Ribociclib pharmaceutical composition

Abstract

Provided are pharmaceutical formulations containing 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide succinate, methods of using the formulations in therapeutic methods, and processes for their preparation.

Description

[Technical field]

[0001] The present invention relates to a powder for oral liquid (PFOS) comprising ribociclib and / or a pharmaceutically acceptable salt thereof, a process for preparing the same, and a method of treatment therewith. For example, the present disclosure relates to a powder for oral liquid (PFOS) comprising ribociclib and / or a pharmaceutically acceptable salt thereof for use in the treatment of cancer. [Background technology]

[0002] Formula (I) [ka] is known as ribociclib or Kisqali®, its chemical name is 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, and its synthesis is specifically described in Example 74 of WO 2010 / 020675 A1.

[0003] The succinate salt of ribociclib has the formula (II): [ka] and which is described in WO 2012 / 064805.

[0004] Ribociclib and its pharma- ceutically acceptable salts have beneficial pharmacological properties and can be used, for example, (1) as inhibitors of cyclin-dependent kinases (particularly cyclin-dependent kinases selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK9); and (2) as modulators and / or inhibitors of glycogen synthase kinase-3 (GSK-3).

[0005] Solid oral pharmaceutical dosage forms are common and useful forms of medicine for dispensing pharma- ceutical active compounds, and a variety of such forms are known, including tablets, capsules, pellets, lozenges, and powders.

[0006] However, formulating an oral solid pharmaceutical dosage form that is acceptable on a commercial scale is not easy. When administered in vivo, each pharmaceutical compound behaves uniquely with respect to therapeutic drug levels. Moreover, pharma- ceutical active compounds, especially antitumor compounds, are often accompanied by undesirable side effects such as toxicity (e.g., genotoxicity, teratogenicity), and undesirable physical or psychological symptoms. In addition to balancing the drug's specific chemical properties with the properties of the excipients, the drug must be administered in a specific amount, or within the therapeutic window of that particular drug, that is sufficient to provide the desired therapeutic drug level, but not enough to produce an unacceptable side effect profile. Furthermore, the formulation and manufacturing process must be such as to provide a monolithic dosage form that maintains its integrity until it is used. The dosage form must also have acceptable dissolution and disintegration properties to provide the desired profile upon use.

[0007] Pharmaceutically active compounds that are poorly soluble and / or in solvate form can present particular challenges in preparing high quality dosage forms. These challenges include the stability and solubility of the drug substance in the pharmaceutical composition, which can lead to compromised pharmacodynamic properties.

[0008] Ribociclib has been approved in the United States, European Union, and other countries in the form of 200 mg film-coated tablets as Kisqali® for use in the treatment of advanced breast cancer in combination with aromatase inhibitors or fulvestrant. Ribociclib is also currently being evaluated in multiple tumor types, such as neuroblastoma (NB) and other solid tumors such as medulloblastoma (MB), high-grade glioma (HGG), malignant rhabdoid tumor (MRT), hepatoblastoma (HB), and rhabdomyosarcoma (RMS), in combination with temozolomide and topotecan (TOTEM).

[0009] Solid dosage forms of ribociclib, specifically 50 mg, 100 mg, 150 mg, 200 mg and 300 mg film-coated tablets, are described in WO 2016 / 166703. The disclosed tablets are acceptable for use in adults, but are not preferred for administration of ribociclib to children or individuals who have difficulty swallowing tablets. In the pediatric population, it is often desirable to have the drug available as a powder that is reconstituted into an oral suspension or solution. Such powders require attempts to dry blend the active substance with various excipients in the hope of providing a powder blend with good flowability and content uniformity.

[0010] There are further challenges with the use of ribociclib in pediatric formulations. For example, ribociclib is classified as a BCS (Biopharmaceutics Classification System) IV compound with poor solubility and permeability. Aqueous solutions containing ribociclib drug substance have presented solubility and stability challenges. Ribociclib drug substance in the form of succinate salt has limited solubility at basic pH compared to acidic pH. To obtain sufficient physical stability and water solubility, the pH of oral solutions of ribociclib succinate needs to be adjusted to the acidic range. In addition, oral solutions of ribociclib have been found to be unstable at room temperature, require storage under refrigerated conditions, and have a limited shelf life of 12 months. In addition, ribociclib drug substance has been found to have a bitter taste, and a flavored solution or suspension is needed that can mask the taste without compromising swallowability.

[0011] Significant realization of these concerns would adversely affect the in vivo administration of ribociclib.

[0012] It would be desirable to provide ribociclib in a formulation suitable for administration to the pediatric population. Summary of the Invention

[0013] The present invention relates to a powder for oral liquid of ribociclib (PFOS), which is well adapted for reconstitution with water. The present invention also relates to prepared aqueous solutions, formulations, particularly stable oral pharmaceutical formulations, comprising ribociclib mixed with an aqueous vehicle. The present invention relates to methods for preparing these formulations. Furthermore, the present invention relates to methods for treating cancer using these formulations in combination with temozolomide and topotecan. In one embodiment, the cancer is neuroblastoma (NB), medulloblastoma (MB), high-grade glioma (HGG), malignant rhabdoid tumor (MRT), hepatoblastoma (HB), and / or rhabdomyosarcoma (RMS). [Brief description of the drawings]

[0014] [Figure 1] 1 shows process steps for preparing an oral solution containing ribociclib 30 mg / ml. [Diagram 2] FIG. 1 shows process steps for preparing a powder in a bottle formulation containing ribociclib 30 mg / ml. [Diagram 3] The study design for a Phase I / II multicenter study of ribociclib in combination with topotecan and temozolomide (TOTEM) in pediatric patients with relapsed or refractory (r / r) neuroblastoma (NB) and other solid tumors is presented. [Figure 4] The dose-finding schema for Phase I-Part A of the study is depicted in Figure 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] In one embodiment, the present invention relates to an oral pharmaceutical dosage form containing ribociclib, preferably said dosage form is in powder form, preferably said dosage form is produced on a commercial scale, these powder forms help provide a safe and effective treatment.

[0016] In one embodiment, the present invention relates to prepared aqueous formulations, preferably stable oral aqueous pharmaceutical formulations, comprising ribociclib in admixture with excipients and an aqueous vehicle. These prepared aqueous formulations help provide a safe and effective treatment.

[0017] As used herein, the term "powder for oral solution (PFOS)" refers to a pharmaceutical formulation containing pharmaceutical excipients and ribociclib. Prior to administration, PFOS is reconstituted with an aqueous vehicle to form a clear or slightly colored solution. The solution is administered based on the patient's weight or body surface area.

[0018] In one embodiment, the present invention relates to a powder for oral liquid (PFOS) containing ribociclib in an amount of about 10-30%, more preferably about 30% w / w, preferably less than 30% w / w, and preferably about 25.96% w / w.

[0019] As used herein, the terms "drug", "drug substance", or "active ingredient" and derivatives thereof, unless otherwise defined, refer to ribociclib or 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, preferably in the form of the succinate salt.

[0020] As used herein, the term "commercial scale" and its derivatives refer to batch-scale preparations of greater than about 800-10,000 units of PFOS, preferably greater than 5000 units, preferably greater than 7500 units, or at least about 10,000 units.

[0021] Ribociclib succinate has been found to have limited solubility at basic pH compared to acidic pH.To achieve a clear solution of ribociclib succinate upon reconstitution, a sufficient amount of acid is required to adjust the pH of the liquid to the acidic range so that ribociclib succinate is completely solubilized.Suitable solubilizers for use in the present invention are in the form of acid.

[0022] Examples of solubilizers, diluents / fillers, lubricants, antiadherents / lubricants, preservatives, sweeteners, and flavors are understood in the art and such ingredients are outlined, for example, in Martindale--The Extra Pharmacopoeia Pharmaceutical Press, London (1993) and Martin (ed.), Remington's Pharmaceutical Sciences, and Handbook of Pharmaceutical Excipients.

[0023] As used herein, a "solubilizer" is a substance (liquid or solid) that helps to keep a drug uniformly dispersed and dissolved in a solution. A solubilizer prevents the dissolved drug from precipitating out of solution. Suitable solubilizers for use in the present invention include, but are not limited to, citric acid, tartaric acid, glutaric acid, lactic acid, ascorbic acid, glycolic acid, mevalonic acid, malic acid, tartronic acid, maleic acid, fumaric acid, malonic acid, or succinic acid. Combinations of solubilizers can also be used. Citric acid has been found to be disadvantageous because of its hygroscopicity, which alters the flow properties of the powder blend, leading to the formation of loose lumps due to the uptake of moisture by the citric acid. Surprisingly, the disadvantages of citric acid were not observed with tartaric acid, which is also hygroscopic. Suitably, the preferred solubilizer is tartaric acid.

[0024] In one embodiment of the present invention, the solubilizer is present in the powder for oral solution (PFOS) in an amount of about 15-40%, more preferably about 25% w / w, preferably less than 25% w / w, preferably about 22.76% w / w. Preferably, the solubilizer is tartaric acid.

[0025] The term "filler" or "diluent" is used herein in the sense established in the field of pharmaceutics, and they aid in processing, for example by imparting practical size for processing or by providing improved physical properties, such as flowability, compressibility, and hardness, for example, for the purpose of producing bulk, e.g., pharmaceutical compositions. Suitable diluents for use in the present invention include, but are not limited to, microcrystalline cellulose, dibasic calcium phosphate, cellulose, lactose, sucrose, mannitol, sorbitol, starch, and calcium carbonate. Suitably, the preferred diluent is mannitol, more preferably mannitol SD200.

[0026] In one embodiment of the present invention, the diluent is present in the powder for oral solution (PFOS) in an amount of about 10-60%, more preferably about 50% w / w, preferably less than 50% w / w, preferably about 48.22% w / w. Preferably, the diluent is mannitol.

[0027] Examples of "anti-adherents" and "lubricants" include, but are not limited to, colloidal silica, magnesium trisilicate, starch, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, and microcrystalline cellulose.

[0028] In one embodiment of the invention, the anti-adherent agent is present in the powder for oral solution (PFOS) in an amount of about 0.1-5%, more preferably about 0.75% w / w, preferably less than 0.75% w / w, preferably about 0.68% w / w. Preferably, the anti-adherent agent is talc.

[0029] In one embodiment of the present invention, the lubricant is present in the powder for oral solution (PFOS) in an amount of about 0.1-2%, more preferably about 0.75% w / w, preferably less than 0.75% w / w, preferably about 0.68% w / w. Preferably, the lubricant is colloidal silica, more preferably anhydrous colloidal silica (e.g., Aerosil 200 PH).

[0030] As used herein, a "preservative" is used to prevent bacterial and / or fungal growth in a liquid formulation. For example, suitable preservatives include, but are not limited to, parabens (methyl, ethyl, propyl, and butyl), paraben sodium salt, potassium sorbate, sodium benzoate, and sorbic acid. Preferably, the total amount of preservative in the formulation according to the present invention is selected from about 0.1-2%, more preferably about 0.75% w / w, preferably less than about 0.75% w / w, and preferably about 0.68% w / w. Preferably, the preservative is sodium benzoate.

[0031] As used herein, a "sweetener" is a substance (solid or liquid) used to improve the palatability of a formulation. For example, suitable sweeteners include, but are not limited to, sucrose, glucose, sorbitol, sodium saccharin, aspartame, sucralose, and maltitol. Preferably, the amount of sweetener in the formulation according to the present invention is selected from about 0.1-2%, more preferably about 0.5%, preferably less than 0.5% w / w, preferably about 0.34% w / w. Preferably, the sweetener is sodium saccharin.

[0032] As used herein, a "flavor" is a substance (liquid or solid) that imparts a distinctive taste and aroma to a formulation. Flavors also serve to improve the palatability of a formulation. For example, flavors include, but are not limited to, strawberry, vanilla, lemon, grape, cherry, and orange. Preferably, the flavor is orange flavor. Preferably, the amount of flavor in a formulation according to the present invention is selected to be about 0.1-1%, more preferably about 0.75%, preferably less than about 0.75% w / w, preferably about 0.68% w / w. Preferably, the flavor is orange.

[0033] As used herein, a "vehicle" is a liquid used to reconstitute a powder into an oral suspension or solution. The vehicle must be compatible with the formulation so that stability can be achieved and maintained. For example, suitable vehicles include, but are not limited to, purified water, sterile water for injection, and sterile water for irrigation. According to one embodiment, the vehicle is purified water or sterile water.

[0034] pH Adjustment and Preservatives A compatible acid is needed for pH adjustment and to improve the solubility of ribociclib succinate without adversely affecting the stability of the formulation. A more acidic pH aids in the dissolution of ribociclib succinate but may impair the solubility of other excipients such as preservatives and patient tolerance to dose administration. The choice of preservative system, the concentration of the selected preservative, and the pH of the reconstituted liquid are determining factors for preservative effectiveness.

[0035] Preliminary studies with ribociclib succinate oral solution showed that clear solutions were obtained within the pH range of 3.5-4.5, methylparaben required a pH slightly higher than 4, potassium sorbate required a pH of about 3.5, and precipitation was observed in formulations with sodium benzoate. Although the methylparaben and potassium sorbate preservative system was suitable for ribociclib succinate in oral solution, this preservative system is not suitable for powders for reconstitution into oral solution due to the low solubility of methylparaben and potassium sorbate. Surprisingly, sodium benzoate was found to be an effective preservative system for ribociclib succinate powder for reconstitution into oral solution, where sufficient shaking and standing time can be used to ensure dissolution of sodium benzoate and achieve a soluble concentration.

[0036] Flavoring and sweetening agents The taste of ribociclib has been described as bitter in summary. The taste of the solution formulation was evaluated using an e-tongue evaluation study.

[0037] Three different flavors (cherry, strawberry, and orange) were tested with ribociclib succinate solution formulation and its corresponding placebo to evaluate the masking efficiency. The addition of flavors was favorable for masking the taste / bitterness. No differences were detected between the flavors tested. The addition of sweeteners had a favorable effect on the taste.

[0038] In one embodiment, a powder for oral liquid formulation is provided comprising: a) about 10-30%, more preferably about 30% w / w, preferably less than 30% w / w, preferably about 25.96% w / w of ribociclib succinate; b) about 10-60%, more preferably about 50% w / w, suitably less than about 50% w / w, suitably about 48.22% w / w of a diluent, preferably mannitol; c) about 15-40%, more preferably about 25% w / w, suitably less than 25% w / w, suitably about 22.76% w / w of a solubilizer, preferably tartaric acid; d) about 0.1-5%, more preferably about 0.75% w / w, suitably less than about 0.75% w / w, suitably about 0.68% w / w of an anti-adherent agent, preferably talc; e) about 0.1-2%, more preferably about 0.75% w / w, suitably less than about 0.75% w / w, suitably about 0.68% w / w of a lubricant, preferably colloidal silica; f) about 0.1-2%; more preferably about 0.75% w / w, preferably less than 0.75% w / w, preferably about 0.68% w / w of a preservative, preferably sodium benzoate; g) about 0.1-2%; more preferably about 0.5%, preferably less than 0.5% w / w, preferably about 0.34% w / w of a sweetener, preferably sodium saccharin; and h) about 0.1 to 1%; more preferably about 0.75%, preferably less than 0.75% w / w, preferably about 0.68% w / w of a flavor, preferably orange flavor.

[0039] In one embodiment, an oral liquid formulation is provided that includes ribociclib succinate, one or more diluents, one or more solubilizing agents, one or more sweeteners, one or more preservatives, one or more antiadherent agents, one or more lubricants, a flavor, and water.

[0040] In one embodiment, an oral solution is provided that includes ribociclib succinate, mannitol as a diluent, tartaric acid as a solubilizing agent, sodium saccharin as a sweetener, sodium benzoate as a preservative, talc as an antiadherent, colloidal silica as a lubricant, orange flavor, and water.

[0041] The powders for oral liquid (PFOS) of the present invention can be administered in therapeutically effective amounts in combination with therapeutically effective amounts of other agents to treat protein kinase-associated disorders, for example as described in the above-referenced WO 2010 / 020675.

[0042] The term "effective amount" and its derivatives refer to an amount of a drug or active ingredient that elicits the biological or medical response of a tissue, system, animal or human that is desired, for example, by a researcher or clinician. Additionally, the term "therapeutically effective amount" refers to an amount that results in the treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a slowing of the rate of progression of a disease or disorder, compared to a corresponding subject not administered such amount. The term also includes within its scope an amount effective to enhance normal physiological function.

[0043] The term "co-administration" as used herein refers to either simultaneous or separate sequential administration of a solid or liquid oral pharmaceutical dosage form containing ribociclib with one or more additional active agents known to be useful in the treatment of cancer, including chemotherapy and radiation therapy. The term one or more additional active agents as used herein includes any compound or therapeutic agent known to have or exhibit advantageous properties when administered to a patient in need of cancer treatment. As used herein, "one or more additional active agents" is used interchangeably with additional antineoplastic agents or drugs. Preferably, when administration is not simultaneous, the compounds are administered in close time proximity to each other. Furthermore, it does not matter whether the compounds are administered in the same dosage form, for example, one compound may be administered by injection and another compound may be administered orally. Suitably, "co-administration" is primarily composed of a solid or liquid oral pharmaceutical dosage form containing ribociclib and a second pharmaceutical dosage form containing an additional active agent. Suitably, the "co-administration" consists primarily of a solid or liquid oral pharmaceutical dosage form containing ribociclib, a second pharmaceutical dosage form containing an additional active agent, and a third pharmaceutical dosage form containing another additional active agent.

[0044] Typically, any anti-neoplastic agent that has activity against the susceptible tumor being treated can be co-administered in the treatment of cancer in the present invention. Examples of such agents are described in Cancer Principles and Practice of Oncology by V.T.Divita and S.Hellman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. Those skilled in the art will be able to identify which combinations of agents are useful based on the specific properties of the agents and the cancer in question. Exemplary antineoplastic agents useful in the present invention include, but are not limited to, microtubule inhibitors such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotics such as anthracyclines, actinomycin, and bleomycin; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogs and antifolate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormone analogs; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; and cancer metabolism inhibitors.

[0045] The method of the present invention for inhibiting the activity of cyclin-dependent kinases (CDK) 4 and 6 in humans comprises administering to a subject in need of such inhibition a therapeutically effective amount of the powder for oral liquid formulation of the present invention.

[0046] The present invention also provides the use of ribociclib in the manufacture of a powder for an oral liquid formulation of the present invention.

[0047] The present invention also provides the use of ribociclib in the manufacture of a powder for an oral liquid formulation of the present invention for use in the treatment of cancer.

[0048] In one embodiment, the cancer is neuroblastoma (NB), medulloblastoma (MB), high-grade glioma (HGG), malignant rhabdoid tumor (MRT), hepatoblastoma (HB) and / or rhabdomyosarcoma (RMS).

[0049] In another embodiment, the cancer is recurrent or refractory neuroblastoma (NB), recurrent or refractory medulloblastoma (MB), recurrent or refractory high grade glioma (HGG), recurrent or refractory malignant rhabdoid tumor (MRT), recurrent or refractory hepatoblastoma (HB) and / or recurrent or refractory rhabdomyosarcoma (RMS).

[0050] The present invention also provides the use of ribociclib in the manufacture of a powder for an oral liquid formulation of the present invention for use in inhibiting CDK.

[0051] The present invention also provides a powder for oral liquid formulation for use as a CDK inhibitor, which comprises ribociclib and a pharma- ceutically acceptable carrier of the present invention.

[0052] The present invention also provides a powder for oral liquid formulation for use in the treatment of cancer, comprising ribociclib and a pharma- ceutically acceptable carrier of the present invention.

[0053] The present invention also provides a powder for oral liquid formulation for use in inhibiting CDK, which comprises ribociclib and a pharma- ceutically acceptable carrier of the present invention.

[0054] In one embodiment, a method is provided for treating a pediatric patient with neuroblastoma, medulloblastoma, high grade glioma, malignant rhabdoid tumor, hepatoblastoma, and / or rhabdomyosarcoma comprising administering ribociclib in a powder for oral liquid formulation of the present invention co-administered with topotecan and temozolomide.

[0055] In yet another embodiment, a method is provided for treating a pediatric patient with relapsed or refractory neuroblastoma, relapsed or refractory medulloblastoma, relapsed or refractory high-grade glioma, relapsed or refractory malignant rhabdoid tumor, relapsed or refractory hepatoblastoma, and / or relapsed or refractory rhabdomyosarcoma, comprising administering ribociclib in a powder for oral solution formulation of the present invention in combination with topotecan and temozolomide. In a preferred embodiment, the pediatric patient has relapsed or refractory neuroblastoma.

[0056] In another embodiment, a method of treating a pediatric patient with neuroblastoma, medulloblastoma, high grade glioma, malignant rhabdoid tumor, hepatoblastoma, and / or rhabdomyosarcoma is provided comprising administering ribociclib in a powder for oral liquid formulation of the present invention sequentially with topotecan and temozolomide.

[0057] In yet another embodiment, a method is provided for treating a pediatric patient with relapsed or refractory neuroblastoma, relapsed or refractory medulloblastoma, relapsed or refractory high-grade glioma, relapsed or refractory malignant rhabdoid tumor, relapsed or refractory hepatoblastoma, and / or relapsed or refractory rhabdomyosarcoma, comprising administering ribociclib in powder for oral liquid formulation of the present invention sequentially with topotecan and temozolomide. In a preferred embodiment, the pediatric patient has relapsed or refractory neuroblastoma.

[0058] In another embodiment, a method is provided for treating a pediatric patient with relapsed or refractory neuroblastoma, relapsed or refractory medulloblastoma, relapsed or refractory high grade glioma, relapsed or refractory malignant rhabdoid tumor, relapsed or refractory hepatoblastoma, and / or relapsed or refractory rhabdomyosarcoma comprising orally administering ribociclib succinate in a powder for oral liquid formulation of the present invention at a dose of 200 mg / m2 / day, 280 mg / m2 / day, or 350 mg / m2 / day on days 1-21 of a 28 day cycle in combination with intravenous topotecan 0.75 mg / m2 / day on days 1-5 of a 28 day cycle, and oral temozolomide 150 mg / m2 / day on days 1-5 of a 28 day cycle.

[0059] In another embodiment, a method is provided for treating a pediatric patient with relapsed or refractory neuroblastoma, relapsed or refractory medulloblastoma, relapsed or refractory high grade glioma, relapsed or refractory malignant rhabdoid tumor, relapsed or refractory hepatoblastoma, and / or relapsed or refractory rhabdomyosarcoma comprising orally administering ribociclib succinate in a powder for oral liquid formulation of the present invention at a dose of 200 mg / m2 / day, 280 mg / m2 / day, or 350 mg / m2 / day on days 6-21 of a 28 day cycle, sequentially with intravenous topotecan 0.75 mg / m2 / day on days 1-5 of a 28 day cycle, and oral temozolomide 150 mg / m2 / day on days 1-5 of a 28 day cycle.

[0060] In another embodiment, a method of treating a pediatric patient with relapsed or refractory neuroblastoma, relapsed or refractory medulloblastoma, relapsed or refractory high grade glioma, relapsed or refractory malignant rhabdoid tumor, relapsed or refractory hepatoblastoma, and / or relapsed or refractory rhabdomyosarcoma is provided comprising administering orally ribociclib succinate at doses of 200 mg / m2 / day, 280 mg / m2 / day, or 350 mg / m2 / day on days 1-21 of a 28 day cycle, co-administered with intravenous topotecan 0.75 mg / m2 / day on days 1-5 of a 28 day cycle, and oral temozolomide 150 mg / m2 / day on days 1-5 of a 28 day cycle.

[0061] In another embodiment, a method of treating a pediatric patient with relapsed or refractory neuroblastoma, relapsed or refractory medulloblastoma, relapsed or refractory high grade glioma, relapsed or refractory malignant rhabdoid tumor, relapsed or refractory hepatoblastoma, and / or relapsed or refractory rhabdomyosarcoma is provided comprising administering orally ribociclib succinate at doses of 200 mg / m2 / day, 280 mg / m2 / day, or 350 mg / m2 / day on days 6-21 of a 28 day cycle, sequentially with intravenous topotecan 0.75 mg / m2 / day on days 1-5 of a 28 day cycle and oral temozolomide 150 mg / m2 / day on days 1-5 of a 28 day cycle.

[0062] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the following examples are to be construed as merely illustrative and not a limitation of the scope of the present invention.

[0063] All excipients utilized herein are standard pharmaceutical grade excipients available from a number of manufacturers well known to those skilled in the art. EXAMPLES

[0064] The symbols and conventions used in these processes, schemes, and examples herein are consistent with those used in the contemporary scientific literature, e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry. All temperatures are expressed in °C (Celsius) unless otherwise noted.

[0065] Example 1 For ease of swallowing, liquid formulations containing ribociclib were evaluated in oral solution form, which may further enhance the absorption rate since such a form does not require in vivo disintegration or dissolution of the drug substance.

[0066] Formulation preparation An oral solution containing 30 mg / ml of ribociclib was prepared according to the procedure set forth in the flow chart of Figure 1. The process of Example 1 resulted in a composition having the following composition as shown in Table 1.

[0067] [Table 1]

[0068] The resulting formulation contains ribociclib 30 mg / mL as a clear to milky orange-flavored aqueous solution. The formulation was found to be unstable at room temperature, requiring storage under refrigerated conditions, and had a limited shelf life of 12 months under refrigerated storage conditions at 2-8 °C. The color of the ribociclib solution changed from orange to dark brown upon storage at room temperature for 6 months. In addition, a significant decrease in the content of the active ingredient ribociclib was observed upon storage at 25 °C / 60% RH for 12 months.

[0069] Example 2 Preparation of formulations To overcome the stability challenges of ribociclib succinate in aqueous solution from Example 1, a bottled powder formulation containing a blend of drug substance with diluents and other excipients was evaluated.

[0070] Table 2 shows a qualitatively similar formulation to Example 1. In Example 2, the more soluble preservative of methylparaben, sodium salt, was used instead of methylparaben. Another change was the addition of the water-soluble diluent mannitol to add bulk to the material and support uniform filling into glass bottles.

[0071] [Table 2]

[0072] Ribociclib succinate was dry blended with the remaining excipients listed in the formulation to form the final powder for oral suspension; the powder was filled into 30 ml amber glass bottles. These bottles were stored under accelerated stability conditions at 40°C / 75% RH (4 weeks). The physical properties of the powder after 4 weeks of accelerated storage were compared to a control sample at 2-8°C.

[0073] The powder blend was observed to turn into a hard mass upon exposure to elevated temperature and humidity; however, the control sample stored at 2-8°C exhibited a free-flowing powder. The change in powder flow characteristics and formation of loose masses is believed to be due to moisture uptake by citric acid due to its hygroscopic nature. Appropriate selection of container closure system and its closure should be considered to protect the formulation from moisture during storage.

[0074] Example 3 Preparation of formulations To improve the physical stability of the drug substance blend and address the undesirable lump formation due to citric acid in the formulation of Example 2, a two-phase system was evaluated in which the citric acid was separated from the drug substance blend in one bottle and kept in solubilized form in another bottle containing the reconstitution vehicle and preservatives. Phase 1 contained a bottled powder of the drug substance blend without citric acid as described in Table 3A, and phase 2 contained the reconstitution solvent containing citric acid and a preservative as described in Table 3B.

[0075] [Table 3]

[0076] [Table 4]

[0077] In Phase 1 (powder phase for reconstitution), a four-step manufacturing process was used resulting in batch E002A with a batch size of 3.016 kg (260 bottles). The first process step involves dividing the mannitol into two equal parts and sieving one part of the mannitol with Aerosil through a 0.4 mm sieve. The second process step involves sieving the strawberry flavor and sodium saccharin through a 0.4 mm sieve and adding it to the first step blend. The third step involves sieving the second part of the mannitol and ribociclib succinate through a 0.4 mm sieve in an isolator and blending together with the second step mixture in a Turbula for 5 minutes. The fourth process step involves adding talc to the Turbula and then blending the mixture again for 5 minutes. The resulting blend is filled by hand into 180 ml bottles with a fill weight of 11.443 g to 11.658 g.

[0078] A four-step manufacturing process was used for the second phase, the liquid phase, resulting in batch E002B with a batch size of 26 L (260 bottles). The first process step involves adding purified water to a 35 L container. The second process step involves sieving sodium methylparaben through a 0.4 mm sieve. The third process step involves dissolving sodium methylparaben in the water from the first step. The fourth process step involves dissolving citric acid in the contents of the third step followed by filling 100 ml ± 5% into 180 ml bottles.

[0079] Example 4 Preparation of formulations To address the undesirable lump formation caused by citric acid in the formulation of Example 2, the formulation shown in Table 4 was evaluated containing an alternative solubilizer, tartaric acid, since the bottled powder formulation cannot contain a desiccant.

[0080] [Table 5]

[0081] The formulation shown in Table 4 was prepared in a 12-step manufacturing process to obtain batch E005 with a batch size of 3.016 kg (260 bottles). The first process step involves sieving half of the mannitol with Aerosil and tartaric acid through a 0.4 mm sieve. The second process step involves mixing the first step blend in a Turbula mixer for 5 minutes. The third process step involves splitting the second step blend into four portions. The fourth process step involves sieving sodium methylparaben through a 0.4 mm sieve and blending with portion 1 of the blend from the third step. The fifth process step involves adding portion 2 of the third step blend to the Turbula mixer with the fourth step blend and mixing for 5 minutes. The sixth process step involves adding portion 3 of the third step blend to the Turbula mixer with the fifth step blend and mixing for 5 minutes. The seventh process step includes adding portion 4 of the third step blend to the turbula mixer containing the sixth step blend and blending for 5 minutes. The eighth process step includes sieving the sodium saccharin and strawberry flavor through a 0.4 mm sieve. The ninth process step includes blending the seventh step content with the eighth step content in the turbula mixer for 5 minutes. The tenth process step includes sieving the remaining half of the mannitol and ribociclib succinate through a 0.4 mm sieve and blending the ninth step content with the turbula mixer for 5 minutes. The eleventh process step includes adding talc to the tenth step blend and blending the content mixture in the turbula mixer for 5 minutes. The twelfth step includes filling 14.7 g ± 0.5% of the eleventh step blend into 180 ml glass bottles.

[0082] Example 5 Formulation preparation Table 5 shows formulations qualitatively similar to Example 4. Both formulations were manufactured using the same unit operations and processing parameters, except that citric acid was used instead of tartaric acid. Batch E004 was produced at a batch size of 2.352 kg (160 bottles).

[0083] The process of Example 5 resulted in a formulation having the composition shown in Table 5.

[0084] [Table 6]

[0085] Example 6 Preparation of formulations To overcome the stability challenges of ribociclib succinate in aqueous solution in Example 1, a solution formulation containing an antioxidant: sodium metabisulfite was evaluated to stabilize the drug substance in aqueous solution, as shown in Table 6.

[0086] [Table 7]

[0087] The formulation shown in Table 6 was prepared in a six-step manufacturing process to obtain Batch E006 with a batch size of 1.6 L (160 bottles). The first process step involves adding 90% of the total amount of water to a stainless steel container. The second process step involves dissolving sodium metabisulfite, sodium saccharin, and sodium methylparaben in the water of the first step. The third process step involves adding ribociclib succinate to the contents of the second step to form a uniform dispersion. The fourth process step involves adding citric acid to the contents of step 3 and stirring to form a clear solution. The fifth step involves adding orange flavor to the solution of step 4 and adding the remaining purified water. The sixth step involves flushing the container with nitrogen gas to remove dissolved oxygen and filling the resulting solution into glass bottles.

[0088] Example 7 Stability testing The formulations of Examples 3-6 were comparatively evaluated for chemical and physical stability. Based on early observations, testing with the formulation of Example 6 (Batch E006) was discontinued due to high levels of impurities. The remaining formulations (Examples 3-5) were evaluated at various time points under storage conditions of 25°C / 60% RH and 40°C / 75% RH, as summarized in Tables 7B, 7C, and 7D. The biphasic system of Example 3 performed well at 3 months, but stability testing of the formulations of Example 3 (Batches E002A and E002B) was discontinued after 6 months due to a significant decrease in the content of methylparaben. Comparative observations of the batches of Examples 4 and 5 after 12 months are summarized in Table 7A.

[0089] [Table 8]

[0090] [Table 9]

[0091] [Table 10]

[0092] [Table 11]

[0093] Further stability testing with the formulation of Example 5 was discontinued based on observation of cake formation in the bottles of batch E004 under accelerated stability conditions of 40° C. / 75% RH after 6 months (Table 7C) and under long-term stability conditions of controlled room temperature (CRT) of 25° C. / 60% RH after 12 months (Table 7A).

[0094] Example 8 Preparation of formulations A bottled powder formulation containing a blend of drug substance with diluents and other excipients that can be reconstituted in water to provide a ribociclib concentration of 30 mg / ml was prepared according to the procedure set forth in the flow chart in Figure 2. The process of Example 8 resulted in a composition having the following composition as shown in Table 8:

[0095] [Table 12]

[0096] A 12-step manufacturing process was used to prepare the formulation shown in Table 8. The first two process steps involve deagglomerating the two portions of mannitol (portions 2A and 2B) by sieving through a 1.0 mm screen using a hand sieve or suitable equipment. Process steps 3 and 4 involve deagglomerating the tartaric acid through a 0.8 mm screen using a hand sieve or suitable equipment and pre-sieving the material through a 0.5 mm screen using a hand sieve or suitable equipment. The fifth process step involves adding the mannitol of part 2A to a suitable blender containing sodium benzoate to 25%-70% of the container / blender filling and blending the contents at 476 total revolutions. The sixth process step involves screening the fifth step blend through a 0.5 mm sieve. The seventh process step involves screening the sixth step material through a 0.8 mm sieve. The eighth process step involves adding the sieved material from steps six and seven to a suitable size blender along with talc, aerosil, orange flavor, tartaric acid (from step four) and the remaining amount of mannitol (portion 2B) to achieve a fill of 50% to 65% and blending the contents at 476 total revolutions. The ninth process step involves sieving the eighth step blend through a 0.5 mm screen. The tenth process step involves sieving the ninth step material through a 0.8 mm screen. The eleventh process step involves adding the API drug substance along with the ninth and tenth step sieved blend to the eighth step blender and blending at 644 total revolutions. The twelfth process step involves filling the eleventh step contents into 180 mL amber glass bottles using bottle filling and sealing equipment.

[0097] During step 12, in-process controls (IPCs) evaluate the final blend against acceptance criteria for appearance, blend uniformity of ribociclib succinate (BU), blend uniformity of preservatives (BU), moisture content, loss on drying (LOD), bulk density, tapped density, and particle size distribution (PSD), and in-process controls evaluate bottle filling of the final blend against acceptance criteria for appearance, preservative content uniformity (CU), moisture content, weight variation, ribociclib succinate content, preservative content, microbial limit testing (MET), reconstitution time, and degradation products.

[0098] Example 9 Clinical trials using ribociclib A phase I / II multicenter study evaluating the efficacy and safety of ribociclib in combination with topotecan and temozolomide (TOTEM) in pediatric patients with relapsed or refractory (r / r) neuroblastoma (NB) and other solid tumors such as medulloblastoma (MB), high-grade glioma (HGG), malignant rhabdoid tumor (MRT), hepatoblastoma (HB) and rhabdomyosarcoma (RMS). The study design is illustrated in Figure 3. The study consists of Phase I-Part A (dose finding), followed by multiple expansion cohorts (Phase I-Part B) corresponding to r / rNB, r / rMB, r / rHCG, r / r MRT, r / rHB and r / rRMS, respectively. Phase II will begin after confirmation of antitumor activity in the expansion cohorts of r / rNB patients.

[0099] Participation criteria 1. Age ≥ 12 months and ≤ 21 years at the time of signing the consent form 2. Histologically or cytologically confirmed solid tumors listed below that are progressing despite standard treatment or for which no effective standard treatment exists. a. Neuroblastoma (Phase I and II) i. Histologically proven neuroblastoma according to the International Neuroblastoma Staging System (INSS) ii. Recurrent: recurrent or progressive high-risk neuroblastoma iii. Refractory high-risk disease: when a patient cannot proceed to consolidation therapy (e.g., myeloablative chemotherapy) due to lack of sufficient response to frontline therapy. iv. Patients who are not candidates for anti-GD2 therapy v. Measurable or evaluable disease by cross-sectional imaging (uptake on MIBG scan with or without bone marrow imaging) vi. Baseline scan should be obtained at least 4 weeks after receiving any previous treatment vii. Patients must have MYCN amplification status available prior to screening. If local MYCN results are not available, patients must be willing to provide a tumor biopsy for institutional testing of MYCN amplification status. b. Medulloblastoma (Phase I) Groups 3 or 4, regardless of genetic status (i.e., WNT-activated or non-WNT, SHH-activated or non-SHH). c. High-grade glioma (Phase I study) WHO grade III or WHO grade IV d. Malignant rhabdoid tumor (for Phase I): Includes atypical teratoma / rhabdoid tumor (AT / RT), rhabdoid tumor of the kidney (RTK), and other soft tissue diagnoses defined by two of the following three criteria; (1)+(2) or (1)+(3): i. Morphology and immunophenotypic panel consistent with rhabdoid tumor ii. Deficiency of SMARCB1 confirmed by immunohistochemistry iii. If SMARCB1 immunohistochemistry is equivocal, molecular confirmation of tumor-specific biallelic SMARCB1 deletion / mutation is encouraged and required if SMARCB1 immunohistochemistry is not available. e. Hepatoblastoma (for Phase I studies). Note: Patients with hepatocellular carcinoma (HCC) are not eligible for this study. f. Rhabdomyosarcoma (in Phase I trials) 3. Patients with CNS disease should receive stable doses of steroids with no titration schedule for at least 7 days prior to receiving the first dose of ribociclib. 4. Evaluable or measurable disease as defined by standard imaging criteria appropriate for the patient's tumor type (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1 for HB, MRT (primary non-CNS tumors), and RMS; Revised assessment in neuro-oncology [RANO] criteria for MB, HGG, MRT (primary CNS tumors); International neuroblastoma response criteria [INRC] for NB patients). 5. Applicable to neuroblastoma patients: Patients must have MYCN amplification status available prior to screening; if local MYCN results are not available, patients must be willing to provide a tumor biopsy for institutional testing of MYCN amplification status. 6. Performance Status: A patient who is unable to walk due to paralysis but can sit in a wheelchair without assistance is considered ambulatory for the purposes of assessing the performance score. a. Age ≦16: Lansky Play score ≧50% b. >16 years: Karnofsky Performance Status ≥50% or ECOG <3 7. Life expectancy at the time of enrollment ≥ 12 weeks Adequate bone marrow function (bone marrow may be involved in the tumor) and organ function as defined as: b. Peripheral blood absolute neutrophil count (ANC) ≥ 1000 / mm without growth factor support within 7 days of testing 3 C. Platelet count ≥ 75,000 / mm without growth factor support within 7 days of testing 3 D. Hemoglobin ≥ 8.0 g / dL (transfusion is permitted) e. Total bilirubin ≤ 1.5 x ULN for age (for Gilbert's syndrome, ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN for age) f. Adequate liver function defined as serum total bilirubin ≤ 1.5 x ULN and alanine aminotransferase (ALT) / aspartate aminotransferase (AST) ≤ 3 x ULN (AST / ALT ≤ 5 x ULN in the case of liver metastases) g. Adequate renal function (creatinine clearance or radioisotope-based glomerular filtration rate (GFR) ≥ 60 mL / min / 1.73 m 2 , or serum creatinine ≤ 1.5 × age / gender normal (ULN). h. Adequate cardiac function as defined by echocardiogram as a corrected QT interval (QTc) ≤ 450 msec, fractional shortening (SF) > 29% (> 35% for children < 3 years of age), and left ventricular ejection fraction (LVEF) ≥ 50%. 8. The following laboratory values ​​are within normal range or have been corrected to within normal range with supplements prior to the first dose of study drug: Potassium B. Magnesium c. Total calcium (corrected for serum albumin) 9. Sexually active women must agree to use highly effective contraception during and for 6 months after treatment. In addition, women of childbearing potential must have a negative serum pregnancy test within 7 days prior to receiving the first dose of study drug. Pregnant or breastfeeding women are ineligible for this study. 10. Sexually active men (including those who have had a vasectomy) who do not agree to abstinence must be willing to use condoms during sexual intercourse during study treatment and for 6 months after cessation of treatment. 11. Subject and / or guardian are able to understand and willing to sign an informed consent document.

[0100] Dosage regimen In Phase I-Part A (dose-finding phase), topotecan and temozolomide (TOTEM) are administered at fixed doses while ribociclib doses are escalated until the maximum tolerated dose (MTD) and / or recommended phase II dose (RP2D) of ribociclib in combination with TOTEM is found, as shown in Figure 4.

[0101] Patients received ribociclib at 200 mg / m on days 1–21 of a 28-day cycle. 2 10 mg / m PO (orally) on days 1 to 5 with topotecan (0.75 mg / m PO) on days 1 to 5. 2 / day IV) and temozolomide (150 mg / m 2 / day PO-oral) will be administered concomitantly. The dose of ribociclib will be increased to dose level 2 (280 mg / m 2 / day) and dose level 3 (350 mg / m 2 / day) until the MTD or a lower ribociclib dose suitable for the co-administration schedule is found. The MTD is the highest drug dose expected to avoid dose-limiting toxicity (DLT) in more than 33% of treated patients during the first cycle of ribociclib treatment in combination with TOTEM. The RP2D will be determined based on a comprehensive review of safety data and potential pharmacokinetic, biomarker and preliminary efficacy data.

[0102] If the MTD / RP2D of ribociclib is not met for the concurrent dosing schedule despite additional / immediate dosing levels being evaluated, topotecan (0.75 mg / m 2 / day IV) and temozolomide (150 mg / m on days 1 to 5 2 / day PO-oral), followed by ribociclib 200 mg / m on days 6-21 of a 28-day cycle. 2 A sequential dosing schedule will be explored in which patients will be treated with a starting dose (dose level 1) of 280 mg / m PO (orally) on subsequent 28-day cycles. Ribociclib doses will be increased to dose level 2 (280 mg / m PO) on subsequent 28-day cycles depending on tolerance. 2 / day) and dose level 3 (350 mg / m 2 / day) until the MTD or a lower ribociclib dose suitable for the sequential dosing schedule is found. Once the MTD / RP2D of the sequential dosing schedule is found, dose-finding for Phase I, Part A will be considered complete and Phase I, Part B will be initiated to evaluate the above MTD / RP2D of the sequential dosing schedule in more patients.

[0103] Criteria for starting a new treatment cycle To start a new treatment cycle, patients must meet the following criteria: - Peripheral blood absolute neutrophil count (ANC) ≥ 1000 / mm 3 -Platelet count ≥75,000 / mm 3 - All non-hematologic toxicities must be ≤ Grade 1 or baseline levels, whichever is lower -No other DLTs listed in the DLT table

[0104] Do not start a new treatment cycle until the above criteria are met: - If a new treatment cycle can be started after ≦7 days, resume treatment at the same dose level. -If a new treatment cycle can be initiated >7-28 days later, resume treatment at a lower dose level. - If a new treatment cycle is delayed >28 days, discontinue treatment.

[0105] Criteria for Defining Dose-Limiting Toxicity (DLT) Using CTCAE v5.0 Dose-limiting toxicity (DLT) was defined as any adverse event (AE) or laboratory abnormality suspected to be related to treatment with ribociclib (i.e., assessed as unrelated to disease progression, intercurrent illness, or concomitant medications) and included AEs and laboratory abnormalities that resulted in failure to meet criteria for retreatment or initiation of a new treatment cycle within 7 days of the planned start of the new cycle. The criteria for defining DLT are shown in Table 9.

[0106] [Table 13]

[0107] [Table 14]

[0108] Duration of treatment Patients will continue combination treatment for up to 12 cycles of the investigational combination regimen until discontinuation of study treatment due to unacceptable toxicity, confirmed disease progression (according to corresponding tumor assessment criteria), death, or other reasons (e.g., loss to follow-up, subject / parent / guardian decision, or withdrawal of consent).

[0109] After completion of 12 cycles of investigational combination therapy, if clinical benefit (stable disease or better) continues with acceptable toxicity, patients may continue to receive ribociclib alone at the same dose as they received in combination with TOTEM (or matching placebo for patients enrolled in the Phase II study and randomized to the control arm) for 21 consecutive days, until further treatment is not possible due to disease progression or the occurrence of unacceptable toxicity.

[0110] The study will not allow crossover of treatment from one arm to another.

[0111] While the preferred embodiments of the present invention have been illustrated above, it is to be understood that the invention is not limited to the detailed indications disclosed herein, and the right to all modifications falling within the scope of the following claims is reserved.

Claims

1. a) about 10% to about 30% w / w of ribociclib succinate; b) from about 10% to about 60% w / w of one or more diluents; c) about 15% to about 40% w / w of one or more solubilizing agents; and d) A powder for oral liquid containing from about 0.1% to about 2% w / w of one or more preservatives.

2. e) from about 0.1% to about 5% w / w of one or more anti-adherent agents; f) from about 0.1% to about 2% w / w of one or more lubricants: g) from about 0.1% to about 2% w / w of one or more sweeteners; and 10. The powder of claim 1, further comprising h) about 0.1% to about 1% w / w of a flavor.

3. 3. The powder of claim 1 or 2, wherein the one or more diluents is mannitol.

4. 3. The powder of claim 1 or 2, wherein the one or more solubilizing agents is tartaric acid.

5. 3. The powder of claim 1 or 2, wherein the one or more preservatives is sodium benzoate.

6. 3. The powder of claim 2, wherein the one or more anti-adherent agents is talc.

7. 3. The powder of claim 2, wherein the one or more antiglidants is colloidal silica.

8. 3. The powder of claim 2, wherein the one or more sweeteners is sodium saccharin.

9. 3. The powder of claim 2, wherein the flavor is orange.

10. An oral liquid formulation, a) about 10% to about 30% w / w of ribociclib succinate; b) from about 10% to about 60% w / w of one or more diluents; c) about 15% to about 40% w / w of one or more solubilizing agents; d) from about 0.1% to about 2% w / w of one or more preservatives; and e) An oral solution comprising an aqueous vehicle in an amount sufficient to bring the final volume of said oral solution to a desired volume.

11. f) from about 0.1% to about 5% w / w of one or more anti-adherent agents; g) from about 0.1% to about 2% w / w of one or more lubricants: h) from about 0.1% to about 2% w / w of one or more sweeteners; and 11. The oral liquid formulation of claim 10, comprising: i) about 0.1% to about 1% w / w of a flavor.

12. 11. The oral solution of claim 10, wherein the one or more diluents is mannitol.

13. 12. The oral solution of claim 10 or 11, wherein the one or more solubilizing agents is tartaric acid.

14. 12. The oral solution of claim 10 or 11, wherein the one or more preservatives is sodium benzoate.

15. 12. The oral solution of claim 11, wherein the one or more anti-adherent agents is talc.

16. 12. The oral solution of claim 11, wherein the one or more antiglidants is colloidal silica.

17. 12. The oral solution of claim 11, wherein the one or more sweeteners is sodium saccharin.

18. The oral liquid of claim 11 , wherein the flavor is orange.

19. a) about 20% to about 30% w / w of ribociclib succinate; b) about 40% to about 60% w / w mannitol; c) about 15% to about 25% w / w tartaric acid; and d) A powder for oral liquid comprising about 0.5% to about 1% w / w sodium benzoate.

20. An oral liquid formulation, a) about 20% to about 30% w / w of ribociclib succinate; b) about 40% to about 60% w / w mannitol; c) about 15% to about 25% w / w tartaric acid; and d) about 0.5% to about 1% w / w sodium benzoate; and e) An oral solution comprising an aqueous vehicle in an amount sufficient to bring the final volume of said oral solution to a desired volume.

21. 21. The formulation of any one of claims 1, 2, 10, 11, 19, and 20 for use in the treatment of cancer in a human.

22. 21. The formulation of any one of claims 1, 2, 10, 11, 19, and 20 for use in inhibiting cyclin-dependent kinases (CDKs) 4 and 6 in humans.

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