Wee1 inhibitor combination therapy dosing regimen

Abstract

Disclosed herein is use of a combination of an effective amount of Compound (A) (e.g., azenosertib) and an effective amount of Compound (B) (e.g., gemcitabine), for treating osteosarcoma.

Description

WEE1 INHIBITOR COMBINATION THERAPY DOSING REGIMENINCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Application Nos. 63 / 637,537, filed April 23, 2024 and 63 / 654,860, filed May 31, 2024, each of which is incorporated by reference in their entireties.Field

[0002] The present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are combination therapies, and methods of treating diseases and / or conditions with a combination therapy described herein.Description

[0003] Osteosarcoma is one of the most common primary bone malignancies and its therapeutic approach includes cytotoxic chemotherapy and surgery. Relapsed osteosarcoma occurs in 30-50% of patients with initial localized disease and 80% of patients presenting with metastatic disease. Patients with relapsed and / or refractory osteosarcoma have poor outcomes with a historical 16-week event-free survival (EFS) of -12% after treatment with salvage therapy. Historic disease control rates with the combination of gemcitabine and docetaxel have been similarly poor (-22% to -43%). There exists an urgent unmet need for new and effective therapies for osteosarcoma, including, but not limited to, relapsed and / or refractory osteosarcoma.SUMMARY

[0004] Some embodiments described herein relate to the use of a combination of an effective amount of Compound (A) and an effective amount of Compound (B) for treatingan osteosarcoma in a subject. Compound (a pharmaceutically acceptable salt thereof. The effective amount of Compound (A) comprises about a daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, or an equivalent thereof in one or more dosing weeks. Compound (B) ispharmaceutically acceptable salt thereof. The effective amount of Compound (B) comprises at least one dose of about 400 mg / m2, about 425 mg / m2,450 mg / m2, about 475 mg / m2, about 500 mg / m2, about 525 mg / m2, about 550 mg / m2, about575 mg / m2, about 600 mg / m2, about 625 mg / m2, about 650 mg / m2, about 675 mg / m2, about700 mg / m2, about 725 mg / m2, about 750 mg / m2, about 775 mg / m2, about 800 mg / m2, about825 mg / m2, about 850 mg / m2, about 875 mg / m2, about 900 mg / m2, about 925 mg / m2, about950 mg / m2, about 975 mg / m2, about 1000 mg / m2, about 1025 mg / m2, about 1050 mg / m2, about 1075 mg / m2, about 1100 mg / m2, about 1125 mg / m2, about 1150 mg / m2, about 1175 mg / m2, about 1200 mg / m2, or an equivalent thereof, in the one or more dosing weeks.BRIEF DESCRIPTION OF THE DRAWINGS

[0005] FIG. 1 is a schematic diagram showing the design of the dose finding and dose escalation study described in Example 1 .

[0006] FIG. 2 is a chart showing the treatment schedule during the course of the study described in Example 1.

[0007] FIG. 3 is a flow chart showing the disposition of the 31 patients at the end of the treatment.

[0008] FIG. 4 is a Kaplan-Meier curve of the event- free survival rates of the study described in Example 1.

[0009] FIG. 5 is a spider plot illustrating the percent change from baseline in the sum of longest diameters for target lesions in the study described in Example 1.

[0010] FIG. 6 is a plot of point estimates of event-free survival (EFS) and progression-free survival (PFS) for the study described in Example 1 and historical osteosarcoma clinical studies.DETAILED DESCRIPTIONDefinitions

[0011] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0012] The term “pharmaceutically acceptable salt” refers to a salt of a compound, e.g., Compound (A) and Compound (B), that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutically acceptable salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid e.g. , hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutic lly acceptable salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p- toluensulfonic, trifluoroacetic, benzoic, salicylic, 2-oxopentanedioic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N-methyl-D- glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine,triethanolamine, ethylenediamine and salts with amino acids such as arginine and lysine. Those skilled in the art understand that when a salt is formed by protonation of a nitrogen- based group (for example, NH2), the nitrogen-based group can be associated with a positive charge (for example, NH2 can become NITA) and the positive charge can be balanced by a negatively charged counterion (such as CT).

[0013] It is understood that, in any compound described herein, e.g., Compound (A) and Compound (B), having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of ^-configuration or 5- configuration or a mixture thereof. Thus, the compounds provided herein, e.g., Compound (A) and Compound (B), may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.

[0014] It is to be understood that where compounds disclosed herein, e.g., Compound (A) and Compound (B), have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).

[0015] It is understood that the compounds described herein e.g., Compound (A) and Compound (B), can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0016] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts,solvates and hydrates of the compounds described herein, e.g., Compound (A) and Compound (B). In some embodiments, the compounds described herein, e.g., Compound (A) and Compound (B), exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein, e.g., Compound (A) and Compound (B), can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds, e.g., Compound (A) and Compound (B), and methods provided herein.

[0017] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

[0018] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean “including, without limitation,” “including but not limited to,” or the like; the term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term “having” should be interpreted as “having at least;” the term “includes” should be interpreted as “includes but is not limited to;” the term “example” is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof. In addition, the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least.” When used in the context of a compound, composition or device, the term “comprising” means that the compound, composition or device includes at least the recited features or components but may also include additional features or components.

[0019] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from thesingular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.Compounds

[0020] Some embodiments described herein relate to the use of a combination of an effective amount of Compound (A) and an effective amount of Compound (B) for treating an osteosarcoma in a subject. Compound(also known as azenosertib or ZN-c3), or a pharmaceutically acceptable salt thereof.Compound(2',2'-difluoro 2'deoxycytidine or dFdC;IUPAC name4-Amino-l-(2-deoxy-2,2-difhioro-P-D-erytAro-pentofuranosyl)pyrimidin-2(lH)-one; CASRegistry No. 95058-81-4; international nonproprietary name (INN) = gemcitabine), or a pharmaceutically acceptable salt thereof (e.g., gemcitabine hydrochloride). In one embodiment, Compound (B) is(gemcitabine hydrochloride). It should be noted that whenever the terms “Compound (A)” and “Compound(B)” are used throughout this disclosure, their respective pharmaceutically acceptable salts are expressly included.

[0021] Compound (B) is marketed under many brand names worldwide, including but not limited to: Abine, Accogem, Acytabin, Antoril, Axigem, Bendacitabin, Biogem, Boligem, Celzar, Citegin, Cytigem, Cytogem, Daplax, DBL, Demozar, Dercin, Emcitab, Enekamub, Eriogem, Fotinex, Gebina, Gemalata, Gembin, Gembine, Gembio, Gemcel, Gemcetin, Gemcibine, Gemcikal, Gemcipen, Gemcired, Gemcirena, Gemcit, Gemcitabin, Gemcitabina, Gemcitabine, Gemcitabinum, Gemcitan, Gemedac, Gemtlor, Gemful, Gemita, Gemko, Gemliquid, Gemmis, Gemnil, Gempower, Gemsol, Gemstad, Gemstada, Gemtabine, Gemtavis, Gemtaz, Gemtero, Gemtra, Gemtro, Gemvic, Gemxit, Gemzar, Gentabim, Genuten, Genvir, Geroam, Gestredos, Getanosan, Getmisi, Gezt, Gitrabin, Gramagen, Haxanit, Jemta, Kalbezar, Medigem, Meditabine, Nabigem, Nallian, Oncogem, Oncoril, Pamigeno, Ribozar, Santabin, Sitagem, Symtabin, Yu Jie, Ze Fei and Zefei. The scope of Compound (B), as used herein, encompasses all of these listed brand names and any other brand name not listed herein.

[0022] Another aspect of this disclosure relates to a method of treating an osteosarcoma in a subject comprising administering an effective amount of Compound (A) as defined above and an effective amount of Compound (B) as defined above to the subject. In one embodiment, Compound (B) is gemcitabine hydrochloride.

[0023] Yet another aspect of this disclosure relates to a combination of an effective amount of Compound (A) as defined above and an effective amount of Compound (B) as defined above for use in treating an osteosarcoma. The use includes administering to a subject suffering from an osteosarcoma a combination of an effective amount of Compound (A) as defined above and an effective amount of Compound (B) as defined above. In one embodiment, Compound (B) is gemcitabine hydrochloride.Effective Amounts (Dosages)

[0024] As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of osteosarcoma. Any alleviation of any undesired signs or symptoms of osteosarcoma, to any extent can be considered treatment and / or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.

[0025] The term “effective amount” is used to indicate an amount of an active compound or pharmaceutical agent, e.g., Compound (A) and Compound (B), that elicits the biological or medicinal response indicated. For example, an effective amount of compound, e.g., Compound (A) and Compound (B), salt or composition can be the amount needed to prevent, alleviate or ameliorate symptoms of the disease or condition, or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The effective amount of the compounds disclosed herein, e.g., Compound (A) and Compound (B), required as a dose will depend on the route of administration, the type of animal, including human, being treated and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. In one embodiment, an effective amount of Compound (A) refers to an amount, including, but not limited to, a minimum amount, of Compound (A) in combination with an effective amount of Compound (B) that is sufficient to result in >10% (e.g., >15%, >20%, >25%, >30%, >35%, >40%) of a statistically significant population of subjects (e.g., at least 30 subjects) achieving an at least 18-week event-free survival (EFS) per RECIST vl.l (i.e., time from treatment initiation until disease progression or death due to any cause). In one embodiment, an effective amount of Compound (B) refers to an amount, including, but not limited to, a minimum amount, of Compound (B) in combination with an effective amount of Compound (A) that is sufficient to result in >10% (e.g., >15%, >20%, >25%, >30%, >35%, >40%)) of a statistically significant population of subjects (e.g., at least 30 subjects) achieving an at least 18-week event-free survival (EFS) per RECIST vl.l.

[0026] In one embodiment, an effective amount of Compound (A) refers to an amount, including, but not limited to, a minimum amount, of Compound (A) in combination with an effective amount of Compound (B) that is sufficient to result in a statistically significant population of subjects (e.g., at least 30 subjects) achieving and maintaining a stable disease (SD) status for at least 16 weeks. In one embodiment, an effective amount of Compound (B) refers to an amount, including, but not limited to, a minimum amount, ofCompound (B) in combination with an effective amount of Compound (A) that is sufficient to result in a statistically significant population of subjects (e.g., at least 30 subjects) achieving and maintaining a stable disease (SD) status for at least 16 weeks.

[0027] In one embodiment, an effective amount of Compound (A) refers to an amount, including, but not limited to, a minimum amount, of Compound (A) in combination with an effective amount of Compound (B) that is sufficient to result in a statistically significant population of subjects (e.g., at least 30 subjects) achieving a disease control rate (DCR) of >40% (e.g., >45%, >50%, >55%, >60%, >65%). In one embodiment, an effective amount of Compound (B) refers to an amount, including, but not limited to, a minimum amount, of Compound (B) in combination with an effective amount of Compound (A) that is sufficient to result in a statistically significant population of subjects (e.g., at least 30 subjects) achieving a disease control rate (DCR) of >40% (e.g., >45%, >50%, >55%, >60%, >65%).

[0028] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, or an equivalent thereof in the one or more dosing weeks.

[0029] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, or an equivalent thereof in the one or more dosing weeks.

[0030] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, or an equivalent thereof in the one or more dosing weeks.

[0031] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount ofCompound (A) comprises a daily dose of about 50 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 75 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 100 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 125 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 150 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 175 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 200 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 225 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 250 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 275 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 300 mg or an equivalent thereof in the one ormore dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 325 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 350 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 375 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 400 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 425 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 450 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 475 mg or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 500 mg or an equivalent thereof in the one or more dosing weeks.

[0032] As used herein, the term “about” when referring to a dose of Compound (A) or Compound (B) or an effective amount of Compound (A) or Compound (B) mean the immediately ensuing amount ±10% of the amount. For example, “about 100 mg” means 90 mg to 110 mg.

[0033] As used herein, the term “an equivalent thereof’ refers to a compound, e.g. , Compound (A) and Compound (B), that contains the same active ingredient(s), e.g., salt orester of the therapeutic moiety, optionally, of the substantially same dosage form and route of administration, and substantially identical in strength and / or concentration. As used herein, the term “equivalent” includes “pharmaceutical alternatives” that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form, or the salt or ester, and “therapeutic equivalents” which are bioequivalent and have similar clinical effect and safety profile. An equivalent does not necessarily contain the same inactive ingredients; and may differ in characteristics such as shape, release mechanism, labeling, scoring and / or excipients, including colors, flavors, and / or preservatives. As used herein, the term “equivalent dose” refers to an effective amount as described above of the compound e.g.. Compound (A) in other salt or ester forms, or Compound (B) in other salt or ester forms.

[0034] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose of about 400 mg / m2, about 425 mg / m2, 450 mg / m2, about 475 mg / m2, about 500 mg / m2, about 525 mg / m2, about 550 mg / m2, about 575 mg / m2, about 600 mg / m2, about 625 mg / m2, about 650 mg / m2, about 675 mg / m2, about 700 mg / m2, about 725 mg / m2, about 750 mg / m2, about 775 mg / m2, about 800 mg / m2, about 825 mg / m2, about 850 mg / m2, about 875 mg / m2, about 900 mg / m2, about 925 mg / m2, about 950 mg / m2, about 975 mg / m2, about 1000 mg / m2, about 1025 mg / m2, about 1050 mg / m2, about 1075 mg / m2, about 1100 mg / m2, about 1125 mg / m2, about 1150 mg / m2, about 1175 mg / m2, about 1200 mg / m2, or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises two doses of about 400 mg / m2, about 425 mg / m2, 450 mg / m2, about 475 mg / m2, about 500 mg / m2, about 525 mg / m2, about 550 mg / m2, about 575 mg / m2, about 600 mg / m2, about 625 mg / m2, about 650 mg / m2, about 675 mg / m2, about 700 mg / m2, about 725 mg / m2, about 750 mg / m2, about 775 mg / m2, about 800 mg / m2, about 825 mg / m2, about 850 mg / m2, about 875 mg / m2, about 900 mg / m2, about 925 mg / m2, about 950 mg / m2, about 975 mg / m2, about 1000 mg / m2, about 1025 mg / m2, about 1050 mg / m2, about 1075 mg / m2, about 1100 mg / m2, about 1125 mg / m2, about 1150 mg / m2, about 1175 mg / m2, about 1200 mg / m2, or an equivalent thereof in the one or more dosing weeks.

[0035] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose of about 400 mg / m2, about 425 mg / m2, 450 mg / m2, about 475 mg / m2, about 500 mg / m2, about 525 mg / m2, about 550 mg / m2, about 575 mg / m2, about 600 mg / m2, about 625 mg / m2, about 650 mg / m2, about 675 mg / m2, about 700 mg / m2, about 725 mg / m2, about 750 mg / m2, about 775 mg / m2, about 800 mg / m2, about 825 mg / m2, about 850 mg / m2, about 875 mg / m2, about 900 mg / m2, about 925 mg / m2, about 950 mg / m2, about 975 mg / m2, about 1000 mg / m2, or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises two doses of about 400 mg / m2, about 425 mg / m2, 450 mg / m2, about 475 mg / m2, about 500 mg / m2, about 525 mg / m2, about 550 mg / m2, about 575 mg / m2, about 600 mg / m2, about 625 mg / m2, about 650 mg / m2, about 675 mg / m2, about 700 mg / m2, about 725 mg / m2, about 750 mg / m2, about 775 mg / m2, about 800 mg / m2, about 825 mg / m2, about 850 mg / m2, about 875 mg / m2, about 900 mg / m2, about 925 mg / m2, about 950 mg / m2, about 975 mg / m2, about 1000 mg / m2, or an equivalent thereof in the one or more dosing weeks.

[0036] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose of about 500 mg / m2, about 525 mg / m2, about 550 mg / m2, about 575 mg / m2, about 600 mg / m2, about 625 mg / m2, about 650 mg / m2, about 675 mg / m2, about 700 mg / m2, about 725 mg / m2, about 750 mg / m2, about 775 mg / m2, about 800 mg / m2, 825 mg / m2, or an equivalent thereof in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises two doses of about 500 mg / m2, about 525 mg / m2, about 550 mg / m2, about 575 mg / m2, about 600 mg / m2, about 625 mg / m2, about 650 mg / m2, about 675 mg / m2, about 700 mg / m2, about 725 mg / m2, about 750 mg / m2, about 775 mg / m2, about 800 mg / m2, 825 mg / m2, or an equivalent thereof in the one or more dosing weeks.

[0037] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 500 mg / m2, or anequivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 525 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 550 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 575 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 600 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 625 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 650 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 675 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 700 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 725 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of acombination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 750 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 775 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 800 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 825 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 850 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 975 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 1000 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 1025 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 1050 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as describedherein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 1075 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 1100 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 1125 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 1150 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 1175 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 1200 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

[0038] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 200 mg, or an equivalent thereof, in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 1000 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

[0039] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 100 mg, or an equivalent thereof, in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g. , two doses) of about 800 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) fortreating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 150 mg, or an equivalent thereof, in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 800 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 200 mg, or an equivalent thereof, in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 800 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 250 mg, or an equivalent thereof, in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 800 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

[0040] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 100 mg, or an equivalent thereof, in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g. , two doses) of about 675 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 150 mg, or an equivalent thereof, in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 675 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 200 mg, or an equivalent thereof, in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 675 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 250mg, or an equivalent thereof, in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 675 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

[0041] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 100 mg, or an equivalent thereof, in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g. , two doses) of about 500 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 150 mg, or an equivalent thereof, in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 500 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 200 mg, or an equivalent thereof, in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 500 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 250 mg, or an equivalent thereof, in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 500 mg / m2, or an equivalent thereof, in the one or more dosing weeks.Dosing Schedule / Dosing Regimen

[0042] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) is provided on an intermittent dosing schedule, during which one or more dosing parameters, such as dosage amount and / or dosage interval are varied or changed. For example, an intermittent dosing phase may comprise a period of continuous administration (e.g., 6 days, 5 days, 4 days, 3 days, 2 days in a week) followed by a “rest” phase (e.g., 1 day, 2 days, 3 days, 4 days, 5 days in the same week) during which Compound (A) is notadministered or is administered at a reduced dosage amount and / or less frequently. A dosing regimen may further comprise one or more repeated cycles of intermittent dosing regimens. In one embodiment, the effective amount of Compound (A) is provided on an intermittent dosing schedule comprising 5 days with dosing and 2 days without dosing in each of the one or more dosing weeks. In one embodiment, the effective amount of Compound (A) is provided on an intermittent dosing schedule comprising 5 consecutive days with dosing and 2 consecutive days without dosing in each of the one or more dosing weeks. In one embodiment, the effective amount of Compound (A) is provided on an intermittent dosing schedule comprising 4 days with dosing and 3 days without dosing in each of the one or more dosing weeks. In one embodiment, the effective amount of Compound (A) is provided on an intermittent dosing schedule comprising 4 consecutive days with dosing and 3 consecutive days without dosing in each of the one or more dosing weeks. In one embodiment, the effective amount of Compound (B) is provided as a weekly dose.

[0043] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the daily dose of Compound (A) is administered to the subject once a day (QD). In alternative embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the daily dose of Compound (A) is administered to the subject twice a day (BID). The QD and BID dosing regimens may be varied from one dosing week to another.

[0044] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the first of the daily dose of Compound (A) is administered to the subject prior to the dose of Compound (B) in at least one of the one or more dosing weeks. In alternative embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the first of the daily dose of Compound (A) is administered to the subject subsequent to the dose of Compound (B) in at least one of the one or more dosing weeks. As long as there is at least a 15-minute gap between the administration of Compound (A) and the administration of Compound (B), the two compounds are not considered to have been administered concurrently or concomitantly. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the first of the daily dose of Compound (A) is administered to the subject prior to the weekly dose of Compound (B) in atleast one of the one or more dosing weeks. In alternative embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the first of the daily dose of Compound (A) is administered to the subject subsequent to the weekly dose of Compound (B) in at least one of the one or more dosing weeks. As long as there is at least a 15-minute gap between the administration of Compound (A) and the administration of Compound (B), the two compounds are not considered to have been administered concurrently or concomitantly.

[0045] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the daily dose of Compound (A) is the same in each of the one or more dosing weeks. In alternative embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the daily dose of Compound (A) is different in each of the one or more dosing weeks.

[0046] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the dose of Compound (B) is the same in each of the one or more dosing weeks. In alternative embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the dose of Compound (B) is different in each of the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the weekly dose of Compound (B) is the same in each of the one or more dosing weeks. In alternative embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the weekly dose of Compound (B) is different in each of the one or more dosing weeks.

[0047] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 200 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 1000 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

[0048] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount ofCompound (A) comprises a daily dose of about 100 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g. , two doses) of about 800 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 150 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 800 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In one embodiment of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 150 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks e.g., three dosing weeks or a 21-day treatment cycle) and the effective amount of Compound (B) comprises at least one dose (e.g., a first dose on Day 1 and a second dose on Day 8) of about 800 mg / m2, or an equivalent thereof, in the one or more dosing weeks (e.g., the three dosing weeks or the 21-day treatment cycle). In one embodiment of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 150 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks (e.g., four dosing weeks or a 28-day treatment cycle) and the effective amount of Compound (B) comprises at least one dose (e.g., a first dose on Day 1 and a second dose Day 15) of about 800 mg / m2, or an equivalent thereof, in the one or more dosing weeks (e.g., the four dosing weeks or the 28-day treatment cycle). In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 200 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 800 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In one embodiment of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 200 mg, or an equivalent thereof, on a 5days on / 2 days off intermittent dosing schedule in the one or more dosing weeks (e.g., three dosing weeks or a 21-day treatment cycle) and the effective amount of Compound (B) comprises at least one dose (e.g., a first dose on Day 1 and a second dose on Day 8) of about 800 mg / m2, or an equivalent thereof, in the one or more dosing weeks (e.g., three dosing weeks or the 21-day treatment cycle). In one embodiment of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 200 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks (e.g., four dosing weeks or a 28-day treatment cycle) and the effective amount of Compound (B) comprises at least one dose (e.g., a first dose on Day 1 and a second dose on Day 15) of about 800 mg / m2, or an equivalent thereof, in the one or more dosing weeks (e.g., the four dosing weeks or the 28-day treatment cycle). In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 250 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 800 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

[0049] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 100 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g. , two doses) of about 675 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 150 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 675 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 200 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosingschedule in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 675 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In one embodiment of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 200 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks (e.g., three dosing weeks or a 21-day treatment cycle) and the effective amount of Compound (B) comprises at least one dose (e.g., a first dose on Day 1 and a second dose on Day 8) of about 675 mg / m2, or an equivalent thereof, in the one or more dosing weeks (e.g., three dosing weeks or a 21-day treatment cycle). In one embodiment of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 200 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks (e.g., four dosing weeks or a 28-day treatment cycle) and the effective amount of Compound (B) comprises at least one dose (e.g., a first dose on Day 1 and a second dose on Day 15) of about 675 mg / m2, or an equivalent thereof, in the one or more dosing weeks (e.g., the four dosing weeks or the 28-day treatment cycle). In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 250 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 675 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

[0050] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 100 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g. , two doses) of about 500 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 150 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or moredosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 500 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 200 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one dose (e.g., two doses) of about 500 mg / m2, or an equivalent thereof, in the one or more dosing weeks. In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the effective amount of Compound (A) comprises a daily dose of about 250 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in the one or more dosing weeks and the effective amount of Compound (B) comprises at least one e.g., two doses) dose of about 500 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

[0051] In some embodiments, the one or more dosing weeks can be three dosing weeks or a 21 -day treatment cycle. In other embodiments, the one or more dosing weeks can be four dosing weeks or a 28-day treatment cycle.Prior Therapies, Treated Conditions, and Synergistic Combination

[0052] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the subject is an adult human that is of >18 years of age. In alternative embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the subject is a pediatric subject that is <18 years of age (such as a child (i.e., > 1 year and < 18 years old) or an infant (i.e., < 1 year old)).

[0053] In some embodiments of the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein, the subject has received at least one prior therapy, e.g., 1 to 9 prior therapies, 1 to 8 prior therapies, 1 to 7 prior therapies, 1 to 6 prior therapies, 1 to 5 prior therapies, 1 to 4 prior therapies, 1 to 3 prior therapies, 1 to 2 prior therapies, 1 prior therapy, 2 prior therapies, 3 prior therapies, etc. Standard osteosarcoma therapy includes surgical resection alone or in combination of multi-agent chemotherapy with agents (such as doxorubicin, cisplatin, high-dose methotrexate, ifosfamide, liposomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE), gemcitabine, docetaxel, topotecan,irinotecan, rebeccamycin, imatinib, oxaliplatin, ixabepilone, etc.). In one embodiment, the subject has received at least one prior therapy (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or more than 9 prior therapies) that comprises gemcitabine or Compound (B), alone or in combination with docetaxel.

[0054] Cancers are known to return, recur or relapse after treatment. Similarly, osteosarcomas that return after any number of prior therapies is referred to as “relapsed osteosarcoma” or “recurrent osteosarcoma.” Sometimes, the osteosarcoma can become resistant to a prior therapy, which can lead to recurrence of the osteosarcoma. Osteosarcomas that progress despite receiving treatment (e.g., a osteosarcoma progress or does not shrink) or progress less than 3 months after the last treatment dose are referred to as “refractory osteosarcoma.” The specific osteosarcoma subtype treated in the use of a combination of Compound (A) and Compound (B) for treating an osteosarcoma as described herein can be any one of the foregoing osteosarcoma subtype. In some embodiments, the use of a combination of Compound (A) and Compound (B) for treating a relapsed osteosarcoma or a recurrent osteosarcoma. In some embodiments, the use of a combination of Compound (A) and Compound (B) for treating a refractory osteosarcoma. In one embodiment, the osteosarcoma is metastatic osteosarcoma.

[0055] Using a combination of Compound (A) and Compound (B) at effective amounts of each compound as described herein can result in additive, synergistic or strongly synergistic effect. A combination of compounds described herein can result in an effect that is not antagonistic.

[0056] As used herein, the term “antagonistic” means that the activity of the combination of compounds is less compared to the sum of the activities of the compounds in combination when the activity of each compound is determined individually (i.e., as a single compound). As used herein, the term “synergistic effect” means that the activity of the combination of compounds is greater than the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually. As used herein, the term “additive effect” means that the activity of the combination of compounds is about equal to the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually.

[0057] A potential advantage of utilizing a combination as described herein may be a reduction in the effective amounts of Compound (A) and Compound (B) that arc effective in treating an osteosarcoma compared to when Compound (B) is administered as a monotherapy or as a combination therapy with docetaxel. For example, the amount of Compound (B) used in a combination with Compound (A) as described herein can be less compared to the amount of Compound (B) needed to achieve the same reduction in a disease marker (for example, tumor size) when Compound (B) is administered as a monotherapy or as a combination therapy with docetaxel. Another potential advantage of utilizing a combination as described herein is that the use of two or more compounds having different mechanisms of action can create a higher barrier to the development of resistance compared to when Compound (B) is administered as a monotherapy or as a combination therapy with docetaxel. Additional advantages of utilizing a combination as described herein may include little to no cross resistance between the compounds of a combination described herein; different routes for elimination of the compounds of a combination described herein; and / or little to no overlapping toxicities between the compounds of a combination described herein. Pharmaceutical Compositions

[0058] Compound (A) can be provided in a pharmaceutical composition. Likewise, Compound (B) can be provided in a pharmaceutical composition.

[0059] The term “pharmaceutical composition” refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components, such as diluents, carriers and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.

[0060] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0061] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.

[0062] As used herein, an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. For example, stabilizers such as anti-oxidants and metal-chelating agents are excipients. In an embodiment, the pharmaceutical composition comprises an anti-oxidant and / or a metalchelating agent. A “diluent” is a type of excipient.

[0063] In some embodiments, Compound (B) can be provided in a pharmaceutical composition that includes Compound (A). In other embodiments, Compound (B) can be administered in a pharmaceutical composition that is separate from a pharmaceutical composition that includes Compound (A).

[0064] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0065] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0066] Multiple techniques of administering a compound, salt and / or composition exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection,infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, Compound (A) can be provided to a subject by the same route of administration as Compound (B). In other embodiments, Compound (A) can be provided to a subject by a different route of administration as Compound (B). In some embodiments, Compound (A) can be administered orally. In some embodiments, Compound (B) can be administered intravenously

[0067] One may also administer the compound, salt and / or composition in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory disease or condition may be desirable.

[0068] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound and / or salt described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.Miscellaneous

[0069] The amount of compound, salt and / or composition required for use in treatment will vary not only with the particular compound or salt selected, but also with the route of administration, the nature and / or symptoms of the disease or condition being treated, the age and condition of the patient, and will be ultimately at the discretion of the attendantphysician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges described herein in order to effectively and / or aggressively treat particularly aggressive diseases or conditions.

[0070] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, the mammalian species treated, the particular' compounds employed and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies. For example, useful dosages of Compound (A) and Compound (B), can be determined by comparing their in vitro activity, and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as cisplatin and carboplatin.

[0071] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and / or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0072] It should be noted that the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response was not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the disease or condition to be treated and to the route of administration. The severity of the disease orcondition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0073] Compounds, salts and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and / or regime.EXAMPLES

[0074] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.Example 1: Clinical Study Design

[0075] The Phase 1 / 2 clinical study (ClinicalTrials.gov ID NCT04833582) is a single-arm and multicenter dose escalation and dose expansion study that assessed the combination of Compound (A) and Compound (B) for the treatment of adult and pediatric subjects with relapsed or refractory osteosarcoma and are of >12 years of age. The primary objective of this study is to evaluate and determine the safety, tolerability, and maximum tolerated dose (MTD) of Compound (A) in combination with Compound (B), with an additional objective of evaluating preliminary antitumor activity. The key eligibility criteria for patient enrollment include:• Age >12 years• Relapse or metastatic osteosarcoma, tumors progressed on or after standard of care (SOC)• Adequate hematological and organ function• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) < 2 (Lansky > 50%)• No prior treatment with a WEE1 inhibitor

[0076] As of November 2023, 31 patients had been treated in accordance with the dosing regimens as indicated in Table 1 and the dose escalation design as shown in FIG. 1. The study was designed to begin with an initial dose of Compound (A) 200 QD + Compound (B) 1000 mg / m2; dose levels were escalated based on the number of patients experiencing dose-limiting toxicities (DLTs) per 3+3 design parameters. Doses were escalated if no more than 1 / 6 of patients at a given dose level experienced DLTs, otherwise de-escalated until the MTD was reached.

[0077] The treatment schedule during the course of the study is shown in FIG. 2. The disposition of the 31 patients after the end of treatment is shown in FIG. 3. These patients had received a median of 3 (1 to 9) prior therapies; had a median age of 27 years (12 to 76 years), of which 21 (68%) of them were < 39 years of age (see Table 2).Table 1 . Clinical study dosages and dosing regimens for various cohorts.Table 2. Patient demographics and prior treatments.Percentage is based on 31 patients; 3 patients were missing ECOG PS.

[0078] As indicated in FIG. 3, all of the total 31 patients who were treated were evaluable for safety. At the end of the study, the maximum tolerated dose (MTD) was determined to be Compound (A) 150 mg daily on a 5:2 schedule (5 days on, 2 days off) and Compound (B) at 800 mg / m2. Table 3 shows that the combination of Compound (A) and Compound (B) was associated with a manageable safety profile and no new safety signals were identified. At tolerated doses, the most frequent grade >3 adverse events (>20%) included thrombocytopenia and lymphopenia (33% each); there were no grade 4 thrombocytopenia events or instances of febrile neutropenia. DLTs included thrombocytopenia and gastrointestinal toxicity. None of the patients treated at the MTD (N = 6) required dose reductions of Compound (A).Table 3. Reported adverse events of all cohorts and MTD.

[0079] As indicated in FIG. 3, 29 of the total 31 patients who were treated were evaluable for dose-limiting toxicity (DLT). Table 4 shows the breakdown of patients in various cohorts as defined in Table 1 with evaluable DLTs, with DLTs and a brief description of the DLTs. The pharmacokinetic data and dose modifications indicated in Table 5 suggest no evidence of drug-drug interactions (DDI) between Compound (A) and Compound (B), which is consistent with the observations seen in Compound (A) monotherapy and Compound (A) combination therapies with other chemotherapeutic agents.Table 4. Doses evaluated and dose-limiting toxicides (DLTs).Table 5. Dose modifications due to an adverse event (AE).

[0080] The 18-week event-free survival (EFS) (per RECIST vl.l, i.e., time from treatment initiation until disease progression or death due to any cause) was 39% (11 / 28) across all dose levels see FIG. 4). FIG. 5 shows the percent change from baseline in the sum of longest diameters for target lesions. FIG. 6 compares and contextualizes the EFS and progression-free survival (PFS) rates of this study and historical osteosarcoma clinical studies. At the MTDs, the combination of Compound (A) and Compound (B) provided a greater EFS than historical control cohorts of salvage therapy in patients with relapsed and / or refractory osteosarcoma, i.e., ~3-fold higher than the 16-week EFS rates with salvage therapies as described in Lagmay et al. (2016) J. Clin Oncol. 34(25):3031-3038.

[0081] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the present disclosure.

Claims

WHAT IS CLAIMED IS:

1. Use of a combination of an effective amount of Compound (A) and an effective amount of Compound (B) for treating an osteosarcoma in a subject, wherein:Compoundpharmaceutically acceptable salt thereof, and the effective amount of Compound (A) comprises about a daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, or an equivalent thereof, in one or more dosing weeks;Compound (pharmaceutically acceptable salt thereof, and the effective amount of Compound (B) comprises at least one dose of about 400 mg / m2, about 425 mg / m2, 450 mg / m2, about 475 mg / m2, about 500 mg / m2, about 525 mg / m2, about 550 mg / m2, about 575 mg / m2, about 600 mg / m2, about 625 mg / m2, about 650 mg / m2, about 675 mg / m2, about 700 mg / m2, about 725 mg / m2, about 750 mg / m2, about 775 mg / m2, about 800 mg / m2, about 825 mg / m2, about 850 mg / m2, about 875 mg / m2, about 900 mg / m2, about 925 mg / m2, about 950 mg / m2, about 975 mg / m2, about 1000 mg / m2, about 1025 mg / m2, about 1050 mg / m2, about 1075 mg / m2, about 1100 mg / m2, about 1125 mg / m2, about 1150 mg / m2, about 1175 mg / m2, about 1200 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

2. The use of claim 1, wherein the effective amount of Compound (A) comprises a daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, or an equivalent thereof, in the one or more dosing weeks.

3. The use of claim 1 or 2, wherein the effective amount of Compound (A) comprises about a daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, or an equivalent thereof, in the one or more dosing weeks.

4. The use of any one of claims 1 to 3, wherein the effective amount of Compound (A) comprises about a daily dose of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, or an equivalent thereof, in the one or more dosing weeks.

5. The use of any one of claims 1 to 4, wherein the effective amount of Compound (A) comprises about a daily dose of about 100 mg, or an equivalent thereof, in the one or more dosing weeks.

6. The use of any one of claims 1 to 4, wherein the effective amount of Compound (A) comprises about a daily dose of about 125 mg, or an equivalent thereof, in the one or more dosing weeks.

7. The use of any one of claims 1 to 4, wherein the effective amount of Compound (A) comprises about a daily dose of about 150 mg, or an equivalent thereof, in the one or more dosing weeks.

8. The use of any one of claims 1 to 4, wherein the effective amount of Compound (A) comprises about a daily dose of about 175 mg, or an equivalent thereof, in the one or more dosing weeks.

9. The use of any one of claims 1 to 4, wherein the effective amount of Compound (A) comprises about a daily dose of about 200 mg, or an equivalent thereof, in the one or more dosing weeks.

10. The use of any one of claims 1 to 9, wherein the effective amount ofCompound (B) comprises at least one dose of about 400 mg / m2, about 425 mg / m2, 450 mg / m2, about 475 mg / m2, about 500 mg / m2, about 525 mg / m2, about 550 mg / m2, about 575 mg / m2, about 600 mg / m2, about 625 mg / m2, about 650 mg / m2, about 675 mg / m2, about 700 mg / m2, about 725 mg / m2, about 750 mg / m2, about 775 mg / m2, about 800 mg / m2, about 825 mg / m2, about 850 mg / m , about 875 mg / m , about 900 mg / nr, about 925 mg / m , about 950 mg / m , about 975 mg / m2, about 1000 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

11. The use of any one of claims 1 to 10, wherein the effective amount of Compound (B) comprises at least one dose of about 500 mg / m2, about 525 mg / m2, about 550mg / m2, about 575 mg / m2, about 600 mg / m2, about 625 mg / m2, about 650 mg / m2, about 675 mg / m2, about 700 mg / m2, about 725 mg / m2, about 750 mg / m2, about 775 mg / m2, about 800 mg / m2, about 825 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

12. The use of any one of claims 1 to 11, wherein the effective amount of Compound (B) comprises at least one dose of about 500 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

13. The use of any one of claims 1 to 11, wherein the effective amount of Compound (B) comprises at least one dose of about 525 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

14. The use of any one of claims 1 to 11, wherein the effective amount of Compound (B) comprises at least one dose of about 550 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

15. The use of any one of claims 1 to 11, wherein the effective amount of Compound (B) comprises at least one dose of about 575 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

16. The use of any one of claims 1 to 11, wherein the effective amount of Compound (B) comprises at least one dose of about 600 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

17. The use of any one of claims 1 to 11, wherein the effective amount of Compound (B) comprises at least one dose of about 625 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

18. The use of any one of claims 1 to 11, wherein the effective amount of Compound (B) comprises at least one dose of about 650 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

19. The use of any one of claims 1 to 11, wherein the effective amount of Compound (B) comprises at least one dose of about 675 mg / m2, or an equivalent, thereof in the one or more dosing weeks.

20. The use of any one of claims 1 to 11, wherein the effective amount of Compound (B) comprises at least one dose of about 700 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

21. The use of any one of claims 1 to 11 , wherein the effective amount of Compound (B) comprises at least one dose of about 725 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

22. The use of any one of claims 1 to 11, wherein the effective amount of Compound (B) comprises at least one dose of about 750 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

23. The use of any one of claims 1 to 11, wherein the effective amount of Compound (B) comprises at least one dose of about 775 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

24. The use of any one of claims 1 to 11, wherein the effective amount of Compound (B) comprises at least one dose of about 800 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

25. The use of any one of claims 1 to 11, wherein the effective amount of Compound (B) comprises at least one dose of about 825 mg / m2, or an equivalent thereof, in the one or more dosing weeks.

26. The use of any one of claims 1 to 25, wherein the effective amount of Compound (A) is provided on an intermittent dosing schedule.

27. The use of any one of claims 1 to 26, wherein the effective amount of Compound (A) is provided on an intermittent dosing schedule comprising 5 days with dosing and 2 days without dosing in each of the one or more dosing weeks.

28. The use of any one of claims 1 to 27, wherein the daily dose of Compound (A) is administered to the subject once a day.

29. The use of any one of claims 1 to 27, wherein the daily dose of Compound (A) is administered to the subject twice a day.

30. The use of any one of claims 1 to 29, wherein the dose of Compound (B) is administered to the subject as a single dose.

31. The use of any one of claims 1 to 30, wherein the first of the daily dose of Compound (A) is administered to the subject prior to the dose of Compound (B) in at least one of the one or more dosing weeks.

32. The use of any one of claims 1 to 30, wherein the first of the daily dose of Compound (A) is administered to the subject subsequent to the dose of Compound (B) in at least one of the one or more dosing weeks.

33. The use of any one of claims 1 to 32, wherein the daily dose of Compound (A) is the same in each of the one or more dosing weeks.

34. The use of any one of claims 1 to 32, wherein the daily dose of Compound (A) is different in each of the one or more dosing weeks.

35. The use of any one of claims 1 to 34, wherein the dose of Compound (B) is the same in each of the one or more dosing weeks.

36. The use of any one of claims 1 to 34, wherein the dose of Compound (B) is different in each of the one or more dosing weeks.

37. The use of claim 1, wherein: the effective amount of Compound (A) comprises about a daily dose of about 150 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in three dosing weeks; and the effective amount of Compound (B) comprises a first dose of about 800 mg / m2, or an equivalent thereof, on Day 1 and a second dose of about 800 mg / m2, or an equivalent thereof, on Day 8 in the three dosing weeks.

38. The use of claim 1, wherein: the effective amount of Compound (A) comprises about a daily dose of about 200 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in three dosing weeks; and the effective amount of Compound (B) comprises a first dose of about 675 mg / m2, or an equivalent thereof, on Day 1 and a second dose of about 675 mg / m2, or an equivalent thereof, on Day 8 in the three dosing weeks.

39. The use of claim 1, wherein: the effective amount of Compound (A) comprises about a daily dose of about 200 mg, or an equivalent thereof, on a 5 days on / 2 days off intermittent dosing schedule in four dosing weeks; andthe effective amount of Compound (B) comprises a first dose of about 800 mg / m2, or an equivalent thereof, on Day 1 and a second dose of about 800 mg / m2, or an equivalent thereof, on Day 15 in the four dosing weeks.

40. The use of any one of claims 1 to 39, wherein the subject has received at least one prior therapy.

41. The use of claim 40, wherein the at least one prior therapy comprises Compound (B).

42. The use of any one of claims 1 to 41, wherein the subject is an adult human.

43. The use of any one of claims 1 to 41, wherein the subject is a pediatric subject.

44. The use of any one of claims 1 to 43, wherein the osteosarcoma is selected from a relapsed and a refractory osteosarcoma.

45. The use of any one of claims 1 to 44, wherein the osteosarcoma is a relapsed osteosarcoma.

46. The use of any one of claims 1 to 44, wherein the osteosarcoma is a refractory osteosarcoma.

47. The use of any one of claims 1 to 46, wherein the osteosarcoma is a metastatic osteosarcoma.

48. The use of any one of claims 1 to 47, wherein Compound (B) is(gemcitabine hydrochloride).

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