WO2014135572A1

WO2014135572A1 - Tablet formulation of a pi3kalpha inhibitor

Info

Publication number: WO2014135572A1
Application number: PCT/EP2014/054228
Authority: WO
Inventors: Nathalie BAUD; Raghu CAVATUR; Darshan PARIKH; Praveen RAJU
Original assignee: Sanofi
Priority date: 2013-03-05
Filing date: 2014-03-05
Publication date: 2014-09-12
Also published as: TW201521792A

Abstract

Provided herein are pharmaceutical formulations comprising a PI3Kα inhibitor, and methods of use thereof for treating cancer in a patient in need of such treatment.

Description

TABLET FORMULATION OF A PI3Ka INHIBITOR

BACKGROUND

According to National Cancer Institute statistics, 41% of men and women alive today will be diagnosed with cancer at some point in their lives. The widespread occurrence of this disease underscores the need for improved anticancer regimens for the treatment of malignancy.

One important drug target is a group of proteins called kinases. Protein kinases are a large and diverse family of enzymes that catalyze protein phosphorylation and play a critical role in cellular signaling. They can exert positive or negative regulatory effects, depending upon their target protein. Protein kinases are involved in specific signaling pathways which regulate cell functions such as, but not limited to, metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis, and angiogenesis. Malfunctions of cellular signaling have been associated with many diseases, the most characterized of which include cancer and diabetes. The regulation of signal transduction by cytokines and the association of signal molecules with protooncogenes and tumor suppressor genes have been well documented. Similarly, the connection between diabetes and related conditions, and deregulated levels of protein kinases, has been demonstrated. See e.g., Sridhar et al. Pharmaceutical Research, 17(11): 1345-1353 (2000). Viral infections and the conditions related thereto also have been associated with the regulation of protein kinases. Park et al. Cell 101 (7), 777-787 (2000).

Phosphatidylinositol 3-kinase (PI3K or PIK3CA) is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate Ptdlns, PtdIns4P, and PtdIns(4,5)P2. PTEN, a tumor suppressor which inhibits cell growth through multiple mechanisms, can dephosphorylate PIP3, the major product of PIK3CA. PIP3, in turn, is required for translocation of protein kinase B (AKT1, PKB) to the cell membrane, where it is phosphorylated and activated by upstream kinases. The effect of PTEN on cell death is mediated through the PIK3CA/AKT1 pathway.

PI3Ka has been implicated in the control of cytoskeletal reorganization, apoptosis, vesicular trafficking, proliferation and differentiation processes. Increased copy number and expression of PIK3CA is associated with a number of malignancies such as ovarian cancer (Campbell et al, Cancer Res 2004, 64, 7678-7681; Levine et al, Clin Cancer Res 2005, 11, 2875-2878; Wang et al, Hum Mutat 2005, 25, 322; Lee et al, Gynecol Oncol 2005, 97, 26- 34), cervical cancer, breast cancer (Bachman, et al. Cancer Biol Ther 2004, 3, 772-775; Li et al, Breast Cancer Res Treat 2006, 96, 91-95; Saal et al, Cancer Res 2005, 65, 2554-2559; Samuels and Velculescu, Cell Cycle 2004, 3, 1221-1224), colorectal cancer (Samuels, et al. Science 2004, 304, 554; Velho et al. Eur J Cancer 2005, 41, 1649-1654), endometrial cancer (Oda et al. Cancer Res. 2005, 65, 10669-10673), gastric carcinomas (Byun et al, IntJ Cancer 2003, 104, 318-327; Lee et al, Oncogene 2005, 24, 1477-1480), hepatocellular carcinoma (Lee et al., Oncogene 2005, 24, 1477-1480), small and non-small cell lung cancer (Tang et al, Lung Cancer 2006, 51, 181-191; Massion et al, Am J Respir Crit Care Med 2004, 170, 1088-1094), thyroid carcinoma (Wu et al, J Clin Endocrinol Metab 2005, 90, 4688-4693), acute myelogenous leukemia (AML) (Sujobert et al, Blood 1997, 106, 1063- 1066), chronic myelogenous leukemia (CML) (Hickey and Cotter J Biol Chem 2006, 281, 2441-2450), and glioblastomas (Hartmann et al. Acta Neuropathol (Berl) 2005, 109, 639- 642).

A number of PI3K inhibitors are presently undergoing clinical evaluation in patients with cancer, the details of which can be reviewed at the web site ClinicalTrials.gov. For example, human clinical trials are underway to evaluate 2-amino-8-ethyl-4-methyl-6-(lH- pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one either alone or in combination with other therapeutic agents in patients with lymphoma or leukemia (See trials NCTO 1410513 and NCT01403636), malignant neoplasms or solid tumors (See trials NCT01587040,

NCTO 1390818, NCT00485719, NCTO 1596270 and NCT00777699), brain tumors (See trials NCT01240460 and NCT00704080), and breast cancer (See trial NCT01082068).

In light of this compound's established biological activity, optimized forms are needed to achieve maximal patient efficacy. Accordingly, there is an ongoing need for new compositions and methods that specifically target the PI3K signaling pathway for the treatment of cancer.

SUMMARY

In one aspect provided herein is a pharmaceutical formulation comprising 2-amino-8- ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof, a hydrogel polymer and a diluent. In one embodiment, the 2-amino- 8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one is in the free base form. In some embodiments, the hydrogel is selected from the group consisting of microcrystalline cellulose, methyl cellulose, hydroxymethyl cellulose, polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxides, gums, acrylate polymers and methacrylate polymers. In another embodiment the hydrogel is microcrystalline cellulose. In one embodiment, the diluent is selected from the group consisting of sugars, starches, vegetable oils, lactose monohydrate, calcium phosphate, dextrin, dextrose, maltitol, maltose, starch, sucrose and talc. In one embodiment, the diluent is a starch, and the starch is pregelatinized starch or sodium starch glycolate.

In a particular embodiment, provided herein is a pharmaceutical formulation comprising, by weight, 10-30% 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof; 55-65%

microcrystalline cellulose; 5-15% pregelatinized starch and between 0.1- 10.0% each of hypromellose, silicon dioxide and crospovidone Type A.

In another embodiment, provided herein is a pharmaceutical formulation comprising, by weight, about 20% 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin- 7(8H)-one or a pharmaceutically acceptable salt thereof; about 59% microcrystalline cellulose; about 10%> pregelatinized starch, about 4% hypromellose, about 1% silicon dioxide and about 4% crospovidone Type A.

In one embodiment, the pharmaceutical formulations provided above are in tablet form.

In another embodiment, the pharmaceutical formulations provided above are in caplet form. In a further embodiment, the pharmaceutical formulations provided above are in an immediate-release tablet form. The formulations can comprise about 20 mg, 30 mg, 55 mg, or 90 mg of 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof.

In another aspect, compressed solid dosage forms are provided comprising 2-amino- 8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a

pharmaceutically acceptable salt thereof, a hydrogel polymer and a diluent. The dosage form can comprise, by weight, 10-30%) 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof; 55-65%

microcrystalline cellulose; 5-15% pregelatinized starch and between 0.1-10.0% each of hypromellose, silicon dioxide and crospovidone Type A. In another example, the dosage form can comprise, by weight, about 20% 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof; about 59% microcrystalline cellulose; about 10%> pregelatinized starch, about 4% hypromellose, about 1%) silicon dioxide and about 4% crospovidone Type A. The dosage form can comprise about 10 to 100 mg of 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof or about 20 mg, 30 mg, 55 mg, or 90 mg of 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin- 7(8H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the dosage form is a tablet, while in another it is a caplet.

In another aspect, a compressed solid dosage form is provided comprising A) an active agent containing an effective amount of 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof, and B) at least one pharmaceutically acceptable additive, wherein the active agent is present in an amount of more than about 10% by weight based upon the total weight of the compressed solid dosage form. The dosage form can comprise, by weight, 10-30%) 2-amino-8-ethyl-4- methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or pharmaceutically acceptable salt thereof; 55-65%> microcrystalline cellulose; 5-15% pregelatinized starch and between 0.1- 10.0% each of hypromellose, silicon dioxide and crospovidone Type A. In another example, the dosage form can comprise, by weight, about 20% 2-amino-8-ethyl-4-methyl-6-(lH- pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof; about 59% microcrystalline cellulose; about 10%> pregelatinized starch, about 4%

hypromellose, about 1% silicon dioxide and about 4% crospovidone Type A.

In one embodiment, the active agent of the dosage form comprises at least 95% 2- amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof. In another embodiment, the active agent of the dosage form comprises at least 97% 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof, while in another it comprises at least 99% 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof.

In another aspect provided herein is a method of treating cancer in a subject, comprising administering to the subject in need thereof the above pharmaceutical

formulations and dosage forms. In an embodiment, the cancer is a solid tumor or a lymphoma. In a further embodiment, the lymphoma is indolent non-Hodgkins lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), or diffuse large B cell lymphoma (DLBCL).

In one embodiment, the cancer is hematological cancer. In a further embodiment, the hematological cancer is acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), or chronic lymphocytic leukemia (CLL). The treatment can comprise the administration of an additional anticancer agent. Non-limiting examples of such agents include bendamustine, rituximab, erlotinib, letrozole, or temozolomide.

In another aspect, kits are provided comprising pharmaceutical formulations comprising 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof. In one examples, the kit contains a

pharmaceutical composition comprising 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the kit comprises instructions for using the compound or pharmaceutical compositions thereof to treat a patient with cancer.

Other objects, features, and advantages will become apparent from the following detailed description. The detailed description and specific examples are given for illustration only since various changes and modifications with the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. Further, the examples demonstrate the principle of the invention and cannot be expected to specifically illustrate the application of this invention to all the examples where it will be obviously useful to those skilled in the prior art.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts a synthesis scheme for preparing 2-amino-8-ethyl-4-methyl-6-(lH- pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one.

Figure 2 depicts a flow diagram of a process of manufacturing film-coated tablets comprising 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one as the active pharmaceutical ingredient (API).

DETAILED DESCRIPTION

Pharmaceutical formulations are provided comprising 2-amino-8-ethyl-4-methyl-6- (lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (also referred to herein as "Compound I"), a hydrogel polymer, and a diluent. Compressed solid dosage forms comprising 2-amino- 8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one also are provided. The inventive compositions, which are useful for treating cancer, possess superior features over prior formulations of 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one, including improved manufacturability.

Certain terms used herein are described below. Compounds of the present invention are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

''2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one' has the following structure:

Throughout the application, 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one, or a pharmaceutically acceptable salt or solvate thereof, is referred to as "Compound I".

The compound 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one is a selective inhibitor of PI3K (phosphatidylinositol 3-kinase) that exhibits potent inhibitory activity against PI3K signaling in both in vitro and in vivo tumor models. Synthesis and characterization of Compound I are described in US Patent 8,044,062, which is hereby incorporated by reference in its entirety.

"Yield" for each of the reactions described herein is expressed as a percentage of the theoretical yield.

"Subject" for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In a preferred embodiment the patient is a mammal, and in a most preferred embodiment the patient is human.

The terms "effective amount" or "pharmaceutically effective amount" or

"therapeutically effective amount" refer to a sufficient amount of an agent to provide the desired biological, therapeutic, and/or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying, and/or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In reference to cancer, an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation. In some embodiments, an effective amount is an amount sufficient to delay development. In some embodiments, an effective amount is an amount sufficient to prevent or delay recurrence. An effective amount can be administered in one or more administrations. The effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent, and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer. The amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular compound of the invention. The amount also can vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The effective amount can be determined by one of ordinary skill in the art having regard to their knowledge and to this disclosure.

A "pharmaceutically acceptable salt" of a compound means a salt that is

pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in

Remington 's Pharmaceutical Sciences, 17^th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66: 1-19 both of which are incorporated herein by reference.

Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid,

2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid,

2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid and the like. In one embodiment, the hydrochloric acid salt form or hydrochloride salt form of 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one is used. Examples of pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferable salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine,

theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, N- methylglucamine, polyamine resins, and the like. Exemplary organic bases are

isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

Unless otherwise indicated, "treating" or "treatment" of a disease, disorder, or syndrome, as used herein, means inhibiting the disease, disorder, or syndrome, that is, arresting its development; and relieving the disease, disorder, or syndrome, that is, causing regression of the disease, disorder, or syndrome. As is known in the art, in the context of treatment, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art.

The terms "comprising" and "including" are used herein in their open-ended and non- limiting sense unless otherwise noted.

The terms "a" and "an" and "the" and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.

As used herein, the term "about" generally indicates a possible variation of no more than 10%, 5%, or 1% of a value. For example, "about 25 mg/kg" will generally indicate, in its broadest sense, a value of 22.5-27.5 mg/kg, i.e., 25 ± 2.5 mg/kg. The term "oral dosage form," as used herein, means any pharmaceutical composition intended to be administered to the lower gastrointestinal tract of a human or other mammal via the mouth of said human or other mammal. For the purposes of the present invention, the delivered form can be in the form of a compressed tablet.

As used herein, the term "therapeutic effect" denotes achieving a desired biological, therapeutic, and/or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying, and/or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In reference to cancer, the effect may be to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation. In some embodiments, the effect may be to delay development. In some embodiments, the effect may be to delay recurrence. In other aspects, the effect may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent, and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer. Pharmaceutical Formulations Comprising Compound I

Factorial studies were conducted to develop pharmaceutical formulations of

Compound I which achieved optimal compaction profile, ejection force, aspect (e.g., lamination or capping and punch filming), and stability (e.g. measuring impurities, assay values, dissolution profile after storing tablets at 50°C/75% RH for three months) when produced via a fluid bed granulation process. From these studies pharmaceutical

formulations were obtained which comprised 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof, a hydrogel polymer and a diluent. In one embodiment, the 2-amino-8-ethyl-4-methyl-6-(lH- pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one is in free base form.

In some embodiments, the hydrogel is selected from the group consisting of microcrystalline cellulose, methyl cellulose, hydroxymethyl cellulose, polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,

polyethylene oxides, gums, acrylate polymers and methacrylate polymers. In another embodiment the hydrogel is microcrystalline cellulose. In certain embodiments, the diluent is selected from the group consisting of sugars, starches, vegetable oils, lactose monohydrate, calcium phosphate, dextrin, dextrose, maltitol, maltose, starch, sucrose and talc. In one embodiment, the diluent is a starch such as pregelatinized starch or sodium starch glycolate. In one embodiment, provided herein is a pharmaceutical formulation comprising, by weight, 10-30% 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin- 7(8H)-one or a pharmaceutically acceptable salt thereof; 55-65% microcrystalline cellulose;

5- 15%) pregelatinized starch and between 0.1-10.0%) each of hypromellose, silicon dioxide and crospovidone Type A.

In another embodiment, the pharmaceutical formulations provided above are in tablet form. In another embodiment, the pharmaceutical formulations provided above are in caplet form. The formulations can comprise about 10 mg to 100 mg of 2-amino-8-ethyl-4-methyl-

6- (lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof. The formulations can comprise about 20 mg, 30 mg, 55 mg, or 90 mg of2-amino-8- ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof.

In another aspect, compressed solid dosage forms are provided for ease of ingestion. In particular, compressed solid dosage forms are provided comprising 2-amino-8-ethyl-4- methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof, a hydrogel polymer, and a diluent. The dosage form can comprise, by weight, 10-30% 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin- 7(8H)-one or a pharmaceutically acceptable salt thereof; 55-65% microcrystalline cellulose;

5- 15%) pregelatinized starch and between 0.1-10.0%) each of hypromellose, silicon dioxide and crospovidone Type A. In another example, the dosage form can comprise, by weight, about 20% 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof; about 59% microcrystalline cellulose; about 10%) pregelatinized starch, about 4% hypromellose, about 1% silicon dioxide and about 4% crospovidone Type A. The dosage form can comprise about 10 to 100 mg of 2-amino-8- ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof or about 20 mg, 30 mg, 55 mg, or 90 mg of 2-amino-8-ethyl-4-methyl-

6- (lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the dosage form is a tablet, while in another it is a caplet. In another aspect, a compressed solid dosage form is provided comprising A) an active agent containing an effective amount of 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof, and B) at least one pharmaceutically acceptable additive, wherein the active agent is present in an amount of more than about 10% by weight based upon the total weight of the compressed solid dosage form. The dosage form can comprise, by weight, 10-30%) 2-amino-8-ethyl-4- methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or pharmaceutically acceptable salt thereof; 55-65%> microcrystalline cellulose; 5-15% pregelatinized starch and between 0.1- 10.0% each of hypromellose, silicon dioxide and crospovidone Type A. In another example, the dosage form can comprise, by weight, about 20% 2-amino-8-ethyl-4-methyl-6-(lH- pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof; about 59%) microcrystalline cellulose; about 10%> pregelatinized starch, about 4%

hypromellose, about 1% silicon dioxide and about 4% crospovidone Type A.

In another embodiment, the pharmaceutical formulations provided above are in an immediate-release tablet form. "Immediate release" refers to a dosage form which releases the active ingredient substantially immediately upon contact with gastric juices and will result in substantially complete dissolution within about 1 hour.

In some embodiments, pharmaceutical compositions comprising Compound I may take the form of film-coated tablets as detailed in Table 1.

Table 1 - Composition of 20 and 30 mg Compound I film-coated tablets

Components Composition (mg/unit) Function Reference to standards ^a

20 mg 30 mg

Intragranular phase

Compound 1 20.0 30.0 Drug substance

Microcrystalline cellulose 59.0 88.5 Diluent Ph. Eur.-NF

Pregelatinized starch 10.0 15.0 Diluent Ph. Eur.-NF

Colloidal anhydrous silica-Colloidal silicon dioxide 1.0 1.5 Flow aid Ph. Eur.-NF Components Composition (mg/unit) Function Reference to standards ^a

20 mg 30 mg

Hypromellose 6 mPa.s 4.0 6.0 Binder Ph. Eur.-USP

Crospovidone Type A 4.0 6.0 Disintegrant Ph. Eur.-NF

Purified water ^b - - Granulation agent Ph. Eur.-USP

Extragranular phase

Colloidal anhydrous silica-Colloidal silicon dioxide 1.0 1.5 Flow aid Ph. Eur.-NF

Magnesium stearate ^c 1.0 1.5 Lubricant Ph. Eur.-NF

Core mass 100 mg 150 mg

Film-coating

Opadry® II 33G92256 Yellow ^d 4 5 Film-coating agent

Purified water ^b - - Film-coating solvent Ph. Eur.-USP

Film-coating tablet 104 mg 155 mg

a When it is referred to a Pharmacopeia, this means that the current edition of this Pharmacopoeia is applied.

b Removed during manufacture,

c From vegetable origin.

d Opadry® II 33G92256 yellow contains 40% hypromellose 6 mPa.s (Ph. Eur.-USP-JP), 21 % lactose monohydrate (Ph. Eur.-NF-JP), 16.87% titanium dioxide(Ph. Eur.-USP-JP), 8.13% yellow iron oxide (NF-JP), 8% macrogol 3350 (Ph. Eur.-NF), 6% triacetin (Ph. Eur.-USP-JP).

Preparation of a Pharmaceutical Formulation Comprising Compound I

A synthesis scheme for preparing 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound I) is provided in Figure 1.

Figure 2 provides a flow diagram for a manufacturing process, including in-process controls, for preparing film-coated tablets comprising Compound I. In line with the diagram, such film-coated tablets can be prepared via following steps:

1. Weigh all components.

2. Charge microcrystalline cellulose into the blender and mix for about 2 minutes at

about 7 r/min.

3. Charge Compound I, pregelatinized starch, half of crospovidone Type A and colloidal anhydrous silica in the blender containing cellulose and mix all components for about 15 minutes at about 7 r/min.

4. Sieve the blend obtained at step 3 through a 1 mm mesh size.

5. Prepare the binder solution incorporating hypromellose 6 mPa.s into purified water under stirring for about 45 minutes. Concentration set at 9.5%.

6. Charge the blend into the fluid bed granulator. Add the binder solution to the blend

using a flow rate of about 100 g/min and an inlet air temperature of about 65°C, and granulate the wet mixture. Rinse the binder solution pipes with water until obtaining appropriate loss on drying.

7. Dry the wet granules using an inlet air temperature of about 65°C until a loss of

drying similar to that obtained on the dry blend is achieved.

8. Size the granules obtained on a 1 mm screen mesh size.

9. Sieve the other half of crospovidone type A, colloidal anhydrous silica and

magnesium stearate through a 1 mm mesh size.

10. Add the other half of crospovidone type A, colloidal anhydrous silica and magnesium stearate previously sieved to the calibrated granules and proceed to final mixing for about 20 minutes at about 7 r/min to obtain a homogeneous blend.

11. Compress the lubricated granules on a rotative press fitted with 6R6 punches for the 20 mg strength, 8,4R8,4 punches for 55 mg or 9,9R9,9 punches for the 90 mg strength at a nominal mass of 100 mg for the 20 mg strength, 275 mg for 55 mg or 450 mg for the 90 mg strength.

12. In a mixing tank prepare the film-coating suspension with purified water and Opadry II 33G92256 yellow.

13. Place the tablets obtained in step 11 in a film-coating pan with an inlet air temperature of about 65°C. Spray the film-coating suspension onto the tablets until a weight of 104 mg for the 20 mg tablet, 288.75 mg for the 55 mg tablet or 472.5 mg for the 90 mg tablet is obtained.

To assure identity, quality, strength and purity of the Drug Product, the Drug is subject to analytical procedures and acceptance criteria as summarized in Table 2.

Table 2 - Specification for the drug product

Test 20 mg film-coated 30 mg film-coated Stability

tablet Acceptance tablet Acceptance

criteria criteria

Appearance and color Round yellow film-coated Round yellow engraved X

(visual) tablet film-coated tablet

Identification (HPLC) Retention time of sample Retention time of sample

corresponds to retention corresponds to retention

time of reference (± 5%) time of reference (± 5%)

Identification (UV) Conforms to reference Conforms to reference Test 20 mg film-coated 30 mg film-coated Stability tablet Acceptance tablet Acceptance

criteria criteria

Assay (HPLC) 18.0 - 22.0 mg/unit of 27.0 - 33.0 mg/unit of X

Compound I Compound I

(90.0% - 110.0% of label (90.0% - 110.0% of label

claim) claim)

Degradation products (HPLC)

- Any unspecified degradation < 0.20% < 0.20%

product

- Total degradation products < 3.0% < 3.0%

Average mass 98.8 to 109.2 mg (±5%) 147.3 to 162.7 mg X

(±5%)

Dissolution USP (Q = 75 in X 30 minutes)

Stage I

Number of units out of 6 <Q+

5% of label claim

Stage II

Average of 12 units

Number of units out of 12 <Q-

15% of label claim

Stage III

Average of 24 units

Number of units out of 24 <Q-

15% of label claim

Number of units out of 24 <Q- 0 0

25% of label claim

Uniformity of dosage units Ph. Eur. / USP Ph. Eur. / USP

Content uniformity

Stage I:

- Acceptance value for 10 units <15.0 <15.0

(L1)

Stage II:

- Acceptance value for 30 units <15.0 <15.0

(L1) 0 0

- Number of units outside of

0.75*M to 1.25*M

Microbial contamination

- Total viable aerobic count < 10³ CFU/g < 10³ CFU/g

- Yeasts and molds < 10² CFU/g < 10² CFU/g

- Escherichia coli Absence in 1g Absence in 1g

Methods of Treating Cancer with Pharmaceutical Formulations of Compound I In one aspect, the invention provides a method of treating cancer in a subject, comprising administering to the subject an effective amount of a pharmaceutical formulation comprising Compound I, 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one, a hydrogel polymer, and a diluent.

"Cancer" refers to cellular-pro liferative disease states, including but not limited to:

Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondro matous hanlartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,

leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma

(osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondro myxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma

[pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);

Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, SertoliLeydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma,

myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of the above-identified conditions.

In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a lymphoma such as indolent non-Hodgkins lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), or diffuse large B cell lymphoma (DLBCL).

In certain embodiments, the cancer is breast cancer, non-small cell lung cancer, melanoma, colorectal cancer, glioblastoma, astrocytoma, or glioma. In another embodiment, the cancer is breast cancer, colon cancer, rectal cancer, endometrial cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, lymphoma, lung carcinoma, small cell lung cancer, non-small cell lung cancer, melanoma, ovarian cancer, cervical cancer, pancreatic cancer, hematological cancer, prostate adenocarcinoma, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML) or thyroid carcinoma.

In certain embodiments, the cancer is hematological cancer, e.g. acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), or chronic lymphocytic leukemia (CLL).

The treatment can comprise the administration of an additional anticancer agent.

Non-limiting examples of such agents include bendamustine, rituximab, erlotinib, letrozole, or temozolomide.

In certain embodiments of the method, the pharmaceutical formulation comprising Compound I is formulated into a tablet. In a particular, embodiment, the tablet is an immediate-release film-coated tablet. Tablet forms of Compound I can be formulated to contain any required quantity of Compound I. In a particular embodiment, the tablet is formulated to contain 20 mg or 30 mg of 20% w/w Compound I in the free base form or a pharmaceutically acceptable salt thereof. In another embodiment, the tablet is formulated to contain 55 or 90 mg of 20% w/w Compound I in the free base form or a pharmaceutically acceptable salt thereof. In a particular embodiment, the tablet is formulated to contain 20 mg or 30 mg of 20% w/w Compound I in the free base form. In another embodiment, the tablet is formulated to contain 55 or 90 mg of 20% w/w Compound I in the free base form. Administration

Administration of pharmaceutical formulations comprising Compound I can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, specifically in unit dosage forms suitable for simple administration of precise dosages. In a preferred embodiment, administration is by the oral route in tablet form.

In the pharmaceutical compositions disclosed herein, Compound I is administered in an effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of

administration, rate of excretion, drug combination, the severity of the particular disease- states, and the host undergoing therapy. Compound I can be administered to a patient at dosage levels in the range of about 0.1 to about 2,000 mg per day.

The specific dosage used for children will generally be lower due to the smaller size and weight of children, and the doses can be adjusted according to size and weight factors, as well as additional factors. For example, the dosage can depend on additional factors including the requirements of the child, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular child is well known to one of ordinary skill in the art. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent(s) within approved dosage ranges. Compound I alternatively may be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.

Kits

In another embodiment, kits are provided comprising pharmaceutical formulations comprising Compound I, 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one. In one example, the kit contains a pharmaceutical composition comprising Compound I, 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one. In one embodiment, the kit comprises instructions for using the compound or pharmaceutical composition to treat a patient with cancer.

Claims

WE CLAIM:

1. A pharmaceutical formulation comprising 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol- 5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof, a hydrogel polymer and a diluent.

2. The pharmaceutical formulation of claim 1, wherein the 2-amino-8-ethyl-4-methyl-6- (lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one is in the free base form.

3. The pharmaceutical formulation of claims 1 or 2, wherein the hydrogel is selected from the group consisting of microcrystallme cellulose, methyl cellulose, hydroxymethyl cellulose, polyvinyl pyrrolidone, hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxides, gums, acrylate polymers and methacrylate polymers.

4. The pharmaceutical formulation of claims 1 or 2, wherein the hydrogel is

microcrystallme cellulose.

5. The pharmaceutical formulation of claims 1 or 2, wherein the diluent is selected from the group consisting of sugars, starches, vegetable oils, lactose monohydrate, calcium phosphate, dextrin, dextrose, maltitol, maltose, starch, sucrose and talc.

6. The pharmaceutical formulation of claims 1 or 2, wherein the diluent is a starch, and the starch is pregelatinized starch or sodium starch glycolate.

7. The pharmaceutical formulation of claims 1 or 2 comprising, by weight, 10-30% 2- amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof; 55-65% microcrystallme cellulose; 5-15% pregelatinized starch and between 0.1-10.0% each of hypromellose, silicon dioxide and crospovidone Type A.

8. The pharmaceutical formulation of claims 1 or 2 comprising, by weight, about 20% 2- amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof; about 59% microcrystallme cellulose; about 10% pregelatinized starch, about 4% hypromellose, about 1% silicon dioxide and about 4% crospovidone Type A.

9. The pharmaceutical formulation of claim 8, wherein the microcellulose possesses a density grade of PH302 and a particle size of 90 μιη.

10. The pharmaceutical formulation of any one of claims 1-9, wherein the pharmaceutical formulation is on tablet form.

11. The pharmaceutical formulation of claims 10, wherein the pharmaceutical formulation is in caplet form.

12. The pharmaceutical formulation of any one of claims 1-11, wherein the

pharmaceutical formulation is an immediate-release tablet form.

13. The pharmaceutical formulation of any one of claims 1-12, wherein the formulation comprises about 20 mg, 30 mg, 55 mg, or 90 mg of 2-amino-8-ethyl-4-methyl-6-(lH- pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical formulation of any one of claims 1-13, wherein the formulation provides a therapeutic effect.

15. A compressed solid dosage form comprising 2-amino-8-ethyl-4-methyl-6-(lH- pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof, a hydrogel polymer and a diluent.

16. The dosage form of claim 15, comprising, by weight, 10-30% 2-amino-8-ethyl-4- methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof; 55-65%> microcrystallme cellulose; 5-15% pregelatinized starch and between 0.1-10.0%) each of hypromellose, silicon dioxide and crospovidone Type A.

17. The dosage form of claim 15 comprising, by weight, about 20% 2-amino-8-ethyl-4- methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof; about 59% microcrystallme cellulose; about 10%> pregelatinized starch, about 4% hypromellose, about 1% silicon dioxide and about 4% crospovidone Type A.

18. The dosage form of claim 15, wherein the dosage form comprises about 10 to 100 mg of 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof.

19. The dosage form of claim 15, wherein the dosage form comprises about 20 mg, 30 mg, 55 mg or 90 mg of 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof.

20. The dosage form of any one of claims 15 to 19, wherein the dosage form is a tablet.

21. The dosage form of any one of claims 15 to 20, wherein the dosage form is a caplet.

22. A compressed solid dosage form comprising

A) an active agent containing an effective amount of 2-amino-8-ethyl-4-methyl-6- (lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof, and

B) at least one pharmaceutically acceptable additive,

wherein the active agent is present in an amount of more than about 10% by weight based upon the total weight of the compressed solid dosage form.

23. The dosage form of claim 22, comprising, by weight, 10-30% 2-amino-8-ethyl-4- methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or pharmaceutically acceptable salt thereof; 55-65%> microcrystalline cellulose; 5-15% pregelatinized starch and between 0.1- 10.0%) each of hypromellose, silicon dioxide and crospovidone Type A.

24. The dosage form of claim 22 comprising, by weight, about 20% 2-amino-8-ethyl-4- methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof; about 59% microcrystalline cellulose; about 10% pregelatinized starch, about 4% hypromellose, about 1% silicon dioxide and about 4% crospovidone Type A.

25. The dosage form of any one of claims 22 to 24, wherein the active agent comprises at least 95% 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof.

26. The dosage form of any one of claims 22 to 24, wherein the active agent comprises at least 97% 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof.

27. The dosage form of any one of claims 22 to 24, wherein the active agent comprises at least 99% 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmaceutically acceptable salt thereof.

28. A method of treating cancer in a subject in need thereof, comprising administering to the subject the pharmaceutical formulation of any one of claims 1-14.

29. A method of treating cancer in a subject in need thereof, comprising administering to the subject the dosage form of any one of claims 15-27.

30. The method of claim 28 or 29, wherein the cancer is a solid tumor.

31. The method of claim 28 or 29 wherein the cancer is a lymphoma.

32. The method of claim 31 , wherein the lymphoma is indolent non-Hodgkins lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), or diffuse large B cell lymphoma (DLBCL).

33. The method of claim 28 or 29, wherein the cancer is breast cancer, non-small cell lung cancer, melanoma, colorectal cancer, glioblastoma, or glioma.

34. The method of claim 28 or 29, wherein the cancer is hematological cancer.

35. The method of claim 34, wherein the hematological cancer is acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), or chronic lymphocytic leukemia (CLL).

36. The method of any one of claims 28 to 35, wherein the treatment comprises the administration of an additional anticancer agent.

37. The method of claim 36, wherein the anticancer agent is bendamustine, rituximab, erlotinib, letrozole, or temozolomide.