or A146T substitution.

[0240] A23. The method of any one of embodiments A10 or A12-A22, wherein the advanced solid tumor is melanoma, colorectal cancer (carcinoma or adenocarcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, small cell lung carcinoma), breast cancer, ovarian cancer, pancreatic ductal cancer (e.g., carcinoma or ductal adenocarcinoma), glioma, HNSCC, and thyroid cancer, optionally wherein the advanced solid tumor is non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with NRAS amplification.

[0241] A24. The method of any one of embodiments A10-A23, wherein the advanced solid tumor is (a) an advanced solid tumor with HRAS amplification, (b) HNSCC with HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with HRAS amplification.

[0242] A25. The method of any one of embodiments A1-A24, wherein the advanced solid tumor is metastatic, progressive, recurrent, unresectable, recurrent, or refractory, or a combination thereof.

[0243] A26. The method of any one of embodiments A1-A25, comprising orally administering to the subject the compound of formula (I), or a pharmaceutically acceptable form thereof.

[0244] A27. The method of embodiment A26 comprising administering to the subject the compound of formula (I), or a pharmaceutically acceptable form thereof, at a dose of 0.5 mg to 2400 mg per day.

[0245] A28. In some embodiments, the dose of the compound of formula (I), or the pharmaceutically acceptable form thereof, is 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, and 2.0 mg, about 2.5 mg, about 3.0 mg, about 5 mg, About 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 8 5mg, about 90mg, about 95mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, about 250mg, about 275mg, about 300mg, about 325mg, about 350mg, About 375mg, about 400mg, about 425mg, about 450mg, about 475mg, about 500mg, about 525mg, about 550mg, about 575mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg, about 900mg, about 950mg, about 1000mg, about 1050mg, about 1100mg, about 1150mg, about 1200mg, about 1250mg, about 1300mg, about 1350mg, about 1 The method of embodiment A27, wherein the dose is 400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, and about 2400 mg.

[0246] A29. The method of any one of embodiments A1-A28 comprising administering the compound of formula (I), or a pharmaceutically acceptable form thereof, once or twice daily, optionally on days 1-7, 8-14, 15-21, 21-28, 1-7 and 15-21, 1-21, or 1-28 of a 28-day treatment cycle.

[0247] A30. The method of embodiment A29 comprising administering the compound of formula (I), or a pharmaceutically acceptable form thereof, once daily during a 28 day treatment cycle, optionally once daily on days 1 to 7, 8 to 14, 15 to 21, 21 to 28, 1 to 7 and 15 to 21, 1 to 21, or 1 to 28 of the treatment cycle.

[0248] The above-described embodiments are intended to be merely illustrative; those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of this invention and are covered by the appended claims.

[0249] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Claims

1. 1. A method of treating an advanced solid tumor in a subject, comprising administering to said subject a compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable form thereof; and The method further comprises administering a VEGFR inhibitor.

2. 1. A method of reducing, slowing the progression of, or overcoming drug resistance in an advanced solid tumor in a subject, comprising administering to the subject a compound of formula (I): 【Chemistry 2】 or a pharmaceutically acceptable form thereof; and The method further comprises administering a VEGFR inhibitor.

3. 1. A method of preventing or delaying the emergence of drug resistance in advanced solid tumors in a TKI-naive subject, comprising administering to said subject a compound of formula (I): 【Transformation 3】 or a pharmaceutically acceptable form thereof; and The method further comprises administering a VEGFR inhibitor.

4. 4. The method of any one of claims 1 to 3, wherein the subject has an advanced solid tumor, is suffering from an advanced solid tumor, has symptoms associated with an advanced solid tumor, is diagnosed with an advanced solid tumor, or is an advanced solid tumor subject in remission.

5. 5. The method of any one of claims 1 to 4, wherein the advanced solid tumor is metastatic, recurrent, unresectable, relapsed, or refractory, or a combination thereof.

6. 6. The method of any one of claims 1 to 5, wherein the advanced solid tumor is selected from renal cell carcinoma (RCC) (optionally, the RCC is clear cell RCC, papillary RCC, chromophobe RCC, unclassified RCC, or post-nephrectomy RCC), thyroid cancer (optionally, the thyroid cancer is medullary thyroid carcinoma, differentiated thyroid carcinoma, or radioactive iodine refractory), hepatocellular carcinoma, colorectal cancer, gastrointestinal stromal tumor (GIST) (optionally, the GIST is imatinib-promoting or imatinib-intolerant), soft tissue sarcoma, pancreatic neuroendocrine tumor (optionally, the pancreatic neuroendocrine tumor is advanced, differentiated, locally advanced, or metastatic), or endometrial cancer, and wherein the advanced solid tumor is RCC or clear cell RCC, etc.

7. 7. The method of any one of claims 1 to 6, comprising administering to the subject the VEGFR inhibitor orally, optionally once or twice daily, optionally for one or more treatment cycles.

8. The VEGFR inhibitor is selected from cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib, and optionally the VEGFR inhibitor is selected from cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-liquid phosphate, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzarintinib.

8. The method of any one of claims 1 to 7, wherein the VEGFR inhibitor is selected from the group consisting of tivozanib hydrochloride hydrate, sorafenib tosylate, tivozanib hydrochloride hydrate, or fruquintinib free base, zanzarintinib fumarate, and optionally the VEGFR inhibitor is cabozantinib, axitinib, sunitinib, or sorafenib, and optionally the VEGFR inhibitor is cabozantinib, and optionally the VEGFR inhibitor is zanzarintinib or fruquintinib.

9. 9. The method of any one of claims 1 to 8, wherein the method reduces or alleviates toxicity associated with the VEGFR inhibitor, improves efficacy of the VEGFR inhibitor, delays, halts, or prevents progression of the advanced solid tumor, or increases time to progression (TTP), progression-free survival (PFS), event-free survival (EFS), overall survival (OS), overall response rate (ORR), complete response rate (CR rate), or duration of response (DoR), or a combination of two or more thereof, compared to a comparator therapy, optionally wherein the VEGFR inhibitor is cabozantinib, and optionally wherein the advanced solid tumor is renal cell carcinoma or clear cell RCC.

10. 1. A method of treating an advanced solid tumor with squamous histology and HRAS amplification and / or HRAS overexpression, optionally in combination with an HRAS mutation, in a subject, comprising administering to said subject a compound of formula (I): 【Chemistry 4】 or a pharmaceutically acceptable form thereof.

11. 11. The method of claim 10, wherein the advanced solid tumor is HNSCC.

12. 12. The method of claim 10 or claim 11, wherein the aggressive solid tumor with squamous histology has HRAS amplification.

13. The method of any one of claims 10 to 12, wherein the aggressive solid tumor with squamous histology overexpresses HRAS.

14. The method of any one of claims 10 to 13, wherein the advanced solid tumor has an HRAS mutation.

15. 15. The method of any one of claims 1 to 14, wherein the advanced solid tumor is metastatic, progressive, recurrent, unresectable, recurrent, or refractory, or a combination thereof.

16. 16. The method of any one of claims 1 to 15, comprising orally administering to the subject the compound of formula (I), or the pharmaceutically acceptable form thereof.

17. 17. The method of claim 16, comprising administering to the subject the compound of formula (I), or the pharmaceutically acceptable form thereof, at a dose of 0.5 mg to 2400 mg per day.

18. The dose of the compound of formula (I), or the pharmaceutically acceptable form thereof, is 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, and 2.0 mg, about 2.5 mg, about 3.0 mg, about 5 mg, about 10 mg, about 15 mg per day. g, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 m g, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg , about 400mg, about 425mg, about 450mg, about 475mg, about 500mg, about 525mg, about 550mg, about 575mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800m g, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 140 18. The method of claim 17, wherein the dose is about 0 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, and about 2400 mg.

19. 19. The method of any one of claims 1 to 18, comprising administering the compound of formula (I), or a pharmaceutically acceptable form thereof, once or twice daily during a 28 day treatment cycle, optionally once or twice daily on days 1 to 7, 8 to 14, 15 to 21, 21 to 28, 1 to 7 and 15 to 21, 1 to 21, or 1 to 28 of the treatment cycle.

20. 20. The method of claim 19, comprising administering the compound of formula (I), or a pharmaceutically acceptable form thereof, once daily during a 28 day treatment cycle, optionally once daily on days 1 to 7, 8 to 14, 15 to 21, 21 to 28, 1 to 7 and 15 to 21, 1 to 21, or 1 to 28 of the treatment cycle.

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