WO2025226830A1 - Shp2 and egfr inhibitors for the treatment of chordoma - Google Patents

Abstract

The present disclosure provides methods of treating chordoma with combination therapies of a SHP2 inhibitor and EGFR inhibitor.

Description

SHP2 AND EGFR INHIBITORS FOR THE TREATMENT OF CHORDOMA

CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63/637,830 filed April 23, 2024; which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Src Homology-2 phosphatase (SHP2) is a non-receptor protein phosphatase ubiquitously expressed in various tissues and cell types (see reviews: Taj an M et al., Eur J Med Genet 2016 58(10):509-25; Grossmann KS et al. , Adv Cancer Res 2010 106:53-89). SHP2 is composed of two Src homology 2 (N-SH2 and C-SH2) domains in its NH2 -terminus, a catalytic PTP (protein-tyrosine phosphatase) domain, and a C-terminal tail with regulatory properties. At the basal state, the intermolecular interactions between the SH2 domains and the PTP domain prevent the access of substrates to the catalytic pocket, keeping SHP2 into a closed, auto -inhibited conformation. In response to stimulation, SHP2 activating proteins bearing phosphor -tyrosine motifs bind to the SH2 domains, leading to exposure of active site and enzymatic activation of SHP2.

SUMMARY OF THE INVENTION

[0003] The present embodiments disclosed herein generally relate to compositions and methods related to combination therapies to treat chordoma utilizing a SHP2 inhibitor in conjunction with an EGFR inhibitor, while providing an unexpected degree of synergy.

[0004] SHP2 plays important roles in fundamental cellular functions including proliferation, differentiation, cell cycle maintenance and motility. By dephosphorylating its associated signaling molecules, SHP2 regulates multiple intracellular signaling pathways in response to a wide range of growth factors, cytokines, and hormones. Cell signaling processes in which SHP2 participates include the RAS-MAPK (mitogen-activated protein kinase), the PI3K (phosphoinositol 3 -kinase)- AKT, and the JAK- STAT pathways.

[0005] SHP2 also plays a signal -enhancing role on this pathway, acting downstream of RTKs and upstream of RAS. One common mechanism of resistance for pharmacological inhi biton of MAPK signaling involves activation of RTKs that fuel reactivation of the MAPK signaling. RTK activation recruits SHP2 via direct binding and through adaptor proteins. Those interactions result in the conversion of SHP2 from the closed (inactive) conformation to open (active) conformation. SHP2 is an important facilitator of RAS signaling reactivation that bypasses pharmacological inhibition in both primary and secondary resistance. Inhibition of SHP2 achieves the effect of globally attenuating upstream RTK signaling that often drives oncogenic signaling and adaptive tumor escape (see Prahallad, A. et al. Cell Reports 12, 1978-1985 (2015); Chen YN, Nature 535, 148-152(2016)).

[0006] In addition to SHP2, epidermal growth factor receptor (EGFR), a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands, also operates upstream of the RAS pathway. The opportunity to target signal transduction pathways from multiple angles and potentially ameliorate feedback loops upstream of Ras via SHP2 and EGFR provides opportunities for developing methods that employ combination therapies. Described herein are methods of treating chordoma with SHP2 and EGFR inhibitors.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1A shows chordoma cell lines data after being incubated with vehicle and Compound 1. [0008] FIG. IB shows chordoma cell lines data after being incubated with vehicle, Compound 1, cetuximab, and the combination of Compound 1 and cetuximab.

[0009] FIG. 1C shows chordoma cell lines data after being incubated with vehicle, Compound 1, afatinib, and the combination of Compound 1 and afatinib.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0010] Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the embodiments are directed. In addition, any method or material similar or equivalent to a method or material described herein can be used in the practice of the embodiments herein. For purposes of the embodiments disclosed herein, the following terms are defined.

[0011] “A,” “an,” or “the” as used herein not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and reference to “the agent” includes reference to one or more agents known to those skilled in the art, and so forth.

[0012] “Pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and absorption by a subject. Pharmaceutical excipients useful in the present embodiments include, but are not limited to, binders, fillers, disintegrants, lubricants, surfactants, coatings, sweeteners, flavors, and colors. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present embodiments.

[0013] “Treat”, “treating” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, pathology, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. [0014] “Administering” refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject. In the context of the combination therapies disclosed herein, administration can be at separate times or simultaneous or substantially simultaneous.

[0015] “Co-administering” or “administering in combination with” as used herein refers to administering a composition described herein at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds provided herein can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Coadministration is meant to include administration of the compounds on the same day, within the same week, and/or within the same treatment schedule. Compounds may have different administration schedules but still be co-administered if they are administered within the same treatment schedule. For example, the EGFR inhibitor may be administered once a day for three weeks within a four week treatment schedule, and Compound 1 is co-administered with the EGFR inhibitor if it is administered at any time within the four week treatment schedule.

[0016] “Therapeutically effective amount” refers to a dose that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins), each of which is incorporated herein by reference in its entirety for all of its teachings, including without limitation all methods, compounds, compositions, data and the like, for use with any of the embodiments and disclosure herein. In sensitized cells, the therapeutically effective dose can often be lower than the conventional therapeutically effective dose for non- sensitized cells.

[0017] “Inhibition,” “inhibits” and “inhibitor” refer to a compound that partially or completely blocks or prohibits or a method of partially or fully blocking or prohibiting, a specific action or function.

[0018] “Subject” refers to aliving organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, horse, and other non-mammalian animals. In some embodiments, the patient is human.

SHP2 Inhibitors

[0019] SHP2 plays important roles in fundamental cellular functions including proliferation, differentiation, cell cycle maintenance and motility, and regulates multiple intracellular signaling pathways in response to wide range of growth factors, cytokines, and hormones. Cell signaling processes in which SHP2 participates include MAPK, PI3K and JAK pathways. SHP2 inhibitors have the potential to attenuate upstream RIK signaling that often drives oncogenic signaling and adaptive tumor escape globally, and to become a broad-spectrum anticancer drug.

[0020] In some embodiments, the SHP2 inhibitor is Sodium stibogluconate, RMC-4550, NSC87877, SPI-112, TNO155, IACS-13909, GDC01971, or SHP099 HC1. In some embodiments, the SHP2 inhibitor is Compound 1.

Compound 1

[0021] Compound 1 is (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(((6aS,8S)-

8-((methoxymethoxy)methyl)-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[l,2-d][l,4]oxazin-4- yl)thio)pyrazin-2-yl)methanol: . In some embodiments,

Compound 1 is in the form of a pharmaceutically acceptable salt thereof.

EGFR Inhibitors

[0022] “EGFR inhibitor” refers to any inhibitor of wild-type EGFR or an EGFR mutant. EGFR mutations include, but are not limited to, any of those disclosed in US2018/0235968, which is incorporated herein by reference in its entirety. EGFR mutations include, without limitation, single nucleotide polymorphisms, exon insertion and deletions, polysomy, and the like. Specific examples of mutations include, without limitation, EGFR gene copy gain, EGFR gene amplification, chromosome 7 polysomy, EGFR L858R, EGFR exon 19 deletions/insertions (e.g., E746_A750del, E746_T751delinsI, E746_T751delinsIP, E746_S752delinsA, E746_S752delinsV, E746_S752delinsV, L747_S752del, L747_T751del, and L747_P753delinsS), EGFR L861Q, EGFR L718Q, EGFR G719C, EGFR G719S, EGFRG724S, EGFR G719A, EGFR V765A, EGFR T783A, EGFR exon 20 insertions (e.g., N771dup, N771_H773dup, and P772_H773dup), EGFR splice variants (e.g., Viii, Vvi, and Vii), EGFR A289D, EGFR A289T, EGFR A289V, EGFR G598A, EGFR G598V, EGFR S768I, EGFR T790M, EGFR C797S, and EGFR C797S.

[0023] In some embodiments, one or more of the mutations listed in this paragraph and elsewhere herein can be specifically excluded from the embodiments set forth herein, including without limitation, any methods, kits, and compositions of matter, etc.

[0024] In some embodiments, the EGFR inhibitor is afatinib, amivantamab, cetuximab, dacomitinib, erlotinib, gefitinib, lapatinib, lazertinib, lifirafenib, mirzotamab clezutoclax, mobocertinib, nazartinib, necitumumab, neratinib, nimotuzumab, osimertinib, panitumumab, or vandetanib. [0025] In some embodiments, the EGFR inhibitor is cetuximab or afatinib.

[0026] In some embodiments, the EGFR inhibitor is cetuximab.

[0027] In some embodiments, the EGFR inhibitor is afatinib.

[0028] In some embodiments, the EGFR inhibitor is osimertinib.

[0029] Other EGFR inhibitors include those disclosed in US2020/0002279, US2019/0202920, and US2019/0167686 and WO2012/061299, WO2019/067543, and W02020/ 190765.

Combination Methods

[0030] Disclosed herein are methods of treating chordoma in a subject, the method comprising administering to the subject:

(a) Compound pharmaceutically acceptable salt thereof; and

(b) an EGFR inhibitor.

[0031] In some embodiments, a significant synergy was observed beyond that which had been anticipated for such a combination.

[0032] As will be appreciated by those skilled in the art, tumors may metastasize from a first or primary locus of tumor to one or more other body tissues or sites. In particular, metastases to the central nervous system (z.e., secondary CNS tumors), and particularly the brain (z.e., brain metastases), are well documented for tumors and cancers. As such, the methods disclosed herein can be used for the treatment of metastases (z.e., metastatic tumor growth) to other organs as well.

[0033] In some embodiments, the method may include administering a third agent that is a MAPK pathway inhibitor. Without being bound by theory, suppression of MAPK signaling in cancer cells can result in downregulation of PD-L1 expression and increase the likelihood that the cancer cells are detected by the immune system. Such MAPK pathway inhibitors is based on other mutations of proteins in the MAPK pathway. In some embodiments, any MAPK pathway inhibitor can be employed, including those targeting K-Ras, N-Ras, H-Ras, PDGFRA, PDGFRB, MET, FGFR, ALK, ROS1, TRKA, TRKB, TRKC, EGFR, IGFR1R, GRB2, SOS, ARAF, BRAF, RAFI, MEK1, MEK2, c-Myc, CDK4, CDK6, CDK2, ERK1, and ERK2. Exemplary MAPK pathway inhibitors include, without limitation, afatinib, osimertinib, erlotinib, gefitinib, lapatinib, neratinib, dacomitinib, vandetanib, cetuximab, panitumumab, nimotuzumab, necitumumab, trametinib, binimetinib, cobimetinib, selumetinib, ulixertinib, LTT462, and LY3214996. In some embodiments, one or more of the above-listed inhibitors can be specifically excluded from the embodiments set forth herein, including without limitation, any methods, kits, and compositions of matter, etc.

[0034] The methods disclosed herein can be combined with other chemotherapeutic agents. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers; which is incorporated herein by reference in its entirety for all of its teachings, including without limitation all methods, compounds, compositions, data, and the like, for use with any of the embodiments and disclosure herein. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.

[0035] In some embodiments, the methods can include the co-administration of at least one cytotoxic agent. The term “cytotoxic agent” as used herein refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At211, 1131, 1125, Y90, Rel86, Rel88, Sml53, Bi212, P32, Pb212 and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.

[0036] Examples of cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signaling inhibitors; HD AC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.

[0037] Chemotherapeutic agents include chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib, bortezomib, disulfiram , epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant, sunitinib, letrozole, imatinib mesylate, finasunate, oxaliplatin, 5-FU (5 -fluorouracil), leucovorin, Rapamycin, Lapatinib, Lonafamib (SCH 66336), sorafenib, gefitinib, AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methyl amel amines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC 1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophy cin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5 -alpha-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechl or ethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin yl I and calicheamicin coll; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6 azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti- adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2 -ethylhydrazide; procarbazine; PSK® polysaccharide complex; razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel, and docetaxel; chloranmbucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0038] Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti -estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen, raloxifene, droloxifene, iodoxyfene , 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifine citrate; (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)- imidazoles, aminoglutethimide, megestrol acetate, exemestane, formestanie, fadrozole, vorozole, letrozole, and anastrozole; (iii) anti -androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1,3 -dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECUN®, LEUVECUN®, and VAXID®; PROLEUKIN®, rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0039] Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab; cetuximab; panitumumab, rituximab, pertuzumab, trastuzumab, tositumomab, and the antibody drug conjugate, gemtuzumab ozogamicin. Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti-interleukin- 12 (ABT- 874/J695) which is a recombinant exclusively human-sequence, full-length IgGl X antibody genetically modified to recognize interleukin- 12 p40 protein.

[0040] Chemotherapeutic agent also includes other “EGFR inhibitors, ” which refers to compounds that bind to or otherwise interact directly with EGFR or its mutant forms and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist. ” Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (US4,943, 533) and variants thereof, such as chimerized 225 and reshaped human 225 (H225); IMC-11F8, a fully human, EGFR-targeted antibody; antibodies that bind type II mutant EGFR (US5,212,290); humanized and chimeric antibodies that bind EGFR as described in US5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (WO98/50433); EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A: 636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF -alpha for EGFR binding; human EGFR antibody, HuMax-EGFR; fully human antibodies known as El.l, E2.4, E2.5, E6.2, E6.4, E2. ll, E6. 3 and E7.6. 3 and described in US 6,235,883; MDX-447; and mAb 806 or humanized mAh 806 (Johns el al., J. Biol. Chem. 279(29):30375-30384 (2004)). The anti-EGFR antibody is conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2). EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: WO98/14451, W098/50038, W099/09016, and WO99/24037. Particular small molecule EGFR antagonists include OSI-774 (CP- 358774, erlotinib); PD 183805 (CI 1033, 2-propenamide,N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4- morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride); ZD1839, gefitinib, 4-(3 ’-Chi oro-4’ - fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline); ZM 105180 ((6-amino-4-(3- methylphenyl-amino)-quinazohne); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(l-methyl-piperidin- 4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine); PKI-166 ((R)-4-[4-[(l-phenylethyl)amino]-lH- pyrrolo[2,3-d]pyrimidin-6-yl] -phenol); (R)-6-(4-hydroxyphenyl)-4-[(l-phenylethyl)amino]-7H- pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)armno]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2- butenamide) (Wyeth); AG1478; AG1571 (SU 5271); dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (GSK572016 or N-[3-chloro-4-[(3 fluorophenyljmethoxy] phenyl] - 6 [5 [[[2methylsulfonyl)ethyl] amino] methyl] -2-furanyl] -4-quinazolinamine).

[0041] Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase; dual -HER inhibitors such as EKB-569 which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166; pan-HER inhibitors such as canertinib (CI-1033); Raf-1 inhibitors such as antisense agent ISIS-5132 which inhibit Raf-1 signaling; non-HER targeted TK inhibitors such as imatinib mesylate; multi -targeted tyrosine kinase inhibitors such as sunitinib; VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584); MAPK extracellular regulated kinase I inhibitor CI-1040; quinazolines, such as PD 153035, 4-(3-chloroanilino) quinazoline; pyridopyrimi dines; pyrimidopyrimi dines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3- d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805; antisense molecules (e.g. those that bind to HER- encoding nucleic acid); quinoxalines (US Patent No. 5,804,396); tryphostins (US Patent No. 5,804,396); ZD6474; PTK-787; pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521); imatinib mesylate; PKI 166; GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569; Semaxinib; ZD6474; PTK-787; INC-1C11, rapamycin; or as described in any of the following patent publications: US Patent No. 5,804,396; WO 1999/09016; WO 1998/43960; WO 1997/38983; WO 1999/06378; WO 1999/06396; WO 1996/30347; WO 1996/33978; WO 1996/3397, and WO 1996/33980.

[0042] Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa- 2a, interferon alfa- 2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

[0043] Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone- 17-butyrate, hydrocortisone- 17- valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, cl obetasone- 17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); anti -rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D- penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (INF a) blockers such as etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, Interleukin 1 (IL-1) blockers such as anakinra, T cell costimulation blockers such as abatacept, Interleukin 6 (IL-6) blockers such as tocilizumab; Interleukin 13 (IL- 13) blockers such as lebrikizumab; Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-Ml prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTal/p2 blockers such as Anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g., At²¹¹, 1¹³¹, 1¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu); miscellaneous investigational agents such as thioplatin, PS-341, phenylbutyrate, ET-18- OCH3, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol); beta- lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur; bexarotene; bisphosphonates such as clodronate, etidronate, NE-58095, zoledronic acid/zoledronate, alendronate, pamidronate, tiludronate, or risedronate; and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium; pixantrone; farnesyltransferase inhibitors such as lonafarnib (SCH 6636); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin combined with 5-FU and leucovorin.

[0044] Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etori coxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter’s syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.

[0045] In certain embodiments, chemotherapeutic agents include, but are not limited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, interferons, platinum derivatives, taxanes (e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g., etoposide), cisplatin, an mTOR inhibitor (e.g., a rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5 -fluorouracil, campthothecin, cisplatin, metronidazole, and imatinib mesylate, among others. In other embodiments, a compound disclosed herein is administered in combination with a biologic agent, such as bevacizumab or panitumumab.

[0046] In certain embodiments, compounds disclosed herein, or a pharmaceutically acceptable composition thereof, are administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, BCG live, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, camptothecin, carboplatin, carmustine, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin hydrochloride, dromostanolone propionate, epirubicin, epoetin alfa, elotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, 6- MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate, or zoledronic acid.

[0047] In some embodiments, a patient having an EGFR mutation (a cancer having an EGFR mutation) is selected.

[0048] In some embodiments, the cancer does not have a KRAS mutation (wtKRAS). In some embodiments, the cancer does not have aNRAS mutation (wtNRAS). In some embodiments, the cancer does not have a BRAF mutation (wtBRAF). In some embodiments, the cancer is wtKRAS/wtNRAS/wtBRAF. In some embodiments, the cancer does not have a mutation in KRAS, NRAS or BRAF.

[0049] In some embodiments, the cancer has one or more acquired mutations. In some embodiments, the acquired mutation results from a first-line treatment. In some embodiments, the first-line treatment is an EGFR inhibitor.

[0050] In some embodiments, the acquired mutation is an acquired EGFR mutation. In some embodiments, the acquired EGFR mutation is C797X. In some embodiments, the acquired EGFR mutation is L718Q. In some embodiments, the acquired EGFR mutation is EGFR amplification. In some embodiments, the acquired EGFR mutation is G724S. In some embodiments, the acquired mutation is S768I.

[0051] In some embodiments, the acquired mutation is an acquired amplification mutation. In some embodiments, the acquired mutation is a MET gene amplification. In some embodiments, the acquired mutation is HER2 gene amplification.

[0052] In some embodiments, the acquired mutation is an acquired oncogenic fusion. In some embodiments, the acquired oncogenic fusion is SPTBN1-ALK. In some embodiments, the acquired oncogenic fusion is RET fusion. In some embodiments, the acquired oncogenic fusion is BRAF fusion. [0053] In some embodiments, the acquired mutation is an acquired MAPK-PI3K mutation. In some embodiments, the acquired MAPK-PI3K mutation is BRAF-V600E. In some embodiments, the acquired MAPK-PI3K mutation is PI3KCA. In some embodiments, the acquired MAPK-PI3K mutation is KRAS. In some embodiments, the acquired MAPK-PI3K mutation is HER2.

[0054] In some embodiments, the subject is a subpopulation based on the transcription factor brachyury as a diagnostic marker. See Barresi et al. , “Brachyury : A Diagnostic Marker for the Differential Diagnosis of Chordoma and Hemangioblastoma versus Neoplastic Histological Mimickers,” Disease Markers 2014. [0055] In some embodiments, the subject is a human. In some embodiments, the subject is a mammal other than a human, such as a primate, a rodent, a dog, a cat, or other small animal.

Pharmaceutical Compositions

[0056] In general, the compounds of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.

Therapeutically effective amounts of Compound 1, or a pharmaceutically acceptable salt thereof, may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. A suitable dosage level may be from about 0. 1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0. 1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound of this disclosure, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.

[0057] In general, compounds of this disclosure will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

[0058] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance.

[0059] The compositions are comprised of in general, a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this disclosure. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[0060] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0061] Compound 1 may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g. , in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [0062] The level of the Compound 1 in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.

[0063] Pharmaceutically acceptable salts include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present embodiments contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present embodiments contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al. , “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19), which is incorporated herein by reference in its entirety for all of its teachings, including without limitation all methods, compounds, compositions, data, and the like, for use with any of the embodiments and disclosure herein. Certain specific compounds of the present embodiments contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0064] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent Compound In the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0065] Certain compounds of the present embodiments can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present embodiments. Certain compounds of the present embodiments may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present embodiments and are intended to be within the scope of the present embodiments.

[0066] Certain compounds of the present embodiments possess asymmetric carbon atoms (optical centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present embodiments. The compounds of the present embodiments do not include those which are known in art to be too unstable to synthesize and/or isolate. The present embodiments is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0067] Unless otherwise stated, the compounds of the present embodiments may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds of the present embodiments may be labeled with radioactive or stable isotopes, such as for example deuterium (²H), tritium (³H), iodine- 125 (¹²⁵I), fluorine-18 (¹⁸F), nitrogen-15 (¹⁵N), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), carbon-13 (¹³C), or carbon-14 (¹⁴C). All isotopic variations of the compounds of the present embodiments, whether radioactive or not, are encompassed within the scope of the present embodiments.

[0068] In some embodiments, there are provided pharmaceutical compositions comprising Compound 1 and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions are configured as an oral tablet preparation.

[0069] The compounds of the present embodiments can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. The compounds of the present embodiments can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present embodiments can be administered transdermally. Compound 1 disclosed herein can also be administered by in intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders, and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35: 1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75: 107-111, 1995), which is incorporated herein by reference in its entirety for all of its teachings, including without limitation all methods, compounds, compositions, data, and the like, for use with any of the embodiments and disclosure herein. Accordingly, the present embodiments also provides pharmaceutical compositions including one or more pharmaceutically acceptable carriers and/or excipients and either Compound 1, or a pharmaceutically acceptable salt of Compound 1.

[0070] For preparing pharmaceutical compositions from the compounds of the present embodiments, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, surfactants, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington’s Pharmaceutical Sciences, Maack Publishing Co, Easton PA (“Remington’s”), which is incorporated herein by reference in its entirety for all of its teachings, including without limitation all methods, compounds, compositions, data, and the like, for use with any of the embodiments and disclosure herein.

[0071] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties and additional excipients as required in suitable proportions and compacted in the shape and size desired.

[0072] The powders, capsules and tablets preferably contain from 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other excipients, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0073] Suitable solid excipients are carbohydrate or protein fillers including, but not limited to sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl -cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate. [0074] Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i. e. , dosage). Pharmaceutical preparations disclosed herein can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain Compound 1 mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, Compound 1 may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.

[0075] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0076] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g. , heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame, or saccharin. Formulations can be adjusted for osmolarity.

[0077] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0078] Oil suspensions can be formulated by suspending Compound 1 in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol, or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997, which is incorporated herein by reference in its entirety for all of its teachings, including without limitation all methods, compounds, compositions, data, and the like, for use with any of the embodiments and disclosure herein. The pharmaceutical formulations disclosed herein can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally -occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

[0079] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. [0080] The quantity of active component in a unit dose preparation may be varied or adjusted from 0. 1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

Dosing

[0081] The dosage regimen for the compounds of the present application will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A clinical practitioner can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the disease or disorder.

[0082] By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0. 1 to about 20 mg/kg/day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of between about 10 mg/day and about 200 mg/day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105 mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150 mg/day, 155 mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175 mg/day, 180 mg/day, 185 mg/day, 190 mg/day, 195 mg/day, or 200 mg/day. The dose is any value or subrange within the recited ranges.

[0083] Depending on the patient’s condition and the intended therapeutic effect, the dosing frequency for the therapeutic agent may vary, for example, from once per day to six times per day. That is, the dosing frequency is QD, i.e., once per day, BID, i.e., twice per day; ITO, i.e., three times per day; QID, i.e., four times per day; five times per day, or six times per day. In another embodiment, dosing frequency is BIW, i.e., twice weekly, TIW, i.e., three times a week, or QIW, i.e. four times a week.

[0084] Depending on the patient’s condition and the intended therapeutic effect, the treatment cycle may have a period of time where no therapeutic agent is administered. As used herein, “interval administration” refers to administration of the therapeutic agent followed by void days or void weeks. For example, the treatment cycle is 3 weeks long which includes 2 weeks of dosing of the therapeutic agent(s) followed by 1 week where no therapeutic agent is administered. In some embodiments, the treatment cycle is 4 weeks long which includes 3 weeks of dosing followed by 1 week where no therapeutic agent is administered.

[0085] The term “treatment cycle” as used herein, means a pre- determined period of time for administering Compound 1, or a pharmaceutically acceptable salt thereof,. In some embodiments, the treatment cycle is a three- week cycle, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered for the first two weeks of the three-week cycle. In some embodiments, the treatment cycle is a four- week cycle wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered for the first three weeks of the four-week cycle. Typically, the patient is examined at the end of each treatment cycle to evaluate the effect of the therapy. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for multiple cycles (three- or four-week cycles). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one cycle (three- or four-week cycle). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least two cycles (three- or four-week cycles). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least three cycles (three- or four-week cycles). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least four cycles (three- or four-week cycles). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least five cycles (three- or four-week cycles). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least six cycles (three- or four-week cycles).

[0086] In one embodiment, each of the treatment cycle has about 3 or more days. In another embodiment, each of the treatment cycle has from about 3 days to about 60 days. In another embodiment, each of the treatment cycle has from about 5 days to about 50 days. In another embodiment, each of the treatment cycle has from about 7 days to about 28 days. In another embodiment, each of the treatment cycle has 28 days. In one embodiment, the treatment cycle has about 29 days. In another embodiment, the treatment cycle has about 30 days. In another embodiment, the treatment cycle has about 31 days. In another embodiment, the treatment cycle has about a month-long treatment cycle. In another embodiment, the treatment cycle is any length of time from 3 weeks to 8 weeks. In another embodiment, the treatment cycle is any length of time from 3 weeks to 6 weeks. In yet another embodiment, the treatment cycle is 3 weeks. In another embodiment, the treatment cycle is one month. In another embodiment, the treatment cycle is 4 weeks. In another embodiment, the treatment cycle is 5 weeks. In another embodiment, the treatment cycle is 6 weeks. In another embodiment, the treatment cycle is 7 weeks. In another embodiment, the treatment cycle is 8 weeks. The duration of the treatment cycle may include any value or subrange within the recited ranges, including endpoints.

[0087] In some embodiments, the dosing regimen for Compound 1, or a pharmaceutically acceptable salt thereof, is once daily over a continuous 28-day cycle. In some embodiments, the once daily dosing regimen for Compound 1, or a pharmaceutically acceptable salt thereof, is, but is not limited to, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, or 65 mg/day. Compound 1, or a pharmaceutically acceptable salt thereof, is administered anywhere from 20 mg to 60 mg once a day. The dose is any value or subrange within the recited ranges.

[0088] In some embodiments, the dosing regimen for Compound 1, or a pharmaceutically acceptable salt thereof, is twice daily over a continuous 28-day cycle. In some embodiments, the twice daily dosing regimen for Compound 1, or a pharmaceutically acceptable salt thereof, is, but is not limited to, 10 mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105 mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150 mg/day, 155 mg/day, or 160 mg/day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered anywhere from 5 mg to 80 mg twice a day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered anywhere from 10 mg/day to 160 mg/day. The dose is any value or subrange within the recited ranges.

[0089] In some embodiments, the dosing regimen for Compound 1, or a pharmaceutically acceptable salt thereof, is once daily, anywhere from 10 mg to 140 mg per day for two weeks, followed by a one week break over a period of 3 weeks. In some embodiments, the dosing regimen for Compound 1, or a pharmaceutically acceptable salt thereof, is once daily, anywhere from 20 mg to 80 mg per day for two weeks, followed by a one week break over a period of 3 weeks.

[0090] In some embodiments, the dosing regimen for Compound 1, or a pharmaceutically acceptable salt thereof, is once daily, anywhere from 20 mg to 120 mg per day for two weeks, followed by a one week break in at least one three- week cycle. In some embodiments, the dosing regimen for Compound 1, or a pharmaceutically acceptable salt thereof, is once daily, anywhere from 20 mg to 60 mg per day for two weeks, followed by a one week break in at least one three-week cycle. In some embodiments, the treatment is administered in at least two cycles for a total of at least 6 weeks.

[0091] Disclosed herein is a method of treating chordoma in a subject, the method comprising administering:

(a) a therapeutically effective amount of Compound 1 :

(b) EGFR inhibitor; wherein compound 1, or pharmaceutically acceptable salt thereof, is administered in an amount of 20 mg to 120 mg once a day for two weeks, followed by a one week break in at least one three-week cycle.

[0092] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 20 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[0093] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 25 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[0094] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 30 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[0095] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 35 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[0096] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 40 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[0097] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 45 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[0098] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 50 mg once daily for two weeks, followed by a one week break in at least one three-week cycle. [0099] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 55 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[00100] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 60 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[00101] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 65 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[00102] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 70 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[00103] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 75 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[00104] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 80 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[00105] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 85 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[00106] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 90 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[00107] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 95 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[00108] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 100 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[00109] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 105 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[00110] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 110 mg once daily for two weeks, followed by a one week break in at least one three-week cycle. [00111] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 115 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[00112] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 120 mg once daily for two weeks, followed by a one week break in at least one three-week cycle.

[00113] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is twice daily, anywhere from 10 mg to 80 mg twice a day for two weeks, followed by a one week in at least one three-week cycle. In some embodiments, the treatment is administered in at least two cycles for a total of at least six weeks.

[00114] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is twice daily, anywhere from 40 mg to 120 mg twice a day for two weeks, followed by a one week break in at least one three-week cycle.

[00115] Disclosed herein is a method of treating chordoma in a subject, the method comprising administering:

(a) a therapeutically effective amount of Compound 1 : ;or a pharmaceutically acceptable salt thereof; and

(b) EGFR inhibitor; wherein compound 1, or pharmaceutically acceptable salt thereof, is administered in an amount of 20 mg to 120 mg once a day for three weeks, followed by a one week break in at least one four-week cycle.

[00116] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 20 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00117] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 25 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00118] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 30 mg once daily for three weeks, followed by a one week break in at least one four-week cycle. [00119] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 35 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00120] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 40 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00121] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 45 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00122] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 50 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00123] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 55 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00124] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 60 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00125] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 65 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00126] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 70 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00127] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 75 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00128] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 80 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00129] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 85 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00130] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 90 mg once daily for three weeks, followed by a one week break in at least one four-week cycle. [00131] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 95 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00132] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 100 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00133] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 105 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00134] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 110 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00135] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 115 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00136] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is 120 mg once daily for three weeks, followed by a one week break in at least one four-week cycle.

[00137] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is twice daily, anywhere from 10 mg to 80 mg twice a day for three weeks, followed by a one week break in at least one four-week cycle. In some embodiments, the treatment is administered in two cycles for a total of eight weeks.

[00138] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is twice daily, anywhere from 40 mg to 120 mg twice a day for three weeks, followed by a one week break in at least one four-week cycle.

[00139] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is twice daily, anywhere from 40 mg to 80 mg twice a day for three weeks, followed by a one week break in at least one four-week cycle.

[00140] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is twice daily on days 1 and 2, for four weeks In some embodiments, the dosing amount for Compound 1, or pharmaceutically acceptable salt thereof, is, but is not limited to, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 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, or 160 mg per day. In some embodiments, the dosing amount for Compound 1, or pharmaceutically acceptable salt thereof, is twice daily, anywhere from 40 mg to 120 mg on days 1 and 2. In some embodiments, the dosing amount for Compound 1, or pharmaceutically acceptable salt thereof, is twice daily, anywhere from 40 mg to 80 mg on days 1 and 2. [00141] In some embodiments, the dosing regimen for Compound 1, or pharmaceutically acceptable salt thereof, is once daily on days 1, 2, and 3, for four weeks. In some embodiments, the dosing amount for Compound 1, or pharmaceutically acceptable salt thereof, is, but is not limited to, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 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, or 160 mg per day.

[00142] In some embodiments, the dosing amount for Compound 1, or pharmaceutically acceptable salt thereof, is once daily, anywhere from 80 mg to 200 mg on days 1, 2, and 3. In some embodiments, the dosing amount for Compound 1, or pharmaceutically acceptable salt thereof, is once daily, anywhere from 80 mg to 120 mg on days 1, 2, and 3.

[00143] When Compound 1 is administered multiple times a week, the dose is administered on any day or combination of days within the week. For example, administration three times per week may include administration on days 1, 3, and 5; days 1, 2, and 3; 1, 3, and 5; and so on. Administration two days per week may include administration on days 1 and 2; days 1 and 3; days 1 and 4; days 1 and 5; days 1 and 6; days 1 and 7; and so on.

[00144] Is some embodiments, the EGFR inhibitor is administered from 100 - 500 mg/m² by intravenous infusion. It will be appreciated that each of the recited ranges above can include any subrange or sub-point therein, inclusive of endpoints. A common dose range for adult humans is generally from 400 mg/m² for the initial infusion to 250 mg/m²/weekly infusion. Sub-ranges include 500 mg/m²/bi weekly and 500 mg/m²/triweekly infusions. Sub-ranges include 250 mg/m²/weekly, 250 mg/m²/bi weekly and 250 mg/m²/triweekly infusions. Sub-ranges include 200 mg/m²/weekly, 200 mg/m²/bi weekly and 200 mg/m²/triweekly infusions. Sub-ranges include 150 mg/m²/weekly, 150 mg/m²/bi weekly and 150 mg/m²/triweekly infusions. Sub-ranges include 100 mg/m²/weekly, 100 mg/m²/bi weekly and 100 mg/m²/triweekly infusions. Sub-ranges include 500 mg/m²/120 minutes, 400 mg/m²/120 minutes, 250 mg/m²/60 minutes, 250 mg/m²/120 minutes, 200 mg/m²/60 minutes, 200 mg/m²/120 minutes, 150 mg/m²/60 minutes, 150 mg/m²/120 minutes, 100 mg/m²/60 minutes, or 100 mg/m²/ 120 minutes.

[00145] Is some embodiments, the EGFR inhibitor is administered orally at a dose of 10 mg to 1000 mg once daily. Is some embodiments, the EGFR inhibitor is administered orally at a dose of 10 mg to 500 mg once daily. Is some embodiments, the EGFR inhibitor is administered orally at a dose of 10 mg to 100 mg once daily. Is some embodiments, the EGFR inhibitor is administered orally at a dose of 10 mg once daily. Is some embodiments, the EGFR inhibitor is administered orally at a dose of 20 mg once daily. Is some embodiments, the EGFR inhibitor is administered orally at a dose of 30 mg once daily. Is some embodiments, the EGFR inhibitor is administered orally at a dose of 40 mg once daily. Is some embodiments, the EGFR inhibitor is administered orally at a dose of 50 mg once daily. Is some embodiments, the EGFR inhibitor is administered orally at a dose of 60 mg once daily. Is some embodiments, the EGFR inhibitor is administered orally at a dose of 70 mg once daily. Is some embodiments, the EGFR inhibitor is administered orally at a dose of 80 mg once daily. Is some embodiments, the EGFR inhibitor is administered orally at a dose of 90 mg once daily. Is some embodiments, the EGFR inhibitor is administered orally at a dose of 100 mg once daily.

Kits and Products

[00146] Some embodiments relate to kits and products that include the Compound 1 and/or at least on EGFR inhibitor. For example, the kit or product can include a package or container with Compound 1. Such kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the Compound 1 in combination with an EGFR inhibitor that is separately provided. The kits can be used in the methods of treating cancer as described herein. [00147] In some aspects, the kits or products can include both a Compound 1 and at least one EGFR inhibitor. Such kits can include one or more containers or packages, which include one or both combination drugs together in a single container and/or package, or in separate packages/containers. In some instances, the two drugs are separately wrapped, but included in a single package, container, or box. Such kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the Compound 1 in combination with an EGFR inhibitor. The kits can be used in the methods of treating chordoma as described herein.

EXAMPLES

Example 1: Effect of Compound 1 monotherapy and combination therapy on chordoma cell growth [00148] Chordoma cell lines (JHC7, UMCHOR1, UCH1 and UCH2) were incubated with vehicle or the indicated concentrations of drug(s) in a clonogenic assay for 14 days with a media/drug change at 7 days. The cells were fixed and stained with crystal violet after 14 days of incubation. The amount of staining was quantitated following dye extraction and measurement of absorbance at 560 nM.

Results: Sensitivity of chordoma cell proliferation to Compound 1 and cetuximab

[00149] Compound 1 showed monotherapy activity in 4 out of 4 chordoma cell lines (JHC7, UMCHOR1, UCH1 and UCH2) in clonogenic assays (FIG. 1A) and Compound 1 in combination with cetuximab showed clear benefit relative to each single agent alone in 2 out of 4 chordoma cell lines (FIG. IB). Compound 1 monotherapy achieved a maximum inhibition of approximately 80% and 95% in JHC7 and UCH1 cells, respectively, at the lowest tested concentration of 120 nM. In UMCHOR1 cells and UCH2 cells, dose-dependent activity of Compound 1 monotherapy was observed, with a maximum inhibition of approximately 70% observed in both cell lines at the highest concentration tested (10 pM). The combination of Compound 1 with cetuximab showed combination benefit by inhibiting cellular proliferation by 78% and 82% at 25 and 50 nM in JHC7 cells and by 63% and 68% at 25 and 50 nM in UCH2 cells respectively, while cetuximab alone exhibited approximately 38% inhibition and Compound 1 alone at 25 nM and 50 nM exhibited approximately 46% and 60% inhibition, respectively in both cell lines. UMCHOR1 cells were similarly sensitive to Compound 1 as in JHC7 and UCH2 cells but more sensitive to cextuximab alone, and only modest combination benefit was observed. Combination benefit in UCH1 cells was difficult to assess due to the sensitivity of the cells to either Compound 1 or cetuximab alone. Compound 1 was also assessed in combination with afatinib (FIG. 1C). JHC7, UMCH0R1, and UCH1 cells were highly sensitive to afatinib alone at the concentration tested and combination benefit was difficult to assess. In contrast, the combination of Compound 1 with afatinib showed benefit in UCH2 cells by inhibiting cellular proliferation by 62% and 71% at 25 and 50 nM respectively, while afatinib alone exhibited approximately 43% inhibition and Compound 1 alone at 25 nM and 50 nM exhibited approximately 45% and 57% inhibition, respectively.

[00150] The data is summarized in table 1, 2, and 3.

Table 1

Table 2

Table 3 [00151] Although the foregoing embodiments have been described in some detail by way of illustration and Examples for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method of treating chordoma in a subject; the method comprising administering to the subject

(a) compound pharmaceutically acceptable salt thereof; and

(b) an EGFR inhibitor.

2. The method of claim 1, wherein the EGFR inhibitor is afatinib, amivantamab, cetuximab, dacomitinib, erlotinib, gefitinib, lapatinib, lazertinib, lifirafenib, mirzotamab clezutoclax, mobocertinib, nazartinib, necitumumab, neratinib, nimotuzumab, osimertinib, panitumumab, or vandetanib.

3. The method of claim 1, wherein the EGFR inhibitor is cetuximab or afatinib.

4. A method of treating chordoma in a subject; the method comprising administering to the subject

(a) compound pharmaceutically acceptable salt thereof; and (b) cetuximab.

5. A method of treating chordoma in a subject; the method comprising administering to the subject

(a) compound pharmaceutically acceptable salt thereof; and

(b) afatinib.

6. The method of any one of claims 1-5, wherein the subject is a human.

7. The method of any one of claims 1-6, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered in an amount of 20 mg to 120 mg once a day for two weeks, followed by a one week break in at least one three-week cycle.

8. The method of any one of claims 1-6, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered in an amount of 20 mg to 120 mg once a day for three weeks, followed by a one week break in at least one four-week cycle.

9. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 40 mg to 120 mg.

10. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 40 mg to 100 mg.

11. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 40 mg to 80 mg.

12. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 40 mg to 60 mg.

13. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 20 mg to 100 mg.

14. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 20 mg to 80 mg.

15. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 20 mg to 60 mg.

16. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 20 mg to 40 mg.

17. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 20 mg.

18. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 25 mg.

19. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 30 mg.

20. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 35 mg.

21. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 40 mg.

22. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 45 mg.

23. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 50 mg.

24. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 55 mg.

25. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 60 mg.

26. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 65 mg.

27. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 70 mg.

28. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 75 mg.

29. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 80 mg.

30. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 85 mg.

31. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 90 mg.

32. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 95 mg.

33. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 100 mg.

34. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 105 mg.

35. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 110 mg.

36. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 115 mg.

37. The method of any one of claims 1-8, wherein compound 1, or pharmaceutically acceptable salt thereof, is administered once a day in an amount of 120 mg.

38. The method of any one of claims 1-37, wherein compound 1, or pharmaceutically acceptable salt thereof is administered for at least two three- or four-week cycles.

39. The method of any one of claims 1-37, wherein compound 1, or pharmaceutically acceptable salt thereof is administered for at least three three- or four-week cycles.

40. The method of any one of claims 1-37, wherein compound 1, or pharmaceutically acceptable salt thereof is administered for at least four three- or four-week cycles.

41. The method of any one of claims 1-37, wherein compound 1, or pharmaceutically acceptable salt thereof is administered for at least five three- or four-week cycles.

42. The method of any one of claims 1-37, wherein compound 1, or pharmaceutically acceptable salt thereof is administered for at least six three- or four-week cycles.