CDK4 inhibitors for use in the treatment of mantle cell lymphoma

Abstract

This invention relates to therapies for treating mantle cell lymphoma comprising a cyclin dependent kinase 4 (CDK4) inhibitor or a pharmaceutically acceptable salt thereof, and associated methods of treatment, pharmaceutical compositions, and uses thereof.

Description

[0001] CDK4 INHIBITORS FOR USE IN THE TREATMENT OF MANTLE CELL LYMPHOMA

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to therapies useful for treating mantle cell lymphoma in a subject. In particular, the invention relates to therapies comprising a cyclin dependent kinase 4 inhibitor. The invention also relates to associated methods of treatment, pharmaceutical compositions, and pharmaceutical uses.

[0004] BACKGROUND

[0005] CDK4 is a cyclin-dependent kinase that plays a crucial role in regulating the cell cycle. It works in conjunction with cyclin D1 (CCND1) to initiate the transition from the G1 to the S phase of the cell cycle. CDK4 inhibitors work by specifically inhibiting the CDK4 / cyclin D complex, blocking the transition from the G1 to the S phase of the cell cycle and potentially inhibiting the growth of cancer cells.

[0006] Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphomas (NHLs) characterized by a translocation resulting in overexpression of CCND1 , with an annual incidence of one case per 200,000 people. Nat Lib Med, Jul 2023, https: / / www.ncbi.nlm.nih.gov / books / NBK536985 / . In MCL patients, dysregulated CDK4 signalling has been frequently reported due to elevated expression of CCND1 , results in rapid disease progression.

[0007] There remains a need for improved therapies for the treatment of cancers, such as mantle cell lymphoma. The compounds, compositions and methods of the present invention are believed to have one or more advantages, such as greater efficacy; potential to reduce side effects; potential to reduce drug-drug interactions; potential to enable an improved dosing schedule; or potential to overcome resistance mechanisms, and the like.

[0008] BRIEF SUMMARY OF THE INVENTION

[0009] This present invention relates to methods, combinations, uses, pharmaceutical compositions and kits for treating abnormal cell growth, particularly cancer, comprising a CDK4 inhibitor.

[0010] According to an embodiment of the invention, there is provided a method of treating cancer in a subject in need thereof comprising administering to the subject comprises a therapeutically effective amount of a cyclin-dependent kinase 4 (CDK4) inhibitor, wherein the cancer is mantle cell lymphoma. Described below are embodiments of the invention, where for convenience Embodiment 1 (E1) is identical to the method of treating a cancer in a subject provided above.

[0011] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0012] BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 shows average tumor growth inhibition by PF-07220060 (5, 15, and 30 mg / kg twice per day BID) as single agent compared to palbociclib (10 mg / kg BID) in the Jeko-1-Luc disseminated MCL model.

[0014] DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention may be understood more readily by reference to the following detailed description of the embodiments and preferred embodiments of the invention. It is to be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art.

[0016] E1 A method of treating mantle cell lymphoma in a subject in need thereof, as defined above.

[0017] E2. The method of embodiment 1 , wherein the CDK4 selective inhibitor is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0018] R1is H, F or Cl;

[0019] R2is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R5;

[0020] R3is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R6;

[0021] R4is H or F; and each R5and R6is independently OH, F or C1-C2 alkoxy.

[0022] E3 The method of any one of embodiments 1 to 2, wherein the compound of Formula (I) is 1 ,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1 / 7-benz- imidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f / 7 / 'eo-pentitol.

[0023] E4 The method of any of embodiments 1 to 3, wherein the daily dose is about from 100 mg BID to about 400 mg BID.

[0024] E5 The method of any of embodiments 1 to 4, wherein the daily dose is 100 mg BID.

[0025] E6 The method of any of embodiments 1 to 5, wherein the daily dose is 300 mg BID.

[0026] E7 The method of any of embodiments 1 to 6, wherein the subject is human.

[0027] E8 The method of any of embodiments 1 to 7, wherein the subject is human.

[0028] E9 Use of a CDK4 inhibitor in the manufacture of a medicament for treating mantle cell lymphoma.

[0029] E10 A pharmaceutical composition comprising a CDK4 inhibitor and a pharmaceutically acceptable carrier.

[0030] Each of the embodiments of the present invention described herein may be combined with one or more other embodiments of the present invention described herein which is not inconsistent with the embodiment(s) with which it is combined. In addition, each of the embodiments below describing the invention envisions within its scope the pharmaceutically acceptable salts of the compound of the invention.

[0031] The present invention may be understood more readily by reference to the following detailed description of the preferred embodiments of the invention and the Examples included herein. It is to be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art.

[0032] As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents. The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of, and "consisting of may be replaced with either of the other two terms.

[0033] The term “about” which used to modify a numerically defined parameter means that the parameter may vary by as much as 10% above or below the stated numerical value for that parameter. For example, a dose of about 5mg / kg should be understood to mean that the dose may vary between 4.5mg / kg and 5.5mg / kg.

[0034] Cyclin-dependent kinases (CDKs) and related serine / threonine kinases are important cellular enzymes that perform essential functions in regulating cell division and proliferation. CDK inhibitors include Pan-CDK inhibitors that target a broad spectrum of CDKs or selective CDK inhibitors that target specific CDK(s).

[0035] Cyclin-dependent kinases (CDKs) and related serine / threonine protein kinases are important cellular enzymes that perform essential functions in regulating eukaryotic cell division and proliferation. The CDK catalytic units are activated by regulatory subunits known as cyclins. At least sixteen mammalian cyclins have been identified (Johnson DG, Walker CL. Cyclins and Cell Cycle Checkpoints. Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312). Cyclin B / CDK1 , cyclin A / CDK2, cyclin E / CDK2, cyclin D / CDK4, cyclin D / CDK6, and likely other heterodynes are important regulators of cell cycle progression. Additional functions of cyclin / CDK heterodynes include regulation of transcription, DNA repair, differentiation and apoptosis (Morgan DO, Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).

[0036] CDK inhibitors have been demonstrated to be useful in treating cancer. Increased activity or temporally abnormal activation of cyclin-dependent kinases has been shown to result in the development of human tumors, and human tumor development is commonly associated with alterations in either the CDK proteins themselves or their regulators (Cordon-Cardo C. Mutations of cell cycle regulators: biological and clinical implications for human neoplasia. Am. J. Pathol. (1995) 147:545-560; Karp JE, Broder S. Molecular foundations of cancer: new targets for intervention. Nat. Med. (1995) 1 :309-320; Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv. Cancer Res. (1996) 68:67-108).

[0037] CDK4 selective inhibitors include, but are not limited to, PF-07220060 (Pfizer), BGB- 43395 (BeiGene), HRS-6209 (Jiangsu HengRui) and AU2-94 (Aucentra Therapeutics).

[0038] In an embodiment, CDK4 selective inhibitors of the present invention include “PF- 07220060” which refers to 1 ,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1- (propan-2-yl)-1 / 7-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f / 7 / 'eo-pentitol, which has the following chemical structure, including hydrates, salts and polymorphs thereof:

[0039]

[0040] PF-07220060 is disclosed in International Publication No. WO 2019 / 207463, U.S. Patent Nos. 10,766,884 and 1 1 ,220,494, and US Patent Publication US 2022 / 0089580; and International Publication No. WO 2022 / 058871 , the contents of which are incorporated herein by reference in their entirety. Unless indicated otherwise, all references herein to PF-07220060 include references to salts, solvates, hydrates, and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labelled versions thereof.

[0041] In one embodiment, the CDK4 selective inhibitor having a structure of Formula (I) or a pharmaceucially acceptable salt thereof.

[0042] In one embodiment, the compound of Formula (I) is 1 ,5-anhydro-3-({5-chloro-4-[4-fluoro- 2-(2-hydroxypropan-2-yl)-1 -(propan-2-yl)-1 / 7-benz-imidazol-6-yl]pyrimidin-2-yl}amino)-2,3- dideoxy-D-f / ireo-pentitol or a pharmaceucially acceptable salt thereof.

[0043] In one embodiment, 1 ,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1 - (propan-2-yl)-1 / 7-benz-imidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f / 7 / 'eo-pentitol is 1 ,5- anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1 / 7-benz-imidazol-6- yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f / 7 / 'eo-pentitol monohydrate.

[0044] Another embodiment relates to the pharmaceutically acceptable salts of the compounds described herein. Pharmaceutically acceptable salts of the compounds described herein include the acid addition and base addition salts thereof.

[0045] Another embodiment also relates to the pharmaceutically acceptable acid addition salts of the compounds described herein. Suitable acid addition salts are formed from acids which form non-toxic salts. Non-limiting examples of suitable acid addition salts, i.e., salts containing pharmacologically acceptable anions, include, but are not limited to, the acetate, acid citrate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, bitartrate, borate, camsylate, citrate, cyclamate, edisylate, esylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methanesulfonate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, p-toluenesulfonate, tosylate, trifluoroacetate and xinofoate salts.

[0046] Additional embodiments relate to base addition salts of the compounds described herein. Suitable base addition salts are formed from bases which form non-toxic salts. Non-limiting examples of suitable base salts include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0047] The compounds described herein that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds described herein are those that form non-toxic acid addition salts, e.g., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1 ,T-methylene-bis-(2-hydroxy-3- naphthoate)] salts. The compounds described herein that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.

[0048] The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the compounds described herein that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N- methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

[0049] Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

[0050] For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds described herein are known to one of skill in the art. Administration and Dosing

[0051] "Treat" or "treating" a cancer and / or a cancer-associated disease as used herein means to administer a monotherapy or combination therapy according to the present invention to a subject, participant or patient having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, reversing, alleviating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" or “therapy,” as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and I or prolonging survival of patients the cancer. Positive therapeutic effects in cancer may be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. 50:1 S-10S (2009)).

[0052] As used herein, the terms, “subject”, “participant” and “patient,” are used interchangeably, to refer to any animal, including mammals. Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.

[0053] An “amount” for use and for treating a subject refers to an amount that provides, in single or multiple doses, alone, or in combination with one or more other agents, a detectable response of any duration of time (transient, medium or long term), a desired outcome in or an objective or subjective benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for hours, days, months, years, in remission or cured). Such amounts typically are effective to ameliorate a disease, or one, multiple or all adverse effects I symptoms, consequences or complications of the disease, to a measurable extent, although reducing or inhibiting a progression or worsening of the disease, or providing stability (i.e., not worsening) state of the disease, is considered a satisfactory outcome. The term “therapeutically effective amount” also means an amount of an agent, alone, or in combination with one or more other agents, effective for producing a desired therapeutic effect upon administration to a subject, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis emergence, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and / or (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer. Therapeutic or pharmacological effectiveness of the doses and administration regimens may also be characterized as the ability to induce, enhance, maintain or prolong disease control and / or overall survival in patients with these specific tumors, which may be measured as prolongation of the time before disease progression.

[0054] As used herein, “ameliorate” refers to any reduction in the extent, severity, frequency, and / or likelihood of a symptom or clinical sign characteristic of a particular disease. “Symptom” refers to any subjective evidence of disease or of a subject's condition.

[0055] Administration of the compounds of the present invention may be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration. Each compound may be administered according to the same or different route of administration.

[0056] In a preferred embodiment, the daily dose of a CDK4 inhibitor or a pharmaceutically acceptable salt thereof, is administered orally.

[0057] A CDK4 inhibitor, or a pharmaceutically acceptable salt, may be present in a pharmaceutical composition which includes a pharmaceutically acceptable excipient. "Pharmaceutically acceptable excipient" refers to a component that may be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and causes no significant adverse effects nor therapeutic effects to a subject. The term ’excipient’ is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0058] The amount of a CDK4 inhibitor, or a pharmaceutically acceptable salt, in the pharmaceutical compositions may be any amounts disclosed herein.

[0059] The compounds of the method, use or combination of the present invention may be formulated prior to administration. The formulation will preferably be adapted to the particular mode of administration. These compounds may be formulated with pharmaceutically acceptable excipients as known in the art and administered in a wide variety of dosage forms as known in the art. Dosage unit forms or pharmaceutical compositions suitable for oral administration include, but are not limited to tablets, capsules, such as gelatin capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, packaged in containers adapted for subdivision into individual doses. In another embodiment, the dosage of a compound or pharmaceutical composition described herein may vary within the range depending upon the dosage form employed and the route of administration utilized. In another embodiment, an amount of a compound or pharmaceutical composition described herein administered to a subject may be dependent upon factors known to a skilled artisan, including bioactivity and bioavailability of the compound (e.g., half-life and stability of the compound in the body), chemical properties of the compound (e.g., molecular weight, hydrophobility and solubility), route and frequency of administration, and the like. Further, it will be understood that the specific dose of a pharmaceutical composition comprising a compound as disclosed herein may depend on a variety of factors including physical condition of the subject (e.g., age, gender, weight), and medical history of the subject (e.g., medications being taken, health condition other diseases or disorders). The precise dose of a pharmaceutical composition administered to a subject may be determined by methods known to a skilled artisan such as a pharmacologist, or an anesthesiologist.

[0060] In an embodiment, 1 ,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1- (propan-2-yl)-1 / 7-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f / 7 / 'eo-pentitol is administered to a subject at a daily dosage of from about 1 mg to about 1000 mg per day. In some embodiments, the CDK4 inhibitor is administered to a subject at a daily dosage from about 10 mg to about 500 mg per day. In some embodiments, the CDK4 inhibitor is administered to a subject at a daily dosage from about 10 mg to about 500 mg per day. In some embodiments, the CDK4 inhibitor is administered to a subject at a dosage of from about 25 mg to about 300 mg per day. In some embodiments the CDK4 inhibitor is administered to a subject at dosages of about: 1 , 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 1 15,

[0061] 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210,

[0062] 215, 220, 225, 230, 235, 240, 245, 250, 260, 270, 275, 280, 290, 300, 325, 350, 375, 400, 425,

[0063] 450, 475 or500 mg on a QD, BID, TID or QID schedule. In some embodiments, the CDK4 inhibitor is administered to a subject at dosages of about 100 mg BID to about 400 mg BID.

[0064] In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 50 mg QD. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 75 mg QD. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 100 mg QD. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 200 mg QD. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 300 mg QD. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 400 mg QD. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 500 mg QD. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 50 mg BID. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 75 mg BID. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 100 mg BID. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 200 mg BID. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 300 mg BID. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 400 mg BID.

[0065] Repetition of the administration or dosing regimens may be conducted as necessary to achieve the desired reduction or diminution of cancer cells. A “continuous dosing schedule”, as used herein, is an administration or dosing regimen without dose interruptions, e.g., without days off treatment. Repetition of 28-day treatment cycles without dose interruptions between the treatment cycles is an example of a continuous dosing schedule. In an embodiment, the compounds of the combination of the present invention may be administered in a continuous dosing schedule. In an embodiment, the compounds of the combination of the present invention may be administered concurrently in a continuous dosing schedule.

[0066] Method of Treatment

[0067] In one embodiment, the disclosure provides a method of treating a cancer in a subject in need thereof, which includes administering to the subject an amount of a cyclin-dependent kinase 4 (CDK4) inhibitor as described herein.

[0068] "Treat" or "treating" a cancer and / or a cancer-associated disease as used herein means to administer a monotherapy or combination therapy according to the present invention to a subject, participant or patient having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, reversing, alleviating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" or “therapy,” as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and I or prolonging survival of patients the cancer. Positive therapeutic effects in cancer may be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. 50:1 S-10S (2009)).

[0069] As used herein, the terms, “subject”, “participant” and “patient,” are used interchangeably, to refer to any animal, including mammals. Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.

[0070] An “amount” for use and for treating a subject refers to an amount that provides, in single or multiple doses, alone, or in combination with one or more other agents, a detectable response of any duration of time (transient, medium or long term), a desired outcome in or an objective or subjective benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for hours, days, months, years, in remission or cured). Such amounts typically are effective to ameliorate a disease, or one, multiple or all adverse effects I symptoms, consequences or complications of the disease, to a measurable extent, although reducing or inhibiting a progression or worsening of the disease, or providing stability (i.e., not worsening) state of the disease, is considered a satisfactory outcome. The term “therapeutically effective amount” also means an amount of an agent, alone, or in combination with one or more other agents, effective for producing a desired therapeutic effect upon administration to a subject, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis emergence, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and / or (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer. Therapeutic or pharmacological effectiveness of the doses and administration regimens may also be characterized as the ability to induce, enhance, maintain or prolong disease control and / or overall survival in patients with these specific tumors, which may be measured as prolongation of the time before disease progression.

[0071] As used herein, “ameliorate” refers to any reduction in the extent, severity, frequency, and / or likelihood of a symptom or clinical sign characteristic of a particular disease. “Symptom” refers to any subjective evidence of disease or of a subject's condition.

[0072] Administration of the compounds of the present invention may be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration. Each compound may be administered according to the same or different route of administration.

[0073] As used herein, an “effective dosage”, “effective amount” or “therapeutically effective amount” of a compound or pharmaceutical composition is the amount that, when used as indicated (which may be alone if used as a single agent or together with other agents if used in combination) is sufficient to affect one or more beneficial or desired outcomes, including preventing, ameliorating or treating the biochemical, histological or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease. For prophylactic use, beneficial or desired outcomes may include: eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease. For therapeutic use, beneficial or desired outcomes may include: reducing the incidence or ameliorating one or more symptoms of the disease, reducing the dose of another medication used to treat the disease, enhancing the efficacy or safety of another medication used to treat the disease, or delaying the time to disease progression.

[0074] In reference to the treatment of cancer, beneficial or desired outcomes provided by the invention may include: (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, (4) reducing the incidence or ameliorating (that is, reducing to some extent, preferably, eliminating) one or more signs or symptoms associated with the cancer, (5) decreasing the dosage of another medication required to treat the cancer, (6) enhancing the efficacy or safety of another medication used to treat the cancer, and / or (7) delaying the time to progression of the cancer.

[0075] One of ordinary skill in the art would be able to determine such amounts based on such factors as the patient’s size, the severity of the patient’s symptoms, and the particular combination, composition or route of administration selected. The patient or subject may be a human or non-human mammal in need of treatment. In one embodiment, the patient is human.

[0076] These and other embodiments of the invention, including the exemplary specific embodiments listed below, will be apparent from the teachings contained herein.

[0077] EXAMPLES

[0078] Example 1 - The antitumor efficacy of PF-07220060 in the Jeko-1-Luc mantle cell lymphoma (MCL) disseminated model (in vivo efficacy studies)

[0079] Jeko-1 Luc disseminated model was established by IV implanting 1 x 106 cells into the tail vein of female NSG mice. Leukemic disease progression was monitored longitudinally on an IVIS200 system. Treatment was initiated when the mean value of bioluminescence intensity (BLI) in each group reached approximately 1 .2 x 106 photons / sec. Mice were subsequently treated with 1) vehicle (10% ETOH Z45% Tween 80 / 35% PEG300 / 10% Capmul MCM) BID, PO; 2) palbociclib at 10 mg / kg BID, PO; 3-5) PF-07220060 at 5, 15 and 60mg / kg BID, PO respectively. All mice were treated continuously for a total of 8 weeks, with follow up observation of disease progression. Disease progression was monitored, and mice were euthanized once they developed signs of hind-leg paralysis or lethargy. To evaluate the duration of the treatment response, Kaplan Meier analysis was performed to quantify survival. The efficacy of PF-07220060 was evaluated in the Jeko-1-luc MCL disseminated model. To establish the model, 1 x 106 cells were implanted intravenously (IV) into the tail vein of NSG mice. Leukemic disease progression was monitored longitudinally on an IVIS200 system. Treatment was initiated when the mean value of bioluminescence intensity (BLI) in each group reached approximately 1.2 x 106 photons / sec. Mice were subsequently treated with 1) vehicle (10% ETOH / 45% Tween 80 / 35% PEG300 Z10% Capmul MCM); 2) palbociclib at 10 mg / kg; 3-5) PF-07220060 at 5, 15 and 60 mg / kg respectively. All mice received treatment continuously for total of 8 weeks with follow up observation of the disease progression. All groups treated with either palbociclib or PF07220060 demonstrated significant (p < 0.05) antitumor activity. On day 24, the TGI% values are 60% (palbo 10 mg / kg), 67% (PF0060, 5 mg / kg), 89% (PF0060, 15 mg / kg), and 98% (PF0060, 60 mg / kg). Of note, PF07220060 at 15mg / kg and 60mg / kg exhibited significantly (p<0.05) improved antitumor efficacy compared to palbociclib treatment. In late stage, the Jeko-1 -Luc disease mice were euthanized once developing signs of hind-leg paralysis or lethargy. To evaluate the duration of the treatment response, Kaplan Meier analysis was performed by tracking the survival readout. The median survival in vehicle-treated mice was 32 days, palbociclib (10 mg / kg) and PF07220060 (60 mg / kg) prolonged survival of mice with median survival time as 45 and 73 days, respectively. Importantly, PF07220060 significantly improved survival (p<0.05) compared to palbociclib. No toxicity or any adverse effect was observed throughout the treatment period.

[0080] All publications and patent applications cited in the specification are herein incorporated by reference in their entirety. Although the foregoing invention has been described in some detail by way of illustration and example, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

CLAIMS1 . A method of treating cancer in a subject in need thereof comprising administering to the subject comprises a therapeutically effective amount of a cyclin-dependent kinase 4 (CDK4) inhibitor, wherein the cancer is mantle cell lymphoma.

2. The method of claim 1 , wherein the CDK4 selective inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is H, F or Cl;R2is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R5;R3is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R6;R4is H or F; and each R5and R6is independently OH, F or C1-C2 alkoxy.

3. The method of any one of claims 1 to 2, wherein the compound of Formula (I) is 1 ,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1 -(pro pan-2-yl)-1 / - / -benz- imidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f / 7 / 'eo-pentitol.

4. The method of any of claims 1 to 3, wherein a daily dose of 1 ,5-anhydro-3-({5- chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1 / 7-benz-imidazol-6-yl]pyrimidin-2- yl}amino)-2,3-dideoxy-D-t / ? / -eo-pentitol is administered to the subject.

5. The method of any of claims 1 to 4, wherein the daily dose is about from 100 mg BID to about 400 mg BID.

6. The method of any of claims 1 to 5, wherein the daily dose is 100 mg BID.

7. The method of any of claims 1 to 6, wherein the daily dose is 300 mg BID.

8. The method of any of claims 1 to 7, wherein the subject is human.

9. Use of a CDK4 inhibitor in the manufacture of a medicament for treating mantle cell lymphoma.

10. A pharmaceutical composition comprising a CDK4 inhibitor and a pharmaceutically acceptable carrier.

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