Compositions and methods for treating abnormal cell growth

Abstract

The present invention relates to oral dosage forms and methods for the treatment of abnormal cell growth (e.g., cancer) in mammals, especially humans.

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: January 9, 2015; application number: 202211274002.0; invention name: Compositions and methods for treating abnormal cell growth).

[0002] Priority interest

[0003] This application claims priority to U.S. Provisional Application No. 61 / 925,467, filed on January 9, 2014, which is incorporated herein by reference. Technical Field

[0004] The present invention relates to compositions (eg, oral dosage forms) and methods for treating abnormal cell growth (eg, cancer) in mammals, particularly humans. Background Art

[0005] There is strong evidence that focal adhesion kinase (FAK), a cytoplasmic non-receptor tyrosine kinase, plays an important role in the signal transduction pathway of the cell matrix (Clark and Brugge 1995, Science 268: 233-239) and its abnormal activation is associated with an increased likelihood of tumor metastasis (Owens et al. 1995, Cancer Research 55: 2752-2755). FAK was initially identified as a 125 kDa protein that is highly tyrosine phosphorylated in cells transformed by v-Src. FAK was subsequently found to be a tyrosine kinase concentrated at focal adhesions, which are contact points between cultured cells and their underlying matrix and highly tyrosine phosphorylated sites. FAK is phosphorylated and therefore activated in response to the binding of the extracellular matrix (ECM) to integrins. Currently, studies have shown that increased FAK mRNA levels are associated with invasive transformation of tumors and that the decline of FAK expression (by using antisense oligonucleotides) induces apoptosis of tumor cells (Xu et al. 1996, Cell Growth and Diff. 7: 413-418). In addition to expression in most tissue types, elevated levels of FAK are found in most human cancers, such as in highly invasive metastases.

[0006] Therefore, there is a need for compounds (e.g., inhibitors), compositions (e.g., formulations, e.g., oral formulations (e.g., oral dosage forms)), and methods of using non-receptor tyrosine kinase inhibitors (e.g., FAK) for treating abnormal cell growth. U.S. Patent No. 8,247,411 relates to a large class of new pyrimidine derivatives that are kinase inhibitors, and more specifically, FAK inhibitors. For example, these compounds can be used to treat abnormal cell growth. Summary of the invention

[0007] In one aspect, the invention includes compositions, e.g., pharmaceutical compositions, comprising VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride), e.g., admixed with an excipient (e.g., a binder, e.g., a polymer, e.g., a precipitation inhibitor, e.g., hydroxypropylmethylcellulose (HPMC) or hydroxypropylmethylcellulose (e.g., hydroxypropylmethylcellulose acetate succinate (HPMC-AS) or hydroxypropylmethylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF); e.g., a polyol (e.g., mannitol-starch (e.g., Pearlitol Flash), mannitol, sorbitol)). In some embodiments, the excipient is a binder. In some embodiments, the excipient is a polymer. In some embodiments, the polymer is a precipitation inhibitor. In some embodiments, the precipitation inhibitor is HPMCAS. In some embodiments, the precipitation inhibitor is HPMCAS-HF. In some embodiments, the excipient reduces precipitation (e.g., precipitation of VS-6063 in solution, e.g., in vivo) when administered orally. In some embodiments, the excipient increases the bioavailability (e.g., improves absorption) of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) when administered orally. In some embodiments, the ratio (e.g., relative amount) of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) to the polymer by weight is about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9. In some embodiments, the polymer is a precipitation inhibitor, for example, hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, for example, HPMCAS-H, HPMCAS-M, HPMCAS-HF). In some embodiments, the VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) is present in the composition in an amount of about 10%, 25%, 30%, 31%, 32%, 32.5%, 33%, 34%, 35%, 40%, 45%, 50% or more by weight (w / w) relative to the amount of the provided polymer (e.g., precipitation inhibitor). In some embodiments, the composition is mixed with 5-50%, 5-30%, 10-30%, 10-20%, 12-15% or 13% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per unit weight of the composition.In some embodiments, the polymer is present at 25-55%, 35-45%, 38-43%, or 40% by weight of the polymer per unit weight of the oral dosage form. In some embodiments, the polymer is a precipitation inhibitor, for example, hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, for example, HPMCAS-H, HPMCAS-M, HPMCAS-HF). In some embodiments, the precipitation inhibitor is HPMCAS. In some embodiments, the precipitation inhibitor is HPMCAS-HF.

[0008] In some embodiments, the composition is formulated as an oral dosage form. In some embodiments, the oral dosage form comprises 5-50%, 5-30%, 10-30%, 10-20%, 12-15% or 13% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per unit weight of the oral dosage form. In some embodiments, the VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) is present at 13% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per unit weight of the oral dosage form.

[0009] In some embodiments, the oral dosage form is a tablet. In some embodiments, the tablet is provided by direct compression of a physical blend or mixture. In some embodiments, the physical blend or mixture is provided by a dry granulation process.

[0010] In some embodiments, the tablet has a tablet hardness of about 5-20 kP, 7-17 kP, 5-15 kP or 10-15 kP. In some embodiments, the tablet has a tablet hardness of about 5 kP, 6 kP, 7 kP, 8 kP, 9 kP, 10 kP, 11 kP, 12 kP, 13 kP or more kP. In some embodiments, the tablet has a disintegration time of about 1-20 minutes, 3-17 minutes, 5-15 minutes or 9-15 minutes. In some embodiments, the tablet has a disintegration time of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more minutes.

[0011] In some embodiments, the pharmaceutical composition further comprises one or more fillers (e.g., microcrystalline cellulose (e.g., microcrystalline cellulose PH 102, e.g., Avicel PH 102); lactose (e.g., lactose monohydrate (e.g., FastFlo 316)). In some embodiments, the filler is present at 5-80%, 10-70%, 20-60%, 30-60%, 30-50%, or 42% by weight of the filler per unit weight of the oral dosage form. In some embodiments, the filler is a mixture of two fillers. In some embodiments, one filler is microcrystalline cellulose, microcrystalline cellulose PH 102 (e.g., Avicel PH 102). In some embodiments, one filler is lactose monohydrate (e.g., FastFlo 316). In some embodiments, the filler is present at 10-30%, 15-25%, or 20% by weight of the filler per unit weight of the oral dosage form. In some embodiments, the filler is present in a 1:1 w / w ratio.

[0012] In some embodiments, the oral dosage form comprises a disintegrant (e.g., a polymer, e.g., a cross-linked polymer, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, carboxymethyl cellulose or cross-linked sodium carboxymethyl cellulose; a starch, e.g., a modified starch, e.g., sodium starch glycolate). In some embodiments, the disintegrant is sodium starch glycolate. In some embodiments, the disintegrant is present at 0-5%, 1-5%, 2.5-5%, or 3% by weight of the disintegrant per unit weight of the oral dosage form.

[0013] In some embodiments, the oral dosage form comprises a lubricant (e.g., talc, silicon dioxide, fat, e.g., magnesium stearate). In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is present at 0.1-2% or 0.2-1.5% by weight of lubricant per unit weight of the oral dosage form. In some embodiments, the lubricant is present at 1% w / w. In some embodiments, the lubricant is present at 0.5% w / w.

[0014] In one embodiment, the oral dosage forms described herein have a greater C 20 than a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in the blend. max In one embodiment, the oral dosage form described herein has a C maxThe value is at least 1.1 times (e.g., at least 1.25 times, at least 1.5 times, at least 2 times, at least 3 times, at least 5 times) greater than a reference dosage form of the same dose (e.g., a dosage form having 100 mg of VS-6063 compared to a reference dosage form also having 100 mg of VS-6063). In one embodiment, the C value of the oral dosage form described herein is at least 1.1 times (e.g., at least 1.25 times, at least 1.5 times, at least 2 times, at least 3 times, at least 5 times) greater than a reference dosage form of the same dose (e.g., a dosage form having 100 mg of VS-6063 compared to a reference dosage form also having 100 mg of VS-6063). max The value is at least 1.6 times, at least 1.7 times, at least 1.8 times, at least 1.9 times, at least 2 times, at least 3 times, or at least 4 times that of a reference dosage form having the same dosage.

[0015] In one embodiment, the oral dosage forms described herein have a reduced food effect compared to a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in the blend. In one embodiment, the T of a subject administered an oral dosage form described herein in the fed and fasted states is 2.5 mmol / l. max The difference between the T values ​​for the fed and fasted states of subjects administered the same dose of a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in the blend) is less than the T values ​​for the fed and fasted states of subjects administered the same dose of a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in the blend max The difference between the values.

[0016] In one embodiment, when administered to a subject, the oral dosage forms described herein have consistent exposure. In one embodiment, when administered to a subject, the oral dosage forms described herein provide exposures with less than 50% exposure-related variability across multiple subjects compared to a reference oral dosage form at the same dose. In one embodiment, when administered to a subject, the oral dosage forms described herein provide exposures with less than 40%, 30%, 20%, or 10% exposure-related variability across multiple subjects compared to a reference oral dosage form at the same dose.

[0017] In one aspect, the invention includes an oral dosage form comprising: VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) in an amount of about 5-50% by weight on a dry weight basis; a pharmaceutically acceptable excipient (e.g., a binder, e.g., a polymer, e.g., a precipitation inhibitor, e.g., hydroxypropylmethylcellulose (HPMC) or hydroxypropylmethylcellulose (e.g., hydroxypropylmethylcellulose acetate succinate (HPMC-AS) or hydroxypropylmethylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in an amount of about 25-55% by weight on a dry weight basis; a pharmaceutically acceptable filler (e.g., microcrystalline cellulose, e.g., microcrystalline cellulose PH 102, e.g., Avicel PH102) in an amount of about 10-30% by weight on a dry weight basis; a second pharmaceutically acceptable filler (e.g., lactose, e.g., lactose monohydrate, e.g., FastFlo 316) in an amount of about 10-30% by weight on a dry weight basis; a pharmaceutically acceptable disintegrant (e.g., starch, e.g., modified starch, e.g., sodium starch glycolate) in an amount of about 0-5% by weight on a dry weight basis; and a pharmaceutically acceptable lubricant (e.g., magnesium stearate) in an amount of about 0.1-2% by weight on a dry weight basis. In some embodiments, the present invention includes an oral dosage form comprising: VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) in an amount of about 10-30% by weight on a dry weight basis. pharmaceutically acceptable excipients (e.g., binders, e.g., polymers, e.g., precipitation inhibitors, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF), in an amount of about 35-55% by weight on a dry weight basis; pharmaceutically acceptable fillers (e.g., microcrystalline cellulose, e.g., microcrystalline cellulose PH 102, for example, Avicel PH102), in an amount of about 15-25% by weight on a dry weight basis; a second pharmaceutically acceptable filler (e.g., lactose, for example, lactose monohydrate, for example, FastFlo 316), in an amount of about 15-25% by weight on a dry weight basis; a pharmaceutically acceptable disintegrant (e.g., starch, for example, modified starch, for example, sodium starch glycolate), in an amount of about 2.5-3.5% by weight on a dry weight basis; and a pharmaceutically acceptable lubricant (e.g., magnesium stearate), in an amount of about 0.2-1.5% by weight on a dry weight basis. In some embodiments, the oral dosage form is a compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet.

[0018] In some embodiments, the excipient is one or more binders (e.g., polyvinyl pyrrolidone (e.g., polyvinyl pyrrolidone vinyl acetate copolymer (PVP / VA), copovidone), other copolymers (e.g., including polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g., Soluplus))). In some embodiments, the binder is a polymer, for example, a precipitation inhibitor. In some embodiments, the binder comprises two binders (e.g., polyvinyl pyrrolidone (e.g., polyvinyl pyrrolidone vinyl acetate copolymer (PVP / VA), copovidone), other copolymers (e.g., including polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g., Soluplus))). In some embodiments, the binder is a polymer, for example, a precipitation inhibitor. In some embodiments, the binder is present in an amount of about 37.5% by weight of the binder per unit weight of the oral dosage form. In some embodiments, the binder is present in an amount of about 25% by weight of the binder per unit weight of the oral dosage form. In some embodiments, the filler is a polyol (eg, mannitol-starch (eg, Pearlitol Flash), mannitol, sorbitol).

[0019] In some embodiments, the disintegrant is polyvinylpolypyrrolidone (eg, crospovidone). In some embodiments, the disintegrant is present at 0-30%, 5-25%, 5-20%, 5-15%, or 10% by weight of the disintegrant per unit weight of the oral dosage form.

[0020] In one embodiment, the oral dosage forms described herein have a greater C 20 than a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in the blend. max In one embodiment, the oral dosage form described herein has a C max The value is at least 1.1 times (e.g., at least 1.25 times, at least 1.5 times, at least 2 times, at least 3 times, at least 5 times) greater than a reference dosage form of the same dose (e.g., a dosage form having 100 mg of VS-6063 compared to a reference dosage form also having 100 mg of VS-6063). In one embodiment, the C value of the oral dosage form described herein is at least 1.1 times (e.g., at least 1.25 times, at least 1.5 times, at least 2 times, at least 3 times, at least 5 times) greater than a reference dosage form of the same dose (e.g., a dosage form having 100 mg of VS-6063 compared to a reference dosage form also having 100 mg of VS-6063). max The value is at least 1.6 times, at least 1.7 times, at least 1.8 times, at least 1.9 times, at least 2 times, at least 3 times, or at least 4 times that of a reference dosage form having the same dosage.

[0021] In one embodiment, the oral dosage forms described herein have a reduced food effect compared to a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in the blend. In one embodiment, the T of a subject administered an oral dosage form described herein in the fed and fasted states is 2.5 mmol / l. max The difference between the T values ​​for the fed and fasted states of subjects administered the same dose of a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in the blend) is less than the T values ​​for the fed and fasted states of subjects administered the same dose of a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in the blend max The difference between the values.

[0022] In one embodiment, when administered to a subject, the oral dosage forms described herein have consistent exposure. In one embodiment, when administered to a subject, the oral dosage forms described herein provide exposures with less than 50% exposure-related variability across multiple subjects compared to a reference oral dosage form at the same dose. In one embodiment, when administered to a subject, the oral dosage forms described herein provide exposures with less than 40%, 30%, 20%, or 10% exposure-related variability across multiple subjects compared to a reference oral dosage form at the same dose.

[0023] In one aspect, the invention includes an oral dosage form comprising: VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) in an amount of about 10-15% by weight on a dry weight basis; a pharmaceutically acceptable excipient (e.g., a binder (e.g., polyvinyl pyrrolidone (e.g., polyvinyl pyrrolidone vinyl acetate copolymer (PVP / VA), copovidone)) in an amount of about 15-25% by weight on a dry weight basis; a second pharmaceutically acceptable excipient (e.g., a binder (e.g., polyvinyl acetate (e.g., Soluplus)) in an amount of about 15-25% by weight on a dry weight basis); a pharmaceutically acceptable filler (e.g., a polyol (e.g., mannitol-starch (e.g., Pearlitol Flash))) in an amount of about 30-40% by weight based on dry weight; a pharmaceutically acceptable disintegrant (e.g., crospovidone) in an amount of about 5-15% by weight based on dry weight and a pharmaceutically acceptable lubricant (e.g., magnesium stearate) in an amount of about 0.2-1.5% by weight based on dry weight.

[0024] In some embodiments, the VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) is present in an amount of 10% by weight of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) per unit weight of the oral dosage form. In some embodiments, the VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) is present in an amount of 25% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per unit weight of the oral dosage form. In some embodiments, the VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) is present in an amount of 50% by weight of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) per unit weight of the oral dosage form.

[0025] In some embodiments, the physical blend or mixture is provided by a spray drying dispersion method. In some embodiments, the method provides a solid dispersion comprising at least 10% by weight (e.g., 10%, 20%, 25%, 40%, 50% or more) of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride). In some embodiments, the method provides a solid dispersion comprising 10% by weight of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride). In some embodiments, the method provides a solid dispersion comprising 25% by weight of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride). In some embodiments, the dispersion further comprises a polymer, for example, a polymer matrix (e.g., hydroxypropyl methylcellulose acetate succinate (HPMACS) or hydroxypropyl methylcellulose acetate succinate, for example, HPMCAS-H, HPMCAS-M; hydroxypropyl methylcellulose phthalate (HPMCP) or hydroxypropyl methylcellulose phthalate, for example, HPMCP-HP55, HPMCP-HP55S, Methocol E3LV, PVP-VA, Soluplus, PVAP, polymethacrylic acid (e.g., Eudragit, for example, Eudragit L100-55), Soluplus:PVP-VA mixture, Soluplus, HPMCAS (e.g., HPMCAS-H) mixture). In some embodiments, the dispersion further comprises a polymer matrix (e.g., polymethacrylic acid (e.g., Eudragit, for example, Eudragit L100-55)).

[0026] In one aspect, the invention includes an oral dosage form comprising VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) for use in treating a subject who has been determined to have a cancer disease (e.g., mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma), breast cancer (e.g., triple-negative breast cancer), ovarian cancer (e.g., advanced ovarian cancer), lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutant NSCLC)) or a non-hematological malignancy.

[0027] In one aspect, the invention includes a method of treating a disease in a patient in need thereof, the method comprising administering an oral dosage form comprising 10-500 mg of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride), thereby treating the disease. In some embodiments, the disease is a cancer disease (e.g., mesothelioma (e.g., surgically resectable malignant pleural mesothelioma), breast cancer (e.g., triple-negative breast cancer, ovarian cancer (e.g., advanced ovarian cancer)), lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutant NSCLC)) or a non-hematological malignancy.

[0028] In some embodiments, the administration is performed in combination with administration of an additional agent (eg, an anticancer or antitumor agent, eg, a taxane, eg, paclitaxel).

[0029] In one aspect, the present invention includes a method for preparing a unit dosage form of a direct compression tablet, comprising: (a) mixing (e.g., blending) by weight percentage on a dry weight basis: (i) 5-50% by weight of VS-6063 on a dry weight basis; (ii) a pharmaceutically acceptable excipient (e.g., a binder, e.g., a polymer, e.g., a precipitation inhibitor, e.g., HPMC, e.g., HPMCAS-AS, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF); and (iii) at least one pharmaceutically acceptable excipient selected from a pharmaceutically acceptable filler, a pharmaceutically acceptable disintegrant, and a pharmaceutically acceptable lubricant; to form a VS-6063 formulation in the form of a tableting powder that can be directly compressed into a tablet; and (b) compressing the formulation prepared during step (a) into a compressed VS-6063 tablet in a unit dosage form. In some embodiments, the pharmaceutically acceptable filler is present at 30-60% by weight on a dry weight basis. In some embodiments, the pharmaceutically acceptable disintegrant is present at 2.5-5% by weight on a dry weight basis. In some embodiments, the pharmaceutically acceptable lubricant is present at 0.5-2% by weight on a dry weight basis.

[0030] In one aspect, the present invention includes a method of treating a subject having mesothelioma, e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma (e.g., non-metastatic, unresectable), comprising: providing the subject with an effective amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof), thereby treating the subject. In some embodiments, the method comprises providing the subject with an effective course of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof).

[0031] In some embodiments, the subject carries a mutation in a tumor suppressor gene. In some embodiments, the subject carries a mutation in neurofibromin 2 (NF2). NF2 is a tumor suppressor gene and encodes the protein Merlin, which can be used to limit cell proliferation and promote apoptosis. Merlin regulates FAK at least in part by attenuating the phosphorylation of FAK, which disrupts the ability of FAK to interact with some binding ligands; thereby resulting in inhibition of FAK-mediated signaling pathways. Therefore, mutations in the NF2 gene that result in reduced expression and / or activity of Merlin, or reduced Merlin expression and / or activity in the absence of NF2 mutations, can cause increased sensitivity to FAK inhibitors. Thus, cancer patients with one or more changes in the NF2 gene or changes in Merlin expression and / or activity levels (e.g., reduced levels of Merlin expression) may suffer from cancers characterized by increased sensitivity to FAK inhibitors and may therefore benefit from treatment with a compound described herein (e.g., VS-6063, e.g., VS-6063 free base, or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride)). In some embodiments, the subject has abnormal levels of NF2 and or Merlin, e.g., relative to a reference standard, such as a subject without a mutation in a tumor suppressor gene, a subject without a mutation in NF2, or a subject without cancer. In some embodiments, the subject has an abnormal level (e.g., a low level or a dysfunctional level) of Merlin protein. In some embodiments, the method comprises obtaining, e.g., directly or indirectly, information on NF2 and or the subject's Merlin (i.e., Merlin protein) status. In some embodiments, the NF2 and or Merlin status is determined by immunohistochemistry. In some embodiments, the NF2 and / or Merlin status is determined by DNA sequence analysis. In some embodiments, the method comprises testing the subject for NF2 and / or the subject's Merlin status. In some embodiments, the method comprises administering VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) to the subject based on NF2 and / or Merlin status (e.g., mutated NF2).

[0032] In some embodiments, the Merlin expression level is low, reduced, or absent. In some embodiments, the Merlin expression level is compared to a reference standard. In some embodiments, the Merlin expression level is low, reduced, or absent compared to a reference standard. In some embodiments, the Merlin expression level is assessed by the level of Merlin RNA expression. In some embodiments, the Merlin expression level is determined by assessing the level of RNA encoding Merlin. In some embodiments, the Merlin expression level is assessed by the level of Merlin protein expression. In some embodiments, the level of Merlin protein expression is detected by immunohistochemistry or Western blotting. Immunohistochemistry or IHC refers to a method for locating antigens (e.g., proteins) in tissue section cells using the principle of specific binding of antibodies to antigens in biological tissues. In a preferred embodiment, the level of Merlin protein expression is determined by immunohistochemistry.

[0033] In some embodiments, the patient has one or more changes in the NF2 gene.

[0034] In some embodiments, the changes in the NF2 gene include mutations, chromosomal deletions, or changes to the NF2 gene or NF2 promoter. In some embodiments, the changes to the NF2 promoter include changes in methylation, such as hypermethylation. In some embodiments, the assessment includes obtaining information about the patient's NF2 genotype. In some embodiments, the patient's NF2 genotype is compared to a reference standard.

[0035] In some embodiments, the changes in the NF2 gene include mutations, chromosomal deletions, or changes to the NF2 gene. The NF2 gene includes any regulatory sequence, such as a promoter and an enhancer sequence. In some embodiments, the changes in the NF2 gene include mutations, chromosomal deletions, or changes to the NF2 gene. The NF2 gene includes any regulatory sequence, such as a promoter and an enhancer sequence. In some embodiments, the changes in the NF2 gene are one or more mutations. In some embodiments, the changes are single nucleotide polymorphisms. In some embodiments, the changes are point mutations. In some embodiments, the changes are inactivating mutations. In some embodiments, the changes in the NF2 gene are chromosomal deletions. In some embodiments, the changes are inactivating chromosomal deletions. In some embodiments, the changes in the NF2 gene are hypermethylation of the promoter region of the gene.

[0036] Cancer patients having one or more changes in the NF2 gene or changes in Merlin expression and / or activity levels (eg, decreased levels of Merlin expression) may have cancers characterized by sensitivity or responsiveness to FAK inhibitors and may therefore benefit from treatment with FAK inhibitors.

[0037] In some embodiments, the method includes co-administering a second course of therapy, such as a second anti-tumor or anti-cancer therapy, such as one or more anti-tumor or anti-cancer agents. In some embodiments, the second course of therapy is provided after the diagnosis of mesothelioma. In some embodiments, the course of the second therapy ends before the start of the process of providing VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes providing a first course of the second therapy; administering VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof); and providing a second course of the above-mentioned second therapy. In some embodiments, the first course begins before administering VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the second course replaces the first course and is initiated before, simultaneously with, or after the start of administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the number of administrations, the frequency of administration, the amount of the second therapeutic agent delivered in the administration, or the level of the second therapeutic agent in the subject (e.g., in the blood of the subject) in the second course is reduced compared to the first course. In some embodiments, the second agent is not administered to the subject after the start of administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the second agent is not administered to the subject during administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the second agent is not administered to the subject during a cycle of VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof).

[0038] In some embodiments, the subject has previously received a course of a second therapy, e.g., a second anticancer or antitumor therapy, e.g., one or more anticancer agents or antitumor agents. In some embodiments, the course of the second therapy is administered after the diagnosis of mesothelioma. In some embodiments, the course of the second therapy is ended before, at the same time, or after the start of administration of VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the second therapy is not administered after the first administration of VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes providing a second course of the second therapy. In some embodiments, the second course replaces the first course and is initiated before, at the same time, or after the start of administration of VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the second course is initiated before, simultaneously with, or after the start of administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the number of administrations, the frequency of administration, the amount of the second therapeutic agent delivered in the administration, or the level of the second therapeutic agent in the subject (e.g., in the blood of the subject) during the second course is reduced compared to the first course. In some embodiments, the second agent is not administered to the subject after the start of administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the second agent is not administered to the subject during administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the second agent is not administered to the subject during a cycle of VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof).

[0039] In some embodiments, the second therapy comprises administering a therapeutic agent, e.g., an anti-tumor agent or an anti-cancer agent. In some embodiments, the second therapy comprises administering an additional agent, e.g., an anti-cancer agent or an anti-tumor agent, e.g., an anti-cancer agent or an anti-tumor agent selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens. In some embodiments, the therapeutic agent comprises a platinum drug, e.g., cisplatin or carboplatin. In some embodiments, the therapeutic agent comprises a drug other than a platinum drug, e.g., it comprises a taxane, e.g., docetaxel, paclitaxel; a plant-derived anti-tumor substance, e.g., an alkaloid, e.g., vinorelbine; antimetabolites, e.g., gemcitabine; or a cytotoxic topoisomerase inhibitor, e.g., irinotecan. In some embodiments, the second therapy comprises administering a first and a second therapeutic agent. In some embodiments, the first and second therapeutic agents are each selected from additional therapeutic agents, e.g., anti-tumor or anti-cancer agents, e.g., anti-tumor or anti-cancer agents selected from the following: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens. In some embodiments, the therapeutic agent comprises a platinum drug, e.g., cisplatin or carboplatin. In some embodiments, the therapeutic agent comprises a drug other than a platinum drug, e.g., it comprises a taxane, e.g., docetaxel, paclitaxel; a plant-derived anti-cancer or anti-tumor substance, e.g., an alkaloid, e.g., vinorelbine; antimetabolites, e.g., gemcitabine; or a cytotoxic topoisomerase inhibitor, e.g., irinotecan.

[0040] In one aspect, the invention includes a method of treating a subject having cancer, e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutant NSCLC, comprising: providing the subject with an effective amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof), thereby treating the subject. In some embodiments, the method comprises providing the subject with an effective course of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the cancer is metastatic. In some embodiments, the subject has locally recurrent disease.

[0041] In one aspect, the present invention includes a method for evaluating a subject having cancer, e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), for treatment with VS-6063 or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof); the method comprising: obtaining, e.g., directly or indirectly, the mutation status of a gene in the NSCLC, thereby evaluating the subject. In some embodiments, the gene is selected from the following, including: KRAS, INK4a / Arf, and p53. In some embodiments, the method comprises obtaining the mutation status of KRAS in the NSCLC. In some embodiments, the method comprises obtaining the mutation status of KRAS and INK4a / Arf in the NSCLC. In some embodiments, the method comprises obtaining the mutation status of KRAS and p53 in the NSCLC. In some embodiments, the method comprises obtaining the mutation status of KRAS, INK4a / Arf, and p53 in the NSCLC. In some embodiments, the method includes, according to the above mutation status, selecting the subject for treatment with VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes, according to the determination result that the NSCLC contains a KRAS mutation, selecting the subject for treatment with VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes, according to the determination result that the NSCLC contains a KRAS mutant and an INK4a / Arf mutant, selecting the subject for treatment with VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes, according to the determination result that the NSCLC contains KRAS mutants and p53 mutants, selecting the subject for treatment with VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes, according to the determination result that the NSCLC contains KRAS mutants, INK4a / Arf mutants and p53 mutants, selecting the subject for treatment with VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof).In some embodiments, the method includes testing the subject for a gene mutation in the NSCLC. In some embodiments, the method includes testing the subject for a mutation in the following genes in the NSCLC, the genes including KRAS, INK4a / Arf, and p53. In some embodiments, the method includes testing the subject for a mutation in KRAS in the NSCLC. In some embodiments, the method includes testing the subject for a mutation in KRAS and INK4a / Arf in the NSCLC. In some embodiments, the method includes testing the subject for a mutation in KRAS and p53 in the NSCLC. In some embodiments, the method includes testing the subject for a mutation in KRAS, INK4a / Arf, and p53 in the NSCLC. In some embodiments, the subject (e.g., a subject with NSCLC) has cells comprising KRAS mutants; KRAS mutants and INK4a / Arf mutants; or KRAS mutants, INK4a / Arf mutants, and p53 mutants. In some embodiments, the cancer is metastatic. In some embodiments, the subject has locally recurrent disease.

[0042] In some embodiments, the method includes obtaining the mutation status of a gene in the NSCLC of the subject. In some embodiments, the gene is selected from: KRAS, INK4a / Arf and p53. In some embodiments, the method includes obtaining the mutation status of KRAS in the NSCLC of the subject. In some embodiments, the method includes obtaining the mutation status of KRAS and INK4a / Arf in the NSCLC of the subject. In some embodiments, the method includes obtaining the mutation status of KRAS and p53 of the subject in the NSCLC of the subject. In some embodiments, the method includes obtaining the mutation status of KRAS, INK4a / Arf and p53 in the NSCLC. In some embodiments, the method includes, according to the mutation status, selecting the subject for treatment with VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes, according to the determination result that the NSCLC contains a KRAS mutant, selecting the subject for treatment with VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes, according to the determination result that the NSCLC contains a KRAS mutant and an INK4a / Arf mutant, selecting the subject for treatment with VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes, according to the determination result that the NSCLC contains a KRAS mutant and a p53 mutant, selecting the subject for treatment with VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes, according to the determination results that the NSCLC includes KRAS mutants, INK4a / Arf mutants and p53 mutants, selecting the subject for treatment with VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes testing the subject for a mutation in a gene in the NSCLC. In some embodiments, the method includes testing the subject for a mutation in a gene selected from the following genes in the NSCLC, the genes including: KRAS, INK4a / Arf and p53.In some embodiments, the method includes directly testing the subject for a mutation in KRAS in the NSCLC. In some embodiments, the method includes testing the subject for a mutation in KRAS and INK4a / Arf in the NSCLC. In some embodiments, the method includes testing the subject for a mutation in KRAS and p53 in the NSCLC. In some embodiments, the method includes testing the subject for a mutation in KRAS, INK4a / Arf, and p53 in the NSCLC. In some embodiments, the cell in the subject (e.g., a subject with lung cancer (e.g., NSCLC)) comprises a KRAS mutant; a KRAS mutant and an INK4a / Arf mutant; or a KRAS mutant, an INK4a / Arf mutant, and a p53 mutation.

[0043] In some embodiments, the method includes a course of co-administering a second therapy, such as a second anti-tumor therapy or anti-cancer therapy, such as one or more anti-tumor agents or anti-cancer agents. In some embodiments, the course of the second therapy is provided after the diagnosis of NSCLC. In some embodiments, the course of the second therapy ends before the process of providing VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) begins. In some embodiments, the method includes a first course of providing the second therapy; administering VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof); and providing a second course of the second therapy. In some embodiments, the first course is initiated before administering VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the second course replaces the first course and is initiated before, simultaneously with, or after the start of administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the number of administrations, the frequency of administration, the amount of the second therapeutic agent delivered in the administration, or the level of the second therapeutic agent in the subject (e.g., in the blood of the subject) in the second course is reduced compared to the first course. In some embodiments, the second agent is not administered to the subject after the start of administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the second agent is not administered to the subject during administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the second agent is not administered to the subject during a cycle of VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof).

[0044] In some embodiments, the subject has previously received a course of a second therapy, e.g., a second anti-tumor therapy or anti-cancer therapy, e.g., one or more anti-tumor agents or anti-cancer agents. In some embodiments, the course of the second therapy is administered after the diagnosis of NSCLC. In some embodiments, the course of the second therapy ends before, at the same time, or after the start of administration of VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the second therapy is not administered after the first administration of VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes providing a second course of the second therapy. In some embodiments, the second course replaces the first course and is initiated before, at the same time, or after the start of administration of VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the second course is initiated before, simultaneously with, or after the start of administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the number of administrations, the frequency of administration, the amount of the second therapeutic agent delivered in the administration, or the level of the second therapeutic agent in the subject (e.g., in the blood of the subject) during the second course is reduced compared to the first course. In some embodiments, the second agent is not administered to the subject after the start of administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the second agent is not administered to the subject during administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the second agent is not administered to the subject during a cycle of VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof).

[0045] In some embodiments, the second therapy comprises administering a therapeutic agent, e.g., an anti-tumor agent or an anti-cancer agent. In some embodiments, the second therapy comprises administering an additional agent, e.g., an anti-tumor agent or an anti-cancer agent, e.g., an anti-tumor agent or an anti-cancer agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens. In some embodiments, the therapeutic agent comprises a platinum drug, e.g., cisplatin or carboplatin. In some embodiments, the therapeutic agent comprises a drug other than a platinum drug, e.g., it comprises a taxane, e.g., docetaxel, paclitaxel; a plant-derived anti-tumor substance, e.g., an alkaloid, e.g., vinorelbine; antimetabolites, e.g., gemcitabine; or a cytotoxic topoisomerase inhibitor, e.g., irinotecan. In some embodiments, the second therapy comprises administering a first and a second therapeutic agent. In some embodiments, the first and second therapeutic agents are each selected from an additional therapeutic agent, e.g., an anti-tumor agent or an anti-cancer agent, e.g., an anti-tumor agent or an anti-cancer agent selected from the following: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens. In some embodiments, the therapeutic agent comprises a platinum drug, e.g., cisplatin or carboplatin. In some embodiments, the therapeutic agent comprises a drug other than a platinum drug, e.g., it comprises a taxane, e.g., docetaxel, paclitaxel; a plant-derived anti-tumor or anti-cancer substance, e.g., an alkaloid, e.g., vinorelbine; antimetabolites, e.g., gemcitabine; or a cytotoxic topoisomerase inhibitor, e.g., irinotecan.

[0046] In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered in a cycle of at least 5, 10, 15, 20, 25, 30, or 35 days. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered in a cycle of 5-40, 10-40, 10-30, or 10-25 days. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered in a cycle of 15-40, 15-30, or 15-25 days. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered in a cycle of 21+ / -5, 21+ / -4, 21+ / -3, 21+ / -2, or 21+ / -1 days. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered in a cycle of 21 days. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered 1, 2, 3, or 4 times per day. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered 2 times per day. In some embodiments, the VS-6063 or a pharmaceutically acceptable salt thereof or composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered orally. In some embodiments, 50-800 mg / day, 50-600 mg / day, 50-500 mg / day, 50-400 mg / day, 50-300 mg / day, or 50-200 mg / day of VS-6063 or a pharmaceutically acceptable salt thereof or composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 100-800 mg / day, 100-600 mg / day, 100-500 mg / day, 100-400 mg / day, 100-300 mg / day, or 100-200 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered.In some embodiments, 200-800 mg / day, 200-600 mg / day, 200-500 mg / day, 200-400 mg / day, or 200-300 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 250-800 mg / day, 250-600 mg / day, 250-500 mg / day, 250-400 mg / day, or 250-300 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, the range does not include one or both endpoints, for example, wherein the range does not include the lower endpoint. In some embodiments, 100+ / -50 mg / day, 150+ / -50 mg / day, 200+ / -50 mg / day, 250+ / -50 mg / day, 300+ / -50 mg / day, 400+ / -50 mg / day, 500+ / -50 mg / day, 550+ / -50 mg / day, or 600+ / -50 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 100 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 200 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 400 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered.

[0047] In some embodiments, VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered in multiple cycles (e.g., more than one cycle). In some embodiments, the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered in each cycle remains constant (e.g., the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered is the same). In some embodiments, the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered in one cycle is different from the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered in another cycle (e.g., a second cycle). In some embodiments, the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered in one cycle is less than the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered in a subsequent cycle (e.g., a second cycle). In some embodiments, the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered in one cycle is greater than the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered in a subsequent cycle (e.g., a second cycle).

[0048] In some embodiments, a unit dose formulation of 50+ / -25 mg, 100+ / -50 mg, 150+ / -50 mg, 200+ / -50 mg, 250+ / -50 mg, 300+ / -50 mg, 400+ / -50 mg, 500+ / -50 mg, 550+ / -50 mg, or 600+ / -50 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 100+ / -50 mg / day, 100+ / -25 mg / day, 100+ / -10 mg / day, or 100+ / -5 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, a unit dose formulation of 100+ / -20 mg, 100+ / -10 mg, or 100+ / -5 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, a unit dose formulation of 100 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 200+ / -50 mg / day, 200+ / -25 mg / day, 200+ / -10 mg / day, or 200+ / -5 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, a unit dose formulation of 200+ / -20 mg, 200+ / -10 mg, or 200+ / -5 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, a unit dose formulation of 200 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 400+ / -50 mg / day, 400+ / -25 mg / day, 400+ / -10 mg / day, or 400+ / -5 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered.In some embodiments, a unit dose formulation of 400+ / -20 mg, 400+ / -10 mg, or 400+ / -5 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, a unit dose formulation of 400 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered.

[0049] In one embodiment, the oral dosage forms described herein have a greater C compared to a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in the blend. max In one embodiment, the oral dosage form described herein has a C max The value is at least 1.1 times (e.g., at least 1.25 times, at least 1.5 times, at least 2 times, at least 3 times, at least 5 times) greater than a reference dosage form of the same dose (e.g., a dosage form having 100 mg of VS-6063 compared to a reference dosage form also having 100 mg of VS-6063). In one embodiment, the C value of the oral dosage form described herein is at least 1.1 times (e.g., at least 1.25 times, at least 1.5 times, at least 2 times, at least 3 times, at least 5 times) greater than a reference dosage form of the same dose (e.g., a dosage form having 100 mg of VS-6063 compared to a reference dosage form also having 100 mg of VS-6063). max The value is at least 1.6 times, at least 1.7 times, at least 1.8 times, at least 1.9 times, at least 2 times, at least 3 times, or at least 4 times that of a reference dosage form having the same dosage.

[0050] In one embodiment, the oral dosage forms described herein have a reduced food effect compared to a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in the blend. In one embodiment, the T of a subject administered an oral dosage form described herein in the fed and fasted states is 2.5 mmol / l. maxThe difference between the T values ​​for the fed and fasted states of subjects administered the same dose of a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in the blend) is less than the T values ​​for the fed and fasted states of subjects administered the same dose of a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succi max The difference between the values.

[0051] In one embodiment, when administered to a subject, the oral dosage forms described herein have consistent exposure. In one embodiment, when administered to a subject, the oral dosage forms described herein provide exposures with less than 50% exposure-related variability across multiple subjects compared to a reference oral dosage form at the same dose. In one embodiment, when administered to a subject, the oral dosage forms described herein provide exposures with less than 40%, 30%, 20%, or 10% exposure-related variability across multiple subjects compared to a reference oral dosage form at the same dose.

[0052] In one aspect, the invention includes a unit dosage form containing 50-800 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 50+ / -25 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 50+ / -10 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 50 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the present invention includes a unit dosage form containing 100-800 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 100+ / -50 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 100+ / -10 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 100 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 200 + / - 50 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 200 + / - 10 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 200 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof).In some embodiments, the unit dosage form contains 400 + / - 50 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 400 + / - 10 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 400 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof).

[0053] In one aspect, the invention provides a method of treating a subject having ovarian cancer (e.g., advanced or metastatic ovarian cancer), comprising: providing to the subject an effective amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof), and optionally providing to the subject an effective amount of a second therapeutic agent, e.g., an anticancer agent or an antitumor agent, e.g., a mitotic inhibitor, e.g., a taxane, e.g., paclitaxel; said amounts (alone or in combination) being effective to treat the subject, thereby treating the subject, wherein the subject receives more than 100 or 250 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) for at least one day, e.g., for the entire cycle or course of VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof); the subject receives VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) for at least 5, 10, or 15 days; the second therapeutic agent is provided, e.g., in a different course schedule, e.g., it is not always on the same day as the VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes a process of providing VS-6063 or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) to the subject, and optionally, a process of providing a second therapeutic agent, e.g., an anti-cancer agent or an anti-tumor agent, e.g., a mitotic inhibitor, e.g., a taxane (e.g., paclitaxel), to the subject, which processes (alone or in combination) are effective to treat the subject.

[0054] In one aspect, the present invention provides a method for evaluating a subject with ovarian cancer for treatment with VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof), the method comprising: obtaining, e.g., directly or indirectly, the mutation status of a gene in the ovarian cancer, thereby evaluating the subject. In some embodiments, the method comprises, based on the mutation status, selecting the subject for treatment with VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method comprises testing the subject for a mutation in a gene in the ovarian cancer.

[0055] In some embodiments, the method includes obtaining the mutation status of a gene in the subject's ovarian cancer. In some embodiments, the method includes, according to the mutation status, selecting the subject for treatment with VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes testing the subject for a mutation in a gene in the subject's ovarian cancer. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is locally recurrent. In some embodiments, the cancer is advanced.

[0056] In some embodiments, the method includes co-administering a course of a second therapy, e.g., a second anticancer therapy or antitumor therapy, e.g., one or more anticancer or antitumor agents. In some embodiments, the course of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) and the course of a second therapy (e.g., administration of an anticancer or antitumor agent, e.g., a mitotic inhibitor, e.g., a taxane, e.g., paclitaxel) are co-administered. In some embodiments, the course of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) overlaps with the course of a second therapy (e.g., administration of an anticancer or antitumor agent, e.g., a mitotic inhibitor, e.g., a taxane (e.g., paclitaxel)). In some embodiments, the second therapy includes administering paclitaxel. In some embodiments, the paclitaxel is administered at least twice in a course, for example, every 7+ / -3 days, 7+ / -2 days, 7+ / -1 day, or 7 days. In some embodiments, the paclitaxel is administered at 80+ / -50 mg / m 2 , 80+ / -40mg / m2 , 180+ / -30mg / m 2 , 80 + / - 20 mg / m 2 , 80 + / - 10 mg / m 2 or 80 mg / m 2In some embodiments, the second course of therapy is provided after the diagnosis of ovarian cancer. In some embodiments, the second course of therapy ends before the start of the process of providing VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof), e.g., VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes providing a first course of the second therapy; administering VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof); and providing a second course of the second therapy. In some embodiments, the first course is initiated before administering VS-6063 or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the second course replaces the first course and is initiated before, simultaneously with, or after the start of administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the number of administrations, the frequency of administration, the amount of the second therapeutic agent delivered in the administration, or the level of the second therapeutic agent in the subject (e.g., in the subject's blood) is reduced in the second course compared to the first course. In some embodiments, the second agent is not administered to the subject after the start of administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the second agent is not administered to the subject during, during, or during administration of VS-6063, or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the second agent is not administered to the subject during a cycle of VS-6063, or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof).

[0057] In some embodiments, the subject has previously received a course of a second therapy, e.g., a second anti-cancer therapy or anti-tumor therapy, e.g., one or more anti-cancer agents or anti-tumor agents. In some embodiments, the course of the second therapy is administered after the diagnosis of ovarian cancer. In some embodiments, the course of the second therapy is ended before, simultaneously with, or after the start of administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof).

[0058] In some embodiments, the second therapy is not administered after the first administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes providing a second course of the second therapy. In some embodiments, the second course replaces the first course and is initiated before, simultaneously with, or after the start of administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the second course is initiated before, simultaneously with, or after the start of administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the number of administrations, the frequency of administration, the amount of the second therapeutic agent delivered in the administration, or the level of the second therapeutic agent in the subject (e.g., in the blood of the subject) during the second course is reduced compared to the first course. In some embodiments, the second agent is not administered to the subject after initiation of administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the second agent is not administered to the subject during administration of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof). In some embodiments, the second agent is not administered to the subject during a cycle of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof).

[0059] In some embodiments, the second therapy comprises administering a therapeutic agent, e.g., an anticancer agent or an antitumor agent. In some embodiments, the therapeutic agent comprises, e.g., a mitotic inhibitor, e.g., a taxane, e.g., paclitaxel. In some embodiments, the second therapy comprises administering a first and a second therapeutic agent. In some embodiments, the second therapy comprises administering an additional agent, e.g., an anticancer agent or an antitumor agent, e.g., an anticancer agent or an antitumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, antihormones, and antiandrogens.

[0060] In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered in a cycle of greater than or equal to 5 days, 10 days, 15 days, 20 days, 21 days, 25 days, 28 days, 30 days, 35 days, 40 days, 45 days, or 50 days. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered in a cycle of 5-40 days, 10-40 days, 10-30 days, or 10-25 days. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered in a cycle of 15-40 days, 15-30 days, or 15-25 days. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered in a cycle of 21+ / -5 days, 21+ / -4 days, 21+ / -3 days, 21+ / -2 days, or 21+ / -1 day. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered in a cycle of 21 days. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered in a cycle of 28+ / -5 days, 28+ / -4 days, 28+ / -3 days, 28+ / -2 days, or 28+ / -1 day. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered in a 28-day cycle. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered 1, 2, 3, or 4 times per day. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered 2 times per day. In some embodiments, the VS-6063 or a pharmaceutically acceptable salt thereof or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered orally.In some embodiments, 50-800 mg / day, 50-600 mg / day, 50-500 mg / day, 50-400 mg / day, 50-300 mg / day, or 50-200 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 100-800 mg / day, 100-600 mg / day, 100-500 mg / day, 100-400 mg / day, 100-300 mg / day, or 100-200 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 200-800 mg / day, 200-600 mg / day, 200-500 mg / day, 200-400 mg / day, or 200-300 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 250-800 mg / day, 250-600 mg / day, 250-500 mg / day, 250-400 mg / day, or 250-300 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, the range (e.g., the range described herein) does not include one or both endpoints, e.g., wherein the range does not include the lower endpoint. In some embodiments, 50+ / -25 mg / day, 100+ / -50 mg / day, 150+ / -50 mg / day, 200+ / -50 mg / day, 250+ / -50 mg / day, 300+ / -50 mg / day, 400+ / -50 mg / day, 500+ / -50 mg / day, 550+ / -50 mg / day, or 600+ / -50 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 50 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 100 + / - 50 mg / day, 100 + / - 25 mg / day, 100 + / - 10 mg / day, or 100 + / - 5 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered.In some embodiments, 100 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 200+ / -50 mg / day, 200+ / -25 mg / day, 200+ / -10 mg / day, or 200+ / -5 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 200 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 400+ / -50 mg / day, 400+ / -25 mg / day, 400+ / -10 mg / day, or 400+ / -5 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 400 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered.

[0061] In some embodiments, VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered in multiple cycles (e.g., more than one cycle). In some embodiments, the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered in each cycle remains constant (e.g., the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered is the same). In some embodiments, the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered in one cycle is different from the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered in another cycle (e.g., a second cycle). In some embodiments, the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered in one cycle is less than the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered in a subsequent cycle (e.g., a second cycle). In some embodiments, the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered in one cycle is greater than the amount of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) administered in a subsequent cycle (e.g., a second cycle).

[0062] In some embodiments, a unit dose formulation of 50+ / -25 mg, 100+ / -50 mg, 150+ / -50 mg, 200+ / -50 mg, 250+ / -50 mg, 300+ / -50 mg, 400+ / -50 mg, 500+ / -50 mg, 550+ / -50 mg, or 600+ / -50 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 200+ / -50 mg / day, 200+ / -25 mg / day, 200+ / -10 mg / day, or 200+ / -5 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, a unit dose formulation of 200+ / -20 mg, 200+ / -10 mg, or 200+ / -5 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, a unit dose formulation of 200 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 100+ / -50 mg / day, 100+ / -25 mg / day, 100+ / -10 mg / day, or 100+ / -5 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, a unit dose formulation of 100+ / -20 mg, 100+ / -10 mg, or 100+ / -5 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, a unit dose formulation of 100 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, 50+ / -25 mg / day, 50+ / -10 mg / day, or 50+ / -5 mg / day of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063, or a pharmaceutically acceptable salt thereof) is administered.In some embodiments, a unit dose formulation of 50+ / -20 mg, 50+ / -10 mg, or 50+ / -5 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered. In some embodiments, a unit dose formulation of 50 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof) is administered.

[0063] In one embodiment, the oral dosage forms described herein have a higher C compared to a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in the blend. max In one embodiment, the oral dosage form described herein has a C max The value is at least 1.1 times (e.g., at least 1.25 times, at least 1.5 times, at least 2 times, at least 3 times, at least 5 times) greater than a reference dosage form of the same dose (e.g., a dosage form having 100 mg of VS-6063 compared to a reference dosage form also having 100 mg of VS-6063). In one embodiment, the C value of the oral dosage form described herein is at least 1.1 times (e.g., at least 1.25 times, at least 1.5 times, at least 2 times, at least 3 times, at least 5 times) greater than a reference dosage form of the same dose (e.g., a dosage form having 100 mg of VS-6063 compared to a reference dosage form also having 100 mg of VS-6063). max The value is at least 1.6 times, at least 1.7 times, at least 1.8 times, at least 1.9 times, at least 2 times, at least 3 times, or at least 4 times that of a reference dosage form having the same dosage.

[0064] In one embodiment, the oral dosage forms described herein have a reduced food effect compared to a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in the blend. In one embodiment, the T of a subject administered an oral dosage form described herein in the fed and fasted states is 2.5 mmol / l. maxThe difference between the T values ​​for the fed and fasted states of subjects administered the same dose of a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF) in the blend) is less than the T values ​​for the fed and fasted states of subjects administered the same dose of a reference oral dosage form, e.g., a dosage form that does not include an excipient (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hydroxypropyl methylcellulose acetate succi max The difference between the values.

[0065] In one embodiment, when administered to a subject, the oral dosage forms described herein have consistent exposure. In one embodiment, when administered to a subject, the oral dosage forms described herein provide exposures with less than 50% exposure-related variability across multiple subjects compared to a reference oral dosage form at the same dose. In one embodiment, when administered to a subject, the oral dosage forms described herein provide exposures with less than 40%, 30%, 20%, or 10% exposure-related variability across multiple subjects compared to a reference oral dosage form at the same dose.

[0066] In one aspect, the invention includes a unit dosage form containing 50-800 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 100+ / -50 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 100+ / -10 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 100 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 200 + / - 50 mg of VS-6063, or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 200 + / - 10 mg of VS-6063, or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 200 mg of VS-6063, or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 400 + / - 50 mg of VS-6063, or a pharmaceutically acceptable salt or composition thereof (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 400 + / - 10 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the unit dosage form contains 400 mg of VS-6063, or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). DETAILED DESCRIPTION OF THE INVENTION

[0068] The present invention is not intended to limit the application to the details of the composition (e.g., formulation, e.g., oral dosage form), or the details of the specific preparation or administration sequence of the composition (e.g., formulation, e.g., oral dosage form). The composition, e.g., the dosage form described herein can be appropriately prepared using other techniques and / or administered in various ways. In addition, the wording and terminology used herein are for descriptive purposes and should not be considered restrictive.

[0069] definition

[0070] As used herein, the articles "a" and "an" refer to one or to more than one (eg, to at least one) of the grammatical object of the article.

[0071] "About" and "approximately" shall generally refer to an acceptable degree of error for the amount measured, taking into account the nature or precision of the measurement. An exemplary degree of error is within 20 percent (%) of a given value or range of values, usually within 10%, and more usually within 5%.

[0072] As used herein, the amount of a compound effective for treating a disease (e.g., a disease described herein), "effective amount" or "effective course of treatment" refers to the amount of a compound that can effectively treat a subject, or cure, alleviate, mitigate or improve a subject suffering from a disease (e.g., a disease described herein) after single or multiple doses of administration to the subject, which exceeds the expected effect of not performing such treatment (e.g., placebo treatment).

[0073] The term "pharmaceutically acceptable" as used herein refers to a compound or carrier (e.g., excipient) that can be administered to a subject with a compound described herein (e.g., VS-6063, VS-6063 free base, VS-6063 hydrochloride) without destroying the pharmacological activity of the compound and is non-toxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

[0074] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound described herein (e.g., VS-6063, e.g., VS-6063 free base), wherein the compound is modified by converting an existing acid or base moiety into its salt form (e.g., VS-6063 hydrochloride). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues (e.g., amines); alkali metal or organic salts of acidic residues (e.g., carboxylic acids); and the like. Pharmaceutically acceptable salts of the present invention include, for example, conventional non-toxic salts of the compounds described herein (e.g., VS-6063) formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from compounds described herein (e.g., VS-6063, VS-6063 free base) containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a chemical equivalent of an appropriate base or acid in water or in an organic solvent or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0075] As used herein, the phrase "pharmaceutically acceptable derivative or prodrug" refers to any pharmaceutically acceptable salt, ester, ester salt or other derivative of a compound (VS-6063) that is capable of providing (directly or indirectly) a therapeutic agent upon administration to a recipient. Particularly preferred derivatives and prodrugs are, for example, those that increase the bioavailability of a compound described herein (e.g., VS-6063, VS-6063 free base, VS-6063 hydrochloride) when such compound is administered to a mammal (e.g., so that an orally administered compound can be more readily absorbed into the blood) or that increase the delivery of a compound described herein (e.g., VS-6063, VS-6063 free base, VS-6063 hydrochloride) to a biological compartment relative to a compound described herein (e.g., VS-6063, VS-6063 free base, VS-6063 hydrochloride). Preferred prodrugs include derivatives in which groups that increase water solubility or active transport across the intestinal membrane are attached to the structure of the formula described herein.

[0076] As used herein, the term "oral dosage form" refers to a composition or vehicle for administering a pharmaceutical agent, e.g., VS-6063, to a subject. Typically, oral dosage forms are administered via the mouth, however, "oral dosage form" is intended to encompass any substance that is administered to a subject and crosses the membranes (e.g., mucosa) of the gastrointestinal tract (including, e.g., the mouth, esophagus, stomach, small intestine, large intestine, and colon). For example, "oral dosage forms" include solutions administered into the stomach via a feeding tube.

[0077] As used herein, the term "treat," "treat," "treat," or "treat" refers to the application or administration of a compound, alone or in combination with additional agents, to a subject (e.g., a subject suffering from a disease (e.g., a disease described herein), experiencing symptoms of a disease, or prone to a disease) to cure, rehabilitate, alleviate, mitigate, alter, remedy, improve, enhance, or affect the disease.

[0078] Co-administration, co-application, or co-providing, as used in the context of administering therapies, refers to administration of one therapy simultaneously, prior to (e.g., immediately before, less than 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes; 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 48 ​​hours, 72 hours or more hours before) administration of the second therapy.

[0079] As referred to herein, a course of treatment includes one or more separate administrations of a therapeutic agent. A course of treatment may include one or more cycles of a therapeutic agent.

[0080] The cycle used in the context of the drug administration cycle refers to the duration of drug administration to the patient. For example, if administered in a 21-day cycle, the cyclical administration, for example, continues 21 days of daily administration once or twice. Drug can be administered in more than one cycle. In some embodiments, the first and second or subsequent cycles are identical in one or both aspects of the duration and cyclical administration. In an embodiment, the first and second or subsequent cycles are different in one or both aspects of the duration and cyclical administration. The drug-free period can be between cycles. The drug-free period can be 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or 1 week, 2 weeks, 3 weeks, 4 weeks or more The length of the week.

[0081] Numerical ranges, e.g., ranges of dosages administered per day, are given herein. In some embodiments, the range includes both endpoints. In other embodiments, the range excludes one or both endpoints. For example, the range may exclude the lower endpoint. Thus, in such embodiments, a range of 250-400 mg / day excluding the lower endpoint would encompass an amount less than or equal to 400 mg / day and greater than 250 mg / day.

[0082] The term "subject" as used herein is intended to include humans and non-human animals. Exemplary human subjects include human subjects suffering from a disease (e.g., a disease described herein). The term "non-human animal" of the present invention includes all vertebrates, e.g., non-mammals (e.g., chickens, amphibians, reptiles) and mammals, e.g., non-human primates, domestic and / or agricultural animals, e.g., sheep, dogs, cats, cows, pigs, etc.

[0083] Compound VS-6063

[0084] The active agent (eg, active ingredient) is the compound VS-6063 (eg, VS-6063 free base):

[0085]

[0086] Or a pharmaceutically acceptable salt thereof (eg, VS-6063 hydrochloride), as disclosed in US 7,928, 109. VS-6063 is also known as defactinib or PF-04554878.

[0087] VS-6063 is a potent inhibitor of FAK protein tyrosine kinase and may be suitable for therapeutic use as an antiproliferative agent (e.g., anticancer agent), antitumor agent (e.g., effective against solid tumors), angiogenesis inhibitor (e.g., stopping or preventing the proliferation of blood vessels) in mammals (especially humans). VS-6063 can be used to prevent and treat non-hematological malignancies. In addition, VS-6063 can be used to prevent and treat various human hyperproliferative diseases, such as malignant and benign tumors of the liver, kidney, bladder, breast, stomach, ovary, colorectum, prostate, pancreas, lung, vulva, thyroid, hepatocarcinoma, sarcoma, glioblastoma, head and neck and other proliferative conditions, such as benign hyperplasia of the skin (e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH). VS-6063 can also be used to prevent and treat diseases such as mesothelioma.

[0088] In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 5, 10, 11, 12, 12.5, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60% w / w or more. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 10-50% w / w. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 10% w / w. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof is present in the composition in an amount greater than 10% w / w. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 13% w / w. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 25% w / w. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 50% w / w.

[0089] Pharmaceutical compositions and oral dosage forms

[0090] The pharmaceutical composition can be provided, for example, in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained release formulations, solutions and suspensions. The pharmaceutical composition can be in a unit dosage form suitable for single administration of a precise dose. In addition to VS-6063 or a pharmaceutically acceptable salt thereof, the pharmaceutical composition can include a pharmaceutically acceptable carrier, and can optionally further include one or more pharmaceutically acceptable excipients, such as, for example, stabilizers (e.g., binders, such as polymers, such as precipitation inhibitors, such as hydroxypropylmethylcellulose (HPMC) or hydroxypropylmethylcellulose (e.g., hydroxypropylmethylcellulose acetate succinate (HPMC-AS) or hydroxypropylmethylcellulose acetate succinate, such as HPMCAS-H, HPMCAS-M)), diluents, binders and lubricants. In some embodiments, the composition provides a free-flowing, bonded tableting powder that can be directly compressed into tablets. In addition, the tablets can include other medicinal or pharmaceutical agents, carriers and or adjuvants. Exemplary pharmaceutical compositions include compressed tablets (eg, direct compressed tablets), for example, comprising VS-6063 or a pharmaceutically acceptable salt thereof.

[0091] Tablets are also provided that include an active or therapeutic ingredient (e.g., a compound described herein, e.g., VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride). In addition to the active or therapeutic ingredient, the tablet may contain a variety of inert materials, such as carriers. Pharmaceutically acceptable carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, sesame oil, and the like. Saline solutions and aqueous dextrose solutions can also be used as liquid carriers. Thus, oral dosage forms used in accordance with the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers (including excipients and adjuvants) that facilitate processing of the active ingredient into a pharmaceutically acceptable preparation.

[0092] Excipients can impart good powder flowability and compression properties to the compressed material. Desired properties of excipients may include high compressibility, so that hard tablets can be made with low compression force; good powder flowability, which can improve the powder flow of other excipients in the composition; and adhesion, such as preventing tablets from disintegrating during processing, transportation and handling. These properties are imparted to these excipients by pretreatment steps, such as dry granulation (e.g., by rolling, beating), wet granulation, spray drying spheronization (e.g., spray dried dispersion, solid nanodispersion) or crystallization (e.g., salt form) of the pharmaceutical composition. They can be classified according to the role they play in the final tablet. Some excipients can provide multiple functions. For example, fillers can be binders and or used as precipitation inhibitors. Other excipients that provide physical properties for the finished tablet are colorants and flavorings (e.g., in the case of chewable tablets). Examples of excipients are described in, for example, Handbook of Pharmaceutical Excipients (5th ed.), Raymond C Rowe, Paul J. Sheskey, and Sian C. Owen, eds.; Publisher: Pharmaceutical Press.

[0093] For oral administration, the active ingredient, e.g., a compound described herein (e.g., VS-6063, e.g., VS-6063 free base or VS-6063 hydrochloride), can be readily formulated by combining the active ingredient with a pharmaceutically acceptable carrier well known in the art. Such carriers enable the active ingredient of the invention to be formulated into tablets, pills, capsules, liquids, gels, syrups, slurries, powders or granules, suspensions or solutions in water or non-aqueous media, and the like, for oral ingestion by a subject. Pharmacological preparations for oral use can be prepared by using a solid excipient, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable adjuvants, if desired, to obtain, for example, tablets. Suitable excipients, such as diluents, binders, or disintegrants may be desired.

[0094] Tablets usually contain diluents or fillers, which are added, for example, to increase the bulk weight of the blend to form a practical size for compression. Available diluents or fillers include one or more of the following calcium salts (e.g., calcium hydrogen phosphate) and sugars (e.g., lactose, sucrose, glucose, microcrystalline cellulose, mannitol, and maltodextrin). Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, icing sugar, compressible sugar, dextrates, dextrins, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, and talc. In some embodiments, the diluent or filler is microcrystalline cellulose, which can be manufactured by controlled hydrolysis of alpha-cellulose. Suitable microcrystalline cellulose will have an average particle size of about 20nm to about 200nm. Suitable microcrystalline cellulose includes Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105 and Avicel PH 200, for example, manufactured by FMC Corporation. In some embodiments, the diluent or filler is lactose. In some embodiments, the lactose has an average particle size of about 50 μm to about 500 μm before formulation.

[0095] The pharmaceutical composition will also generally include a lubricant. Lubricants are generally added to prevent the tabletting material from sticking to the punch, minimize friction during tabletting, and allow the compressed tablet to be removed from the mold. This lubricant is generally included in the final tablet mixture, and its amount is generally less than 1% by weight per unit weight composition. Examples of lubricants include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, talcum, magnesium carbonate, magnesium oxide, glyceryl behaptate, polyethylene glycol, ethylene oxide polymers (e.g., carbon wax), sodium lauryl sulfate, magnesium stearate, aluminum stearate, calcium stearate, sodium stearyl fumarate, stearic acid, lauryl magnesium stearate, and a mixture of magnesium stearate and sodium lauryl sulfate. Preferred lubricants include calcium stearate, magnesium stearate, and sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the amount of lubricant used is from about 0.1 to about 2.0% w / w, preferably from about 0.5 to 1.5% w / w.

[0096] Glidants are substances added to powders that improve the flowability of the powder. Examples of glidants include magnesium stearate, colloidal silicon dioxide (e.g., the grade sold as Aerosil), starch, and talc. Glidants may be present in the pharmaceutical composition at a level of 0 to about 5% w / w. In addition, it should be noted that excipients may provide multiple functions. The lubricant, such as magnesium stearate, may also be used as a glidant.

[0097] In addition to diluents / fillers and lubricants, other conventional excipients may also be present in the pharmaceutical compositions of the present invention. Such additional excipients include disintegrants, binders, flavoring agents, colorants, and glidants. Some excipients may provide multiple functions, such as acting as both a binder and a tablet disintegrant.

[0098] Tablet disintegrants may be present in an amount required to accelerate dissolution (e.g., increase the tablet disintegration rate). A disintegrant is an excipient that counteracts the physical forces that bind particles together in a tablet or capsule when the dosage form is placed in an aqueous environment. Disintegrants include starch derivatives and salts of carboxymethylcellulose. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches, e.g., sodium starch glycolate, pregelatinized starch; clays; cellulose; alginates; colloids; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone (e.g., polyvinyl polypyrrolidone, PVPP, crospovidone, crospolividone), cross-linked carboxymethyl cellulose calcium and cross-linked carboxymethyl cellulose sodium (sodiumcroscarmellose); and soybean polysaccharides. In some embodiments, the disintegrant used in the composition is sodium starch glycolate. Typically, the amount of disintegrant may be from 0 to about 25% w / w of the composition, more typically from about 1% to about 15% w / w, and typically less than 15% w / w, less than 10% w / w, or less than 5% w / w. In some embodiments, the amount of disintegrant is about 10% w / w of the composition. In some embodiments, the amount of disintegrant is about 3% w / w of the composition.

[0099] Binders are excipients that promote adhesion of particles to solid dosage forms. Examples of binders include, but are not limited to, polymers, such as starches (e.g., mannitol-starch, e.g., Pearlitol Flash); corn syrup; polysaccharides; gelatin; cellulose and its derivatives, such as microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose (HPMC) or hydroxypropyl methyl cellulose (e.g., hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) or hydroxypropyl methyl cellulose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF), HPMC phthalate (HPMCP), (e.g., HPMCP-HP55, HPMCP-HP55S), Methocel (e.g., Methocel E3LV)), hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, microcrystalline cellulose; and sugars, such as lactose, sucrose, dextrose, glucose, maltodextrin, mannitol, xylitol; polymethacrylates (e.g., Eudragit, e.g., Eudragit L100-55), polyvinylpyrrolidone (e.g., polyvinylpyrrolidone vinyl acetate copolymer (PVP / VA), copovidone), other copolymers (e.g., containing polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g., polyethylene phthalate (PVAP); polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, Soluplus)), sorbitol, pregelatinized starch, alginic acid and its salts, such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, etc. Generally, the amount of binder can vary widely, for example, 0% to 95% w / w of the composition. As described above, the excipient can provide multiple functions. For example, the tableting diluent can also serve as a binder. In some embodiments, the binder is a precipitation inhibitor. A precipitation inhibitor is generally an excipient that mediates supersaturation stabilization (e.g., stabilization of a supersaturated solution) and or slows down and or inhibits (e.g., prevents rapid) precipitation, for example, in a solution or in the gastrointestinal tract.In some embodiments, the binder is selected from: starch (e.g., mannitol-starch, e.g., Pearlitol Flash); cellulose and its derivatives, e.g., microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose (HPMC) (e.g., HPMC acetate succinate (HPMCAS), (e.g., HPMCAS-H, HPMCAS-M), HPMC phthalate (HPMCP), (e.g., HPMCP-HP55, HPMCP-HP55S), Methocel (e.g., Methocel E3LV)), hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, microcrystalline cellulose; and sugars, e.g., lactose, sucrose, dextrose, glucose, maltodextrin, mannitol, xylitol; polymethacrylates (e.g., Eudragit, e.g., Eudragit L100-55), polyvinyl pyrrolidone (e.g., polyvinyl pyrrolidone vinyl acetate copolymer (PVP / VA), copovidone), other copolymers (e.g., copolymers comprising polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g., Soluplus)). In some embodiments, the binder is polyvinyl pyrrolidone (e.g., polyvinyl pyrrolidone vinyl acetate copolymer (PVP / VA), copovidone). In some embodiments, the binder is mannitol-starch, for example, Pearlitol Flash. In some embodiments, the binder is a copolymer (e.g., a copolymer, including polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g., Soluplus). In some embodiments, the binder is a polymer. In some embodiments, the polymer is a precipitation inhibitor. In some embodiments, the precipitation inhibitor is HPMC (e.g., HPMCAS, e.g., HPMCAS-H, HPMCAS-M or HPMCAS-HF).

[0100] In some embodiments, more than one adhesive is used in the composition. In some embodiments, the amount of adhesive is about 0-60% w / w of the composition. In some embodiments, the amount of adhesive present in the composition is 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% or more weight of the composition weight. In some embodiments, the amount of adhesive is about 20-about 80% w / w of the composition. In some embodiments, the amount of adhesive is about 50% w / w of the composition. In some embodiments, the amount of adhesive is about 80% w / w of the composition.

[0101] The dosage may vary depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration and dosage may be selected by each physician according to the patient's condition (see, e.g., Fingl, et al., 1975, in "The Pharmacological Basis of Therapeutics"). Doses lower or higher than those described above may be required. For any particular subject, the specific dosage and treatment regimen will depend on various factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, dosing time, excretion rate, drug combination, severity and course of disease, illness or symptom, the tendency of the subject to suffer from the disease, illness or symptom, and the judgment of the treating physician.

[0102] Tablets can be plain, film-coated or sugar-coated, bisected, embossed, layered or sustained-release tablets. They can be made in a variety of sizes, shapes and colors. Tablets can be swallowed, chewed or dissolved in the mouth or under the tongue.

[0103] Three processes are generally used to prepare compressed tablets: wet granulation, direct compression, and dry granulation. The preparation method and excipient type are selected to provide the tablet formulation with the desired physical properties that allow the tablet to be compressed quickly. After compression, the tablet must have several additional attributes, such as appearance, hardness, disintegration ability, and an acceptable dissolution profile. The choice of fillers and other excipients will depend on the chemical and physical properties of the drug, the behavior of the mixture during processing, and the properties of the final tablet. Pre-formulation studies are performed to determine the chemical and physical compatibility of the active ingredient with the intended excipients.

[0104] Direct compression is a relatively rapid process in which powdered materials are directly compressed without changing the physical and chemical properties of the drug. The active ingredient (e.g., a compound described herein, e.g., VS-6063, e.g., VS-6063 free base or VS-6063 hydrochloride), excipients for direct compression, and other auxiliary substances (e.g., glidants and lubricants) are mixed (e.g., in a twin shell blender or similar low shear instrument) prior to compression into tablets. The process generally consists of mixing the ingredients, dry sieving, lubrication, and compression.

[0105] The dry granulation method can be used where one of the components, whether the drug or the diluent, is sufficiently viscous to form a tablet. The method includes mixing, beating (or rolling) the components, dry sieving, lubricating, and pressing. In some embodiments, dry granulation is used to improve, for example, processability, for example, the flowability of a blend (e.g., a composition described herein, e.g., a composition comprising VS-6063).

[0106] The wet granulation method can be used, for example, to convert a powder mixture into particles with improved flowability and viscosity for tableting. The process consists of mixing the powders in, for example, a suitable agitator and then adding a granulation solution to the mixed powder under shear to obtain granulation. The wet mass is then sieved through a suitable sieve and dried by tray drying or fluidized bed drying. Alternatively, the wet mass can be dried and passed through a grinder. The entire process includes weighing, dry powder mixing, wet granulation, drying, grinding, mixing lubrication and pressing.

[0107] The oral dosage form may, if desired, be present in a package or dispensing device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient. The package may, for example, comprise metal or plastic foil, such as a blister pack. The package or dispensing device may be provided with instructions for administration. The package or dispenser may also be provided with a notice associated with the container in a form indicated by a government agency regulating the manufacture, use or sale of drugs, which notice reflects the form of the composition approved by the agency or the permission for human or veterinary administration. Such notice, for example, may be a label approved by the U.S. Food and Drug Administration for prescription drugs or product inserts.

[0108] Treatment and administration methods

[0109] In particular, the present invention relates to methods of treating abnormal cell growth (eg, cancer) comprising administering an oral dosage form comprising VS-6063 or a pharmaceutically acceptable salt thereof.

[0110] Abnormal cell growth

[0111] Unless otherwise mentioned, abnormal cell growth as used herein refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the following abnormal growth: (1) tumor cells (tumors) that proliferate, for example, by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases, for example, in which abnormal tyrosine kinase activation occurs; (3) any tumor that proliferates, for example, by receptor tyrosine kinases; (4) any tumor that proliferates, for example, by abnormal serine / threonine kinase activation; and (5) benign and malignant cells of other proliferative diseases, for example, in which abnormal serine / threonine kinase activation occurs. Abnormal cell growth can refer to cell growth in the following cells: epithelial cells (e.g., carcinoma, adenocarcinoma); mesenchymal cells (e.g., sarcomas (e.g., leiomyosarcomas, Ewing sarcomas)); hematopoietic cells (e.g., lymphomas, leukemias, myelodysplasias (e.g., premalignant)); or other cells (e.g., melanomas, mesotheliomas, and other tumors of unknown origin).

[0112] Abnormal cell growth can refer to cancer, which includes, but is not limited to, lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutant NSCLC; metastatic cancer), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer (e.g., advanced or metastatic ovarian cancer), rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer (e.g., triple-negative breast cancer (e.g., breast cancer that does not express genes for estrogen receptor, progesterone receptor, and Her2 / neu)), uterine cancer, fallopian tube cancer, endometrial cancer, Cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestinal cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvic cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal tumor, brain stem glioma, pituitary adenoma, mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma) or a combination of one or more of the above cancers. In some embodiments, the cancer is metastatic. In some embodiments, the abnormal cell growth is locally recurrent (e.g., the subject suffers from a locally recurrent disease, e.g., cancer).

[0113] In some embodiments, the method includes administering an oral dosage form of the present invention to a mammal, which is effective in treating non-hematological malignancies. In some embodiments, the method is effective in treating breast cancer, lung cancer, and ovarian cancer. In one embodiment, the breast cancer is triple-negative breast cancer (e.g., breast cancer that does not express estrogen receptors, progesterone receptors, and Her2 / neu genes). In one embodiment, the lung cancer is non-small cell lung cancer (NSCLC), for example, KRAS mutated NSCLC. In one embodiment, the ovarian cancer is advanced ovarian cancer (e.g., advanced ovarian cancer or metastatic ovarian cancer).

[0114] In one embodiment, the method comprises administering to a mammal a composition, e.g., an oral dosage form of the invention, that is effective in treating mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma).

[0115] The method of the present invention is intended to administer a therapeutically effective amount of a composition described herein alone and in multiple doses. Compositions, e.g., compositions described herein, can be administered at regular intervals according to the nature, severity and degree of the subject's condition. In some embodiments, compositions described herein are administered in a single dose. In some embodiments, compositions described herein are administered in multiple doses. In some embodiments, a therapeutically effective amount of a composition, e.g., a composition described herein, can be administered orally and at regular intervals (e.g., every 1 day, 2 days, 3 days, 4 days, 5 days or 6 days, or every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks or 9 weeks, or every 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or longer administration 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times or more times).

[0116] In some embodiments, the compositions described herein are administered at predetermined time intervals (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more days, every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks, or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more months).

[0117] combination

[0118] The oral dosage forms and methods of the present invention can be administered in combination with additional agents (e.g., second agents, secondary agents) (e.g., therapeutic agents). The additional agents may include anti-tumor or anti-cancer agents, for example, anti-tumor agents selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens.

[0119] The oral dosage form of the present invention can be administered as a sole therapy or can contain one or more other anti-tumor substances, such as those selected from the group consisting of, for example, mitotic inhibitors, such as taxanes, e.g., docetaxel (Taxotere), paclitaxel; alkaloids, such as vinblastine; alkylating agents, such as platinum-coordinated alkylating compounds, such as platinums, such as cisplatin, oxaliplatin and carboplatin; and cyclophosphamide; antimetabolites, such as gemcitabine, 5-fluorouracil, capecitabine, cytarabine and hydroxyurea; growth factor inhibitors; cell cycle inhibitors; intercalating antibiotics, such as adriamycin and bleomycin; enzymes, such as interferons; and antihormones, such as anti-estrogens, such as nolvadex (tamoxifen) or, for example, anti-androgens, such as casodex (4′-cyano-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).

[0120] The oral dosage form of the present invention can be used alone or in combination with one or more of various anticancer agents or supportive care agents. For example, the oral dosage form of the present invention can be used with a cytotoxic agent, for example, one or more selected from the following: camptothecin, irinotecan hydrochloride (Camptosar), edotecarin, SU-11248, epirubicin (Ellence); taxanes, for example, docetaxel (Taxotere), paclitaxel; rituximab (Rituxan) bevacizumab (Avastin), imatinib mesylate (Gleevac), Erbitux, gefitinib (Iressa) and combinations thereof. The present invention also includes the use of the oral dosage form of the present invention with hormone therapy, for example, exemestane (Aromasin), leuprorelin acetate, anastrozole (Arimidex), tamoxifen citrate (Nolvadex), Trelstar and combinations thereof. In addition, the present invention provides a single oral dosage form of the present invention or a combination with one or more supportive treatment products, for example, a product selected from the following: filgrastim (Ubojin), ondansetron (Zofran), Fragmin, recombinant human erythropoietin α, palonosetron (Aloxi), emend or a combination thereof. This combination therapy can be achieved by administering the individual treatment components simultaneously, sequentially or separately.

[0121] The oral dosage form of the present invention can be used with the following but not limited to the following examples of additional or second agents, such as, for example, anti-tumor agents, anti-cancer agents, which can be used with the oral dosage form of the present invention.

[0122] o Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, dibromomannitol, carboquinone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and dibromodulcitol; platinum-coordinated alkylating compounds, e.g., platinums such as cisplatin, carboplatin, ethiaplatin, lobaplatin, nedaplatin, oxaliplatin, or satraplatin;

[0123] o Antimetabolites include, but are not limited to, methotrexate, 6-mercaptopurine nucleoside, mercaptopurine, gemcitabine, 5-fluorouracil (5-FU), alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine sodium octadecyl phosphate, enocitabine, S-1, gemcitabine, fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytarabine, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, octadecyl phosphate, pemetrexed disodium, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, adenosine, vincristine, vinorelbine;

[0124] o Antibiotics include, but are not limited to, aclarubicin, actinomycin D, amrubicin, anamycin, bleomycin, daunorubicin, doxorubicin, elsamicin, epirubicin, gadolinium, idarubicin, mitomycin C, nemorubicin, neocarcinostatisin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozotocin, valrubicin, or netastatin;

[0125] o Hormonal therapeutic agents, for example, exemestane (Aromasin), leuprolide acetate, anastrozole (Arimidex), doxorcalciferol, fadrozole, formestane, anti-estrogens, for example, tamoxifen citrate (Nolvadex) and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Furoxime), or anti-androgens, for example, bicalutamide, flutamide, mifepristone, nilutamide, casder (4′-cyano-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide) and combinations thereof;

[0126] o Plant-derived antitumor substances include, for example, those selected from the group consisting of: mitotic inhibitors, such as alkaloids, for example, vinblastine; taxanes, for example, docetaxel (Taxotere), paclitaxel;

[0127] o Cytotoxic topoisomerase inhibitors include one or more drugs selected from the group consisting of aclarubicin, amifide, belothione, camptothecin and camptothecin derivatives, including but not limited to 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan, irinotecan hydrochloride (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lortotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide and topotecan, and combinations thereof;

[0128] oImmunological agents include interferons and many other immune enhancers. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, or interferon gamma-n1. Other drugs include filgrastim, lentinan, schizophyllan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab, ozogamicin, ibritumomab tiuxetan, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), moragastim, OncoVAX-CL, sargramostim, tasonamine, tecleukin, thymalfasin, tositumomab, virulizumab, Z-100, epratuzumab, mitumomab, ogavuzumab, pemtumomab, and Provenge;

[0129] o Biological response modifiers are drugs that modify the defense mechanisms or biological responses of living organisms (e.g., survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity). Such drugs include versicolor polysaccharides, lentinan, sizofuran, hemolytic streptococcal preparations, or ubenimex;

[0130] o Other anticancer drugs including alitretinoin, ampligen, atrasentan, bexarotene, bortezomib, bosentan, calcitriol, exixulin, finasteride, fotemustine, ibandronic acid, miltefosine, mitoxantrone, 1-asparaginase, procarbazine, dacarbazine, hydroxyurea, pegaspargase, pentostatin, tazarotene, TLK-286, Velcade, Tarceva, tretinoin, CTLA4 inhibitors or farnesyl protein transferase inhibitors;

[0131] o Other anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Revlimid, squalamine, ukrain, and Vitaxin;

[0132] o Platinum-coordinated compounds include, but are not limited to, cisplatin, carboplatin, nedaplatin or oxaliplatin;

[0133] o The tyrosine kinase inhibitor is Iressa or SU5416;

[0134] o Antibodies include Herceptin, Erbitux, Avastin, Rituximab, or cytotoxic lymphocyte antigen 4 (CTLA4); and

[0135] o Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a or interferon gamma-n1. BRIEF DESCRIPTION OF THE DRAWINGS

[0136] Figure 1 Shown is an exemplary mean dissolution profile for a 100 mg VS-6063IR tablet formulation

[0137] Figure 2 Shown is an exemplary mean dissolution profile for a 100 mg VS-6063IR tablet formulation

[0138] Figure 3 Shown is an exemplary mean dissolution profile for a 100 mg VS-6063IR tablet formulation

[0139] Figure 4 Shown is an exemplary mean dissolution profile for a 100 mg VS-6063IR tablet formulation in 0.1 M HCl.

[0140] Figure 5 Shown are exemplary plasma mean (n=4) VS-6063 concentrations following oral gavage of VS-6063 in various formulations to male beagle dogs at 10 mg API / kg - linear strength

[0141] Figure 6 Shown are exemplary plasma mean (n=4) VS-6063 concentrations following oral gavage of VS-6063 in various formulations to male beagle dogs at 10 or 20 mg API / kg-linear strength. Example

[0142] The present invention is further described in the following examples, which do not limit the scope of the present claims.

[0143] Example 1. Dry granulation of VS-6063 formulation

[0144] The VS-6063 immediate release (IR) formulation was prepared using a dry granulation method. The composition of the formulation is shown in Table 1:

[0145] Table 1: Composition of 100 mg VS-6063IR tablet formulation

[0146]

[0147] The intragranular blend was prepared by sieving VS-6063 and all excipients through a 600 μm sieve before use. The required amounts of functional excipients and VS-6063 were weighed out and premixed for 1 minute using a large plastic spatula and then mixed on a Turbula mixer at a setting of 32 rpm for 5 minutes. The remaining sieved ingredients (except magnesium stearate) were added to the premix, mixed for 1 minute using a large plastic spatula and then mixed on a Turbula mixer at a setting of 32 rpm for 15 minutes. After the addition of magnesium stearate, the final mix was run on a Turbula mixer at a setting of 32 rpm for 3 minutes. The intragranular blend was then rolled. The particle properties of the two IR tablet formulations were characterized and compared with batches of direct compression tablets of the same composition; as shown in Table 2:

[0148] Table 2: Powder Characteristics of 100 mg VS-6063 Tablet Formulation

[0149]

[0150] Particle size analysis data indicated a bimodal particle size distribution with approximately 20% of the particle size distribution >710 μm and approximately 20% of the particle size distribution <75 μm.

[0151] The physical properties of the blend were determined and compared to the direct compression formulation (HPMC-AS only formulation); (Table 2). The measured Hausner ratio for this blend was >1.3 and the Carr index was >23%, which means that the blend may have poor powder flowability, agglomeration, and high inter-particle friction. However, the angle of repose did indicate acceptable powder flowability.

[0152] Compared to direct compression methods, higher compression forces may be required to achieve the desired tablet hardness for dry granular blends.

[0153] Table 3: Tablet Compression Data for 100 mg VS-6063 Tablet Formulation

[0154]

[0155]

[0156] Figure 1 It was shown that for the HPMC-AS formulation, dry granulation can slow down dissolution after the pH transition (eg, gastric to intestinal pH) compared to the dissolution of tablets prepared using a direct compression process.

[0157] For the PVP VA / Soluplus formulation, the dissolution properties of tablets prepared by the dry granulation method were slower than those prepared using the direct compression method. The resulting dissolution properties were very similar to those of the VS-6063 reference product (e.g., unformulated product).

[0158] Example 2. Dry granulation of VS-6063 immediate release formulation

[0159] One batch of the VS-6063IR formulation was prepared using a dry granulation process (Table 4):

[0160] Table 4: Composition of 100 mg VS-6063 tablet formulation

[0161]

[0162] The intragranular blend was prepared by sieving VS-6063 and all excipients through a 600 μm sieve before use. The required amount of functional excipients and VS-6063 was weighed out and premixed for 1 minute using a large plastic spatula, then mixed for 5 minutes on a Turbula mixer at a setting of 32 rpm. The remaining sieved components (except magnesium stearate) were added to the premix, mixed for 1 minute using a large plastic spatula, then mixed for 15 minutes on a Turbula mixer at a setting of 32 rpm. After magnesium stearate was added, the final mixing was run on a Turbula mixer at a setting of 32 rpm for 3 minutes. The intragranular blend was then rolled.

[0163] After completion of the dry granulation process, the compacted ribbons were passed through 1.4 mm, 1.18 mm and 850 μm sieves.The tablet blend was then prepared by mixing the granules with magnesium stearate using a Turbula mixer at 32 rpm for 3 minutes.

[0164] Table 5: Powder properties of 100 mg VS-6063 tablet formulation

[0165]

[0166] The particle size analysis data indicated that the blend, which consisted mostly of fines (approximately 45% <150 μm), produced harder ribbons than the roller compacted PVP VA / Soluplus formulation (approximately 35% <150 μm).

[0167] The physical properties of the blends before and after roller compaction were also measured and indicated that flowability may not be significantly improved using a dry granulation process (Table 5). The data also indicated that by forming softer ribbons, the powder flowability may not be improved compared to granules formed from harder ribbons (Table 5).

[0168] Compared to direct compression methods, a higher compression force of 8000 lbs may be required for dry granulation formulations to achieve the desired tablet hardness. However, this may be lower than the 10000 lbs compression force that may be required to make tablets from granules made from harder ribbons.

[0169] Table 6: Tablet compression data for 100 mg VS-6063 tablet formulation.

[0170]

[0171]

[0172] To determine whether adding additional crospovidone to the formulation would improve disintegration time, the crospovidone content was further increased to 13% of the total disintegrant content, of which 3% was added to the extragranular blend. Tablets were compressed on a Carver tablet press using an 18.97x10.41 mm oval tool tablet mold. The compression force was adjusted to achieve a tablet hardness of 10–14 kP. Tablet compression data are shown in Table 6.

[0173] Table 7: Tablet compression data for 100 mg VS-6063 tablet formulation.

[0174]

[0175] Granules produced by dry granulation may not improve compressibility or powder flowability compared to direct compression. Although the use of softer ribbons may improve the disintegration time of the resulting tablets, the dissolution properties are not improved compared to the reference product ( Figure 2 ), which means that the function of the precipitation inhibitor in the PVP VA / Soluplus formulation may be lost during the dry granulation process.

[0176] Example 3. Dry granulation of VS-6063 formulation

[0177] A batch of the VS-6063IR formulation was prepared using a dry granulation process (Table 8):

[0178] Table 8: Composition of 100 mg VS-6063IR tablet formulation

[0179]

[0180] The intragranular blend is prepared by sieving VS-6063 and all excipients through a 600 μm sieve before use. The required amount of functional excipients and the API (e.g., VS-6063) is weighed out and premixed for 1 minute using a large plastic spatula, then mixed for 5 minutes on a Turbula mixer at a setting of 32 rpm. The remaining sieved ingredients (except magnesium stearate) are added to the premix, mixed for 1 minute using a large plastic spatula, then mixed for 15 minutes on a Turbula mixer at a setting of 32 rpm. After magnesium stearate is added, the final mix is ​​run on a Turbula mixer at a setting of 32 rpm for 3 minutes. The intragranular blend is then rolled.

[0181] The granule properties of the IR tablet formulation are shown in Table 9 and compared with a direct compression batch of the same composition:

[0182] Table 9: Powder properties of 100 mg VS-6063 tablet formulation

[0183]

[0184]

[0185] The particle size analysis data indicated bimodal particle size distribution for both batches.

[0186] The physical properties of the blends were determined and compared to the direct compression formulations (HPMC-AS formulation only). The data showed that flowability can be improved by using a dry granulation process (Table 9). However, the Hausner ratio for these experiments was >1.3 and the Carr index was >23%, which means possible poor powder flowability, agglomeration, and high inter-particle friction. However, the angle of repose data showed acceptable powder flowability.

[0187] Both dry granulation formulations may require higher compression forces to achieve the desired tablet hardness compared to direct compression methods.

[0188] Table 10: Tablet compression data for 100 mg VS-6063 tablet formulation.

[0189]

[0190] Figure 3 The data showed that for HPMC-AS formulations incorporating the dry granulation method, the dissolution properties of all batches after pH shift were similar to those of tablets prepared using the direct compression method.

[0191] Example 4. In vivo evaluation of the pharmacokinetics of VS-6063 in different formulations

[0192] Abbreviations used:

[0193] Relative bioavailability = AUC inf Test preparation / AUC inf Reference preparation

[0194] C max The maximum observed concentration

[0195] T max Time of maximum concentration

[0196] t 1 / 2 Terminal half-life

[0197] AUC inf The area under the concentration-time curve extending from time zero to infinity

[0198] AUC last The area under the concentration-time curve from time zero to the last measurable concentration

[0199] Study Design

[0200] In 4 groups, 1 male beagle dog in each group received oral gavage of VS-6063 in different formulations in a 4-period crossover design with a minimum washout period of 3 days between dosing periods. In each period, VS-6063, VS-6063-25% SDD in Soluplus / PVP-A, VS-6063-25% physical mixture with Soluplus / PVP-A, and VS-6063-10% SDD in EUDRAGIT L100-55 were administered at a target dose level of 10 mg API / kg. Blood samples (anticoagulant: K2EDTA) were collected from each animal before dosing and at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after dosing in each dosing period. Blood samples were processed to plasma and the plasma was analyzed for VS-6063 by LC-MS / MS. Plasma concentration-time data from individual animals were analyzed to determine the pharmacokinetic profile of VS-6063.

[0201] In 4 groups, 1 male beagle dog in each group received oral gavage of VS-6063 in different formulations in a 4-period crossover design with a minimum washout period of 3 days between dosing periods. In each period, VS-6063-25% physical mixture with Soluplus / PVP-A and VS-6063-25% SDD in Soluplus / PVP-A were administered at a target dose level of 20 mg API / kg and VS-6063-50% physical mixture with Soluplus / PVP-A were administered at target dose levels of 10 and 20 mg API / kg. Blood samples (anticoagulant: K2EDTA) were collected from each animal for the scheduled pre-dose and 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after dosing in each dosing period. Blood samples were processed to plasma and the plasma was analyzed for VS-6063 by LC-MS / MS. Plasma concentration-time data for each animal were analyzed to determine the pharmacokinetic profile of VS-6063.

[0202] Dosage Formulation

[0203] VS-6063 was formulated at a target concentration of 10 mg API / mL in 0.5% (w / v) Methocel A4M aqueous solution containing 0.1% (v / v) Tween 80 (0.934 correction factor). VS-6063-25% SDD in Soluplus / PVP-A was formulated at a target concentration of 10 mg API / mL in 0.5% (w / v) Methocel A4M aqueous solution (0.25 correction factor). VS-6063-25% physical mixture containing Soluplus / PVP-A was formulated at a target concentration of 10 mg API / mL in 0.5% (w / v) Methocel A4M aqueous solution (0.25 correction factor). VS-6063-10% SDD in EUDRAGIT L100-55 was formulated at a target concentration of 10 mg API / mL in 0.5% (w / v) Methocel A4M aqueous solution (0.10 correction factor).

[0204] VS-6063-25% physical mixture containing Soluplus / PVP-A and VS-6063-25% SDD in Soluplus / PVP-A were formulated at a target concentration of 10 mg API / mL in 0.5% (w / v) Methocel A4M aqueous solution (0.25 correction factor). VS-6063-50% physical mixture containing Soluplus / PVP-A was formulated at target concentrations of 5 mg API / mL and 10 mg API / mL in 0.5% (w / v) Methocel A4M aqueous solution (0.50 correction factor).

[0205] Dosage

[0206] In 4 groups, 1 male beagle dog in each group received oral gavage of VS-6063 in different formulations, in a 4-period crossover design with a minimum washout period of 3 days between dosing periods. In each period, VS-6063, VS-6063-25% SDD in Soluplus / PVP-A, VS-6063-25% physical mixture with Soluplus / PVP-A, and VS-6063-10% SDD in EUDRAGIT L100-55 were administered at a target dose level of 10 mg API / kg. Animals were fasted overnight prior to dosing; drinking water was available. Food was resumed 4 hours after dosing.

[0207] Before administration, the body weight of each animal was recorded. The dose was calculated based on the body weight (kg) before treatment and the dose volume of 1 mL / kg (rounded to the nearest 0.01 mL). After oral gavage, the gavage tube was rinsed with 10 to 20 mL of water and then the tube was removed. The syringe was weighed immediately before and after administration of each animal and the amount of preparation administered to each animal was determined from the difference in the weight of the Eustachian tube.

[0208] In 4 groups, 1 male beagle dog in each group received oral gavage of VS-6063 in different formulations, in a 4-period crossover design with a minimum washout period of 3 days between dosing periods. In each period, VS-6063-25% physical mixture with Soluplus / PVP-A and VS-6063-25% SDD in Soluplus / PVP-A were administered at a target dose level of 20 mg API / kg and VS-6063-50% physical mixture with Soluplus / PVP-A was administered at target dose levels of 10 and 20 mg API / kg. Animals were fasted overnight before dosing; drinking water was available. Food was resumed 4 hours after dosing.

[0209] Before administration, the body weight of each animal was recorded. The dosage was calculated based on the body weight (kg) before treatment and the dosage volume of 2mL / kg (rounded to the nearest 0.01mL). After oral gavage, the gavage tube was rinsed with 10 to 20mL of water and then the tube was removed. The Eustachian tube was weighed immediately before and after administration of each animal and the dosage of the preparation administered to each animal was determined from the Eustachian tube weight difference.

[0210] VS-6063 concentration in plasma

[0211] The mean (n=4) plasma concentration-time curves are shown in Figure 5 (straight line scale) shown.

[0212] After a single oral administration of VS-6063 at a target dose of 10 mg / kg for 4 sessions, plasma concentrations increased at a fairly rapid rate and reached maximum concentrations in each animal within 2-4 hours after dosing (average 2.50 hours). The mean concentration then decreased in an apparent first-order manner. The concentration of VS-6063 in all animals was quantifiable throughout the 24 hours after dosing (final time point).

[0213] After single oral administration of VS-6063-25% SDD in Soluplus / PVP-A, VS-6063-25% physical mixture containing Soluplus / PVP-A, and VS-6063-10% SDD in EUDRAGIT L100-55 at a target dose of 10 mg / kg for 4 periods, plasma concentrations increased at a fairly rapid rate and reached maximum concentrations in each animal within 0.5-4 hours after dosing (mean range 1.75-1.88 hours). The mean concentration then declined in an apparent first-order manner. The concentration of VS-6063 in all animals was quantifiable throughout the 24 hours after dosing (final time point).

[0214] Plasma pharmacokinetics of VS-6063

[0215] The plasma pharmacokinetic parameters of VS-6063 are shown in Tables 13 and 14.

[0216] For VS-6063 at a target dose of 10 mg / kg for 4 periods, the average estimated half-life was approximately 3.9 hours. max and average T max The mean AUC was 614 ng / mL and 2.50 hours, respectively. last is 3100ng*hr / mL and the average AUC inf It is 3120ng*hr / mL. (Table 17)

[0217] For VS-6063-25% SDD in Soluplus / PVP-A at a target dose of 10 mg API / kg for 4 periods, the mean estimated half-life was approximately 3.2 hours. max and average T max The mean AUC was 1770 ng / mL and 1.75 hours, respectively. last is 8130ng*hr / mL and the average AUC inf It is 8170ng*hr / mL. (Table 18)

[0218] For VS-6063-25% physical mixture containing Soluplus / PVP-A at a target dose of 10 mg API / kg for 4 periods, the average estimated half-life was approximately 3.7 hours. max and average T max The mean AUC was 1460 ng / mL and 1.75 hours respectively. last is 7320ng*hr / mL and the average AUC inf It is 7410ng*hr / mL. (Table 19)

[0219] For VS-6063-10% SDD in EUDRAGIT L100-55 at a target dose of 10 mg API / kg for 4 periods, the mean estimated half-life was approximately 2.9 hours. max and average T max The mean AUC was 1800 ng / mL and 1.88 hours respectively. last is 8720ng*hr / mL and the average AUC inf It is 8740ng*hr / mL. (Table 20)

[0220] The mean pharmacokinetic data indicated that relative bioavailability was elevated when comparing the test formulations (VS-6063-25% SDD, VS-6063-25% physical mixture, and VS-6063-10% SDD) to the reference formulation (VS-6063), but there was significant variability between animals. The mean relative bioavailability was estimated to be 2.97 (CV 72.7%) for VS-6063-25% physical mixture, 3.21 (CV 43.3%) for VS-6063-10% SDD, and 3.78 (CV 89.9%) for VS-6063-25% SDD. When the crossover data were compared; Animal No. 4001 had the lowest exposure to the reference formulation (VS-6063), which contributed to the overall difference among the treated animals (mean AUC inf CV 52.8%) and contributed to the highest relative bioavailability among the tested formulations.

[0221] Although vomiting was observed in 3 of 4 subjects dosed with VS-6063-25% physical mixture, the mean relative bioavailability compared to the reference formulation was similar to the other formulations tested.

[0222] VS-6063 concentration in plasma

[0223] Mean plasma concentration-time curves Figure 6 (straight line scale) shown.

[0224] After single oral administration of VS-6063-25% physical mixture at a target dose of 20 mg API / kg for 4 periods, plasma concentrations increased at a fairly rapid rate and reached a maximum concentration within 0.25-1 hour after administration (average 0.688 hours). The mean concentration then decreased in an apparent first-order manner. The concentration of VS-6063 was quantifiable in all animals throughout the 24 hours after administration (final time point).

[0225] After single oral administration of VS-6063-25% SDD at a target dose of 20 mg API / kg for 4 sessions, plasma concentrations increased at a fairly rapid rate and reached maximum concentrations within 0.25-2 hours (mean 1.31 hours) post-dose. Mean concentrations then declined in an apparent first-order manner. VS-6063 concentrations were quantifiable in all animals throughout the 24 hours post-dose (final time point).

[0226] After single oral administration of VS-6063-50% physical mixture at target doses of 10 mg API / kg and 20 mg API / kg for 4 periods, plasma concentrations increased at a fairly rapid rate and reached maximum concentrations within 0.5-2 hours (mean 1.38 hours) after dosing at 10 mg API / kg and within 0.5-4 hours (mean 2.13 hours) after dosing at 20 mg API / kg. The mean concentrations then declined in an apparent first order manner. The concentrations of VS-6063 were quantifiable in all animals throughout the 24 hours after dosing (final time point).

[0227] Plasma pharmacokinetics of VS-6063

[0228] The plasma pharmacokinetic parameters of VS-6063 are shown in Tables 15 and 16.

[0229] For VS-6063-25% physical mixture containing Soluplus / PVP-A administered for 4 periods at a target dose of 20 mg API / kg, the average estimated half-life was approximately 3.0 hours. max and average Tmax The mean AUC was 1670 ng / mL and 0.688 hours respectively. last is 8670ng*hr / mL and the average AUC inf It is 8700ng*hr / mL. (Table 21)

[0230] For VS-6063-25% SDD in Soluplus / PVP-A administered for 4 periods at a target dose of 20 mg API / kg, the mean estimated half-life was approximately 3.1 hours. max and average T max The mean AUC was 1300 ng / mL and 1.31 hours respectively. last is 5920ng*hr / mL and the average AUC inf It is 5940ng*hr / mL. (Table 22)

[0231] For VS-6063-50% physical mixture containing Soluplus / PVP-A administered for 4 periods at a target dose of 10 mg API / kg, the average estimated half-life was approximately 3.0 hours. max and average T max The mean AUC was 680 ng / mL and 1.38 hours. last is 3390ng*hr / mL and the average AUC inf It is 3400ng*hr / mL. (Table 23)

[0232] For VS-6063-50% physical mixture containing Soluplus / PVP-A administered for 4 periods at a target dose of 20 mg API / kg, the average estimated half-life was approximately 3.5 hours. max and average T max The mean AUC was 1160 ng / mL and 2.13 hours respectively. last is 6900ng*hr / mL and the average AUC inf It is 6930ng*hr / mL. (Table 24)

[0233] Vomiting was observed corresponding to lower exposures, whereas in other cases, no such association existed.

[0234] Pharmacokinetic data indicated that VS-6063-50% physical mixture was dose proportional at target doses of 10 mg API / kg and 20 mg API / kg: mean dose-normalized AUC inf and C max Can be similar.

[0235] Comparing the data from these two studies, the dose-normalized mean AUC for VS-6063-25% physical mixture (20 mg API / kg) and VS-6063-25% SDD (20 mg API / kg) relative to VS-6063-25% physical mixture (10 mg API / kg) and VS-6063-25% SDD (10 mg API / kg) was inf and C max The effects of 4% paraformaldehyde on the efficacy of the treatment were less dose proportional, as summarized in Table 11 below.

[0236] Table 11.

[0237]

[0238] The mean pharmacokinetic data indicated that the relative bioavailability was similar when the test formulation VS-6063-50% physical mixture was compared to the reference formulation VS-6063 (10 mg / kg) at target doses of 10 mg API / kg and 20 mg API / kg.

[0239] Table 12.

[0240]

[0241] in conclusion

[0242] The mean pharmacokinetic data indicated that relative bioavailability increased when VS-6063-25% SDD in Soluplus (10 mg API / kg), VS-6063-25% physical mixture with Soluplus (10 mg API / kg), and VS-6063-10% SDD in EUDRAGIT L100-55 (10 mg API / kg) were compared to VS-6063 (10 mg / kg), but there was variability between animals. The mean relative bioavailability was estimated to be 2.97 (CV 72.7%) for VS-6063-25% physical mixture, 3.21 (CV 43.3%) for VS-6063-10% SDD, and 3.78 (CV 89.9%) for VS-6063-25% SDD.

[0243] Mean pharmacokinetic data indicate that VS-6063-50% physical mixture containing Soluplus / PVP-A is dose proportional at target doses of 10 mg API / kg and 20 mg API / kg. Mean dose-normalized mean AUC inf and average C max Can be roughly similar.

[0244] Comparing the data from these two studies, the dose-normalized mean AUC was compared when VS-6063-25% physical mixture (10 mg API / kg) and VS-6063-25% SDD (10 mg API / kg) were used. inf and average C max VS-6063-25% physical mixture (20 mg API / kg) and VS-6063-25% SDD (20 mg API / kg) were less dose proportional. The dose-normalized mean pharmacokinetic data suggest that the relative bioavailability may be similar when comparing 10 mg API / kg and 20 mg API / kg target doses of VS-6063-50% physical mixture to VS-6063 (10 mg / kg).

[0245] Table 13: Oral (gavage) dosing of VS-6063 in various formulations to male beagle dogs

[0246]

[0247]

[0248] a Assume a density of 1 g / mL.

[0249] Table 14. Mean (n=4) plasma pharmacokinetic parameters of VS-6063 following oral gavage administration of VS-6063 in various formulations at 10 mg / kg to male beagle dogs

[0250]

[0251] Relative bioavailability = AUC inf Test preparation / AUC inf Reference preparation

[0252] Table 15. Oral (gavage) dosing of VS-6063 in various formulations to male beagle dogs

[0253]

[0254]

[0255] a Assume the density is 1 g / mL.

[0256] Table 16 Mean (n=4) plasma pharmacokinetic parameters of VS-6063 following oral gavage administration of VS-6063 in various formulations to male beagle dogs at 10 or 20 API mg / kg

[0257]

[0258] Table 17 Plasma pharmacokinetic parameters of VS-6063 after oral gavage administration of VS-6063 at 10 mg API / kg to male beagle dogs

[0259]

[0260] Table 18 Plasma pharmacokinetic parameters of VS-6063 following oral gavage administration of VS-6063-25% SDD in Soluplus / PVP-A to male beagle dogs at 10 mg API / kg

[0261]

[0262]

[0263] Table 19 Plasma pharmacokinetic parameters of VS-6063 following oral gavage administration of VS-6063-25% physical mixture containing Soluplus / PVP-A to male beagle dogs at 10 mg API / kg

[0264]

[0265] a Regression R-squared value < 0.9

[0266] Table 20 Plasma pharmacokinetic parameters of VS-6063 following oral gavage administration of VS-6063-10% SDD in EUDRAGIT L100-55 to male beagle dogs at 10 mg API / kg

[0267]

[0268] Table 21 Plasma pharmacokinetic parameters of VS-6063 after oral gavage administration of VS-6063-25% physical mixture containing Soluplus / PVP-A to male beagle dogs at 20 mg API / kg

[0269]

[0270]

[0271] Table 22 Plasma pharmacokinetic parameters of VS-6063 following oral gavage administration of VS-6063-25% SDD in Soluplus / PVP-A to male beagle dogs at 20 mg API / kg

[0272]

[0273] Table 23 Plasma pharmacokinetic parameters of VS-6063 following oral gavage administration of VS-6063-50% physical mixture containing Soluplus / PVP-A to male beagle dogs at 10 mg API / kg

[0274]

[0275] Table 24 Plasma pharmacokinetic parameters of VS-6063 following oral gavage administration of VS-6063-50% physical mixture containing Soluplus / PVP-A to male beagle dogs at 20 mg API / kg

[0276]

[0277]

[0278] Example 5. Clinical Study Protocol: Safety, Bioavailability, and Pharmacodynamics of Selected VS-6063 Formulations Phase I study

[0279] Study Design

[0280] The safety, bioavailability, and pharmacodynamics of the VS-6063 prototype and reference formulations were investigated in healthy male subjects in a Phase I, open-label, single-center, single-dose, partially randomized trial. The study consisted of four time periods, each with an identical study design and involving 24 male subjects aged 40 to 65 years with a body mass index of 18.0 to 35.0 kg / m 2 . Following a 28-day screening period, the subjects were admitted to the hospital on the morning of the day before dosing (Day -1) and dosed on the morning of Day 1. Subjects in Schedules A and B were dosed with VS-6063 after an overnight fast of approximately 10 hours, while subjects in Schedules C and D were dosed with VS-6063 within 30 minutes of starting a high-fat breakfast, which was consumed within 25 minutes. Subjects remained in place until 36 hours after dosing. There was a minimum 7-day washout period between each dosing schedule. Follow-up calls were conducted 7-10 days after the last dose in Time Periods 3 and 4 to ensure the continued health of the subjects.

[0281] Table 25. Summary of Pharmacokinetic Results

[0282]

[0283]

[0284] a Median (range)

[0285] Abbreviation: T lag a: The time from the start of drug administration when VS-6063 can be first quantified in a concentration vs time curve; C max : Maximum observed VS-6063 concentration; T max a :C appears max C is the time from the start of drug administration; 12 : VS-6063 concentration observed at 12 h; C 24 : VS-6063 concentration observed at 24h; AUC last : Area under the concentration-time curve from time zero to the time of the last quantifiable concentration; AUC inf : Area under the concentration-time curve extending from time zero to infinity; AUC ％extrap : AUC explained by extrapolation (0-inf) λ-z: the slope of the regression time through the apparent elimination phase in the concentration-time plot; t 1 / 2 : Apparent elimination half-life; αt 1 / 2 : In C max The distribution half-life of VS-6063 occurs within a time frame of approximately 12 h after administration.

[0286] Statistical methods

[0287] Dose-corrected pharmacokinetic (PK) parameter AUC last , AUC inf and C max Formal statistical analysis was performed to assess relative bioavailability and the effect of food present. The PK parameters were natural log transformed and analyzed using mixed model techniques. To compare different regimens, the adjusted geometric mean ratio (GMR) and the 90% confidence interval (CI) for the adjusted GMR were calculated. The CI was based on the t-distribution and variance estimated by the model using the Kenward-Roger method for calculating degrees of freedom.

[0288] Study Results

[0289] Following administration of 200 mg VS-6063 reference formulation tablets (comprising VS-6063, microcrystalline cellulose PH 102, Fastflo 316, sodium starch glycolate, and magnesium stearate) or 100 mg VS-6063 prototype formulation tablets (comprising VS-6063, HPMCAS-HF, microcrystalline cellulose PH 102, Fastflo 316, sodium starch glycolate, and magnesium stearate) in the fed and fasted states, plasma concentrations increased to a maximum level immediately after administration. This was followed by a biphasic decrease in plasma levels over a 24 h sampling period as VS-6063 dispersed and was eliminated from the systemic circulation. No real half-life differences could be determined between the reference and prototype formulations in the fed or fasted states.

[0290] In the fasting state, the 100 mg prototype formulation administered in Schedule B resulted in significantly higher exposure compared to the 200 mg reference formulation in Schedule A. max and AUC last The adjusted GMR and 90% CI for Regimen B / Regimen A were 421.33 (348.4%, 509.5%) and 433.05 (366.8%, 511.3%), respectively, corresponding to a 4-fold increase in exposure due to the change in formulation. In addition to the increase in bioavailability, there was evidence of a decrease in variability observed after dosing with the prototype formulation related to exposure parameters, from approximately 70% to 30%.

[0291] The time taken to reach the maximum plasma concentration of VS-6063 was 2-4 times longer in the fed state than in the fasted state (e.g., C max and AUC last ), indicating an effect of food on the absorption rate. In addition, exposure determination after administration of 200 mg of VS-6063 reference formulation in the fed and fasted states showed higher exposure levels in the fed state relative to the fasted state, indicating a food effect for the reference formulation. Despite these effects, an increase in VS-6063 exposure was still observed when the prototype formulation was administered compared to the reference formulation in the fed state. Based on C max and AUC last The adjusted GMR and 90% CI for regimen C / regimen D were 129.8 and 125.1, respectively.

[0292] In summary, administration of the prototype formulation in the fasted state achieved maximal exposure. Administration of the prototype formulation in the fed state resulted in maximal exposure to AUC inf Equal exposure is achieved.

[0293] VS-6063 was well tolerated when administered in the fed and fasted states in both the reference and prototype formulations. There were no serious adverse events (AEs) or no serious AEs reported during the study, and no subjects withdrew due to AEs. The overall incidence of total AEs was low, with 9 subjects reporting 12 AEs. Scheme C (5 subjects) had the highest incidence of AEs compared to Schemes A, B, and D (3 subjects, 2 subjects, and 1 subject, respectively). The most common AE was headache, which occurred in 3 subjects. All other AEs were reported by 1 subject. No subject reported AEs related to VS-6063, and almost all AEs were mild in severity. There were no significant clinical findings in any laboratory evaluation, test of vital signs, ECG, or physical examination.

[0294] In general, the present invention relates to the following scheme:

[0295] 1. A pharmaceutical composition comprising VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride), mixed with an excipient (e.g., a binder, e.g., a polymer, e.g., a precipitation inhibitor, e.g., HPMC, e.g., HPMCAS, e.g., HPMCAS-HF; a binder (e.g., polyvinyl pyrrolidone (e.g., polyvinyl pyrrolidone vinyl acetate copolymer (PVP / VA), copovidone), other copolymers (e.g., containing polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g., Soluplus))).

[0296] 2. The pharmaceutical composition of 1, wherein the excipient is a polymer.

[0297] 3. The pharmaceutical composition of 2, wherein the polymer is a precipitation inhibitor.

[0298] 4. The pharmaceutical composition of 3, wherein the precipitation inhibitor is HPMCAS.

[0299] 5. The pharmaceutical composition of 3, wherein the precipitation inhibitor is HPMCAS-HF.

[0300] 6. The pharmaceutical composition of 1, wherein the excipient reduces precipitation (e.g., precipitation of VS-6063 in solution, e.g., in vivo) when administered orally.

[0301] 7. The pharmaceutical composition of 1, wherein the excipient increases the bioavailability (e.g., increases absorption) of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) when administered orally.

[0302] 8. The pharmaceutical composition of 2, wherein the ratio (e.g., relative amount) of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) to the polymer is about 1:1, 1:2, 1:3 or 1:4 by weight.

[0303] 9. The pharmaceutical composition of 8, wherein the polymer is a precipitation inhibitor (e.g., HPMC, e.g., HPMCAS, e.g., HPMCAS-HF).

[0304] 10.1. The pharmaceutical composition of claim 1, wherein VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) is present in the composition in an amount of about 25% w / w, 30% w / w, 31% w / w, 32% w / w, 32.5% w / w, 33% w / w, 34% w / w, 35% w / w, 40% w / w, 45% w / w, 50% w / w, or more relative to the amount of the provided polymer (e.g., precipitation inhibitor).

[0305] 11. The pharmaceutical composition of 1, wherein the composition is mixed with 5-50% by weight, 5-30% by weight, 10-30% by weight, 10-20% by weight, 12-15% by weight, or 13% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per unit weight of the composition.

[0306] 12. The pharmaceutical composition of 1, wherein the composition is formulated into an oral dosage form.

[0307] 13. A pharmaceutical composition of 1, comprising VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride), wherein the oral dosage form comprises 5-50% by weight, 5-30% by weight, 10-30% by weight, 10-20% by weight, 12-15% by weight, 13% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per unit weight of the oral dosage form.

[0308] 14. The pharmaceutical composition of 1, wherein the VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) is present in an amount of 13% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per unit weight of the oral dosage form.

[0309] 15. The oral dosage form of 12, wherein the oral dosage form is a tablet.

[0310] 16. The oral dosage form of 15, wherein the tablet is provided by direct compression of a physical blend or mixture.

[0311] 17. The oral dosage form of 16, wherein the physical blend or mixture is provided by a dry granulation process.

[0312] 18. The oral dosage form of 2, wherein the polymer is present in an amount of 25-55%, 35-45%, 38-43%, or 40% by weight of the polymer per unit weight of the oral dosage form.

[0313] 19. The oral dosage form of 18, wherein the polymer is a precipitation inhibitor (e.g., HPMC, e.g., HPMCAS, e.g., HPMCAS-HF).

[0314] 20. An oral dosage form of 1, further comprising one or more fillers (e.g., microcrystalline cellulose (e.g., microcrystalline cellulose PH 102, e.g., Avicel PH 102); lactose (e.g., lactose monohydrate (e.g., FastFlo 316)).

[0315] 21. The oral dosage form of 20, wherein the filler is present in an amount of 5-80% by weight, 10-70% by weight, 20-60% by weight, 30-60% by weight, 30-50% by weight, or 42% by weight of the filler per unit weight of the oral dosage form.

[0316] 22. The oral dosage form of 20, wherein the filler is a mixture of two fillers.

[0317] 23. The oral dosage form of 22, wherein one filler is microcrystalline cellulose PH 102 (e.g., Avicel PH 102).

[0318] 24. The oral dosage form of 22, wherein one of the fillers is lactose monohydrate (e.g., FastFlo 316).

[0319] 25. The oral dosage form of 23 or 24, wherein the filler is present in an amount of 10-30% by weight, 15-25% by weight, or 20% by weight of the filler per unit weight of the oral dosage form.

[0320] 26. The oral dosage form of 22, wherein the fillers are present in a 1:1 w / w ratio with respect to each other.

[0321] 27. An oral dosage form of 1, further comprising a disintegrant (e.g., a cross-linked polymer, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, carboxymethyl cellulose or cross-linked sodium carboxymethyl cellulose; a modified starch, e.g., sodium starch glycolate).

[0322] 28. The oral dosage form of 27, wherein the disintegrant is sodium starch glycolate.

[0323] 29. The oral dosage form of 27, wherein the disintegrant is present in an amount of 0-5% by weight, 1-5% by weight, 2.5-5% by weight, or 3% by weight of the disintegrant per unit weight of the oral dosage form.

[0324] 30. An oral dosage form of 1, further comprising a lubricant (e.g., talc, silicon dioxide, fat, e.g., magnesium stearate).

[0325] 31. The oral dosage form of 30, wherein the lubricant is magnesium stearate.

[0326] 32. The oral dosage form of 30, wherein the lubricant is present in an amount of 0.1-2% by weight, 0.2-1.5% by weight, 1% by weight, or 0.5% by weight of the lubricant per unit weight of the oral dosage form.

[0327] 33. An oral dosage form comprising:

[0328] VS-6063 (e.g., VS-6063 or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) in an amount of about 5-50% by weight on a dry weight basis,

[0329] a pharmaceutically acceptable filler (e.g., microcrystalline cellulose, e.g., microcrystalline cellulose PH 102, e.g., Avicel PH 102) in an amount of about 10-30% by weight on a dry weight basis,

[0330] a second pharmaceutically acceptable filler (e.g., lactose, e.g., lactose monohydrate, e.g., FastFlo 316) in an amount of about 10-30% by weight on a dry weight basis,

[0331] additional pharmaceutically acceptable excipients (e.g., precipitation inhibitors, e.g., HPMC-AS, e.g., HPMC-ASHF) in an amount of about 25-55% by weight on a dry weight basis,

[0332] a pharmaceutically acceptable disintegrant (e.g., starch, e.g., modified starch, e.g., sodium starch glycolate) in an amount of about 0-5% by weight on a dry weight basis, and

[0333] A pharmaceutically acceptable lubricant (eg, magnesium stearate) in an amount of about 0.1-2% by weight on a dry weight basis.

[0334] 34. The oral dosage form of 33, comprising:

[0335] VS-6063 (e.g., VS-6063 free base, or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) in an amount of about 10-15% by weight on a dry weight basis,

[0336] a pharmaceutically acceptable filler (e.g., microcrystalline cellulose, e.g., microcrystalline cellulose PH 102, e.g., Avicel PH 102) in an amount of about 15-25% by weight on a dry weight basis,

[0337] a second pharmaceutically acceptable filler (e.g., lactose, e.g., lactose monohydrate, e.g., FastFlo 316) in an amount of about 15-25% by weight on a dry weight basis,

[0338] additional pharmaceutically acceptable excipients (e.g., precipitation inhibitors, e.g., HPMC-AS, e.g., HPMC-ASHF) in an amount of about 35-55% by weight on a dry weight basis,

[0339] a pharmaceutically acceptable disintegrant (e.g., starch, e.g., modified starch, e.g., sodium starch glycolate) in an amount of about 2.5-3.5% by weight on a dry weight basis, and

[0340] A pharmaceutically acceptable lubricant (eg, magnesium stearate) in an amount of about 0.2-1.5% by weight on a dry weight basis.

[0341] 35. The oral dosage form of 33 or 34, wherein the oral dosage form is a compressed pharmaceutical tablet or a direct compressed pharmaceutical tablet.

[0342] 36. An oral dosage form of 1, wherein the excipient is one or more binders (e.g., polyvinylpyrrolidone (e.g., polyvinylpyrrolidone vinyl acetate copolymer (PVP / VA), copovidone), other copolymers (e.g., containing polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g., Soluplus))).

[0343] 37. An oral dosage form of 36, wherein the binder comprises two binders (e.g., polyvinyl pyrrolidone (e.g., polyvinyl pyrrolidone vinyl acetate copolymer (PVP / VA), copovidone), other copolymers (e.g., comprising polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g., Soluplus))).

[0344] 38. The oral dosage form of 37, wherein the binder is present in an amount of about 37.5% by weight of the binder per unit weight of the oral dosage form.

[0345] 39. The oral dosage form of 37, wherein the binder is present in an amount of about 25% by weight of the binder per unit weight of the oral dosage form.

[0346] 40. The oral dosage form of 20, wherein the filler is a polyol (e.g., mannitol-starch (e.g., Pearlitol Flash), mannitol, sorbitol).

[0347] 41. The oral dosage form of 27, wherein the disintegrant is polyvinylpolypyrrolidone (eg, crospovidone).

[0348] 42. The oral dosage form of 27, wherein the disintegrant is present in an amount of 0-30% by weight, 5-25% by weight, 5-20% by weight, 5-15% by weight, 10% by weight of the disintegrant per unit weight of the oral dosage form.

[0349] 43. An oral dosage form comprising:

[0350] VS-6063 (e.g., VS-6063 free base, or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) in an amount of about 10-15% by weight on a dry weight basis,

[0351] a pharmaceutically acceptable excipient (e.g., a binder (e.g., polyvinylpyrrolidone (e.g., polyvinylpyrrolidone vinyl acetate copolymer (PVP / VA), copovidone)) in an amount of about 15-25% by weight on a dry weight basis,

[0352] a second pharmaceutically acceptable excipient (e.g., a binder (e.g., polyvinyl acetate (e.g., Soluplus))) in an amount of about 15-25% by weight on a dry weight basis,

[0353] a pharmaceutically acceptable filler (e.g., for example, a polyol (e.g., mannitol-starch (e.g., Pearlitol Flash))) in an amount of about 30-40% by weight on a dry weight basis,

[0354] A pharmaceutically acceptable disintegrant (e.g., crospovidone in an amount of about 5-15% by weight on a dry weight basis, and

[0355] A pharmaceutically acceptable lubricant (eg, magnesium stearate) in an amount of about 0.2-1.5% by weight on a dry weight basis.

[0356] 44. The oral dosage form of 1, wherein the VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) is present in an amount of 10% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per unit weight of the oral dosage form.

[0357] 45. The oral dosage form of 1, wherein the VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) is present in an amount of 25% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per unit weight of the oral dosage form.

[0358] 46. ​​The oral dosage form of 1, wherein the VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) is present in an amount of 50% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per unit weight of the oral dosage form.

[0359] 47. The oral dosage form of 16, wherein the physical blend or mixture is provided by a spray drying dispersion method.

[0360] 48. The oral dosage form of 47, wherein the method provides a solid dispersion comprising at least 10% by weight (e.g., 10%, 20%, 25%, 40%, 50% or more) of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride).

[0361] 49. The oral dosage form of 47, wherein the method provides a solid dispersion comprising 10% by weight of VS-6063 (eg, VS-6063 free base) or a pharmaceutically acceptable salt thereof (eg, VS-6063 hydrochloride).

[0362] 50. The oral dosage form of 47, wherein the method provides a solid dispersion comprising 25% by weight of VS-6063 (eg, VS-6063 free base) or a pharmaceutically acceptable salt thereof (eg, VS-6063 hydrochloride).

[0363] 51. An oral dosage form of 47, wherein the dispersion further comprises a polymer matrix (e.g., HPMACS (e.g., HPMCAS-H, HPMCAS-M), HPMCP (e.g., HPMCP-HP55, HPMCP-HP55S), Methocol E3LV, PVP-VA, Soluplus, PVAP, Eudragit L100-55, Soluplus:PVP-VA mixture, Soluplus, HPMCAS (e.g., HPMCAS-H)) mixture.

[0364] 52. The oral dosage form of 51, wherein the dispersion further comprises a polymer, e.g., a polymer matrix (e.g., polymethacrylic acid (e.g., Eudragit L100-55)).

[0365] 53. An oral dosage form comprising VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) for treating a subject diagnosed with a cancer disease (e.g., mesothelioma (e.g., surgically resectable malignant pleural mesothelioma), triple-negative breast cancer, ovarian cancer (e.g., advanced ovarian cancer), lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutant NSCLC)), non-hematological malignancies).

[0366] 54. A method of treating a disease in a patient in need thereof, the method comprising administering an oral dosage form comprising 10-500 mg of VS-6063 (eg, VS-6063 free base) or a pharmaceutically acceptable salt thereof (eg, VS-6063 hydrochloride), thereby treating the disease.

[0367] 55. The method of 54, wherein the disease is a cancer disease (e.g., mesothelioma (e.g., surgically resectable malignant pleural mesothelioma), breast cancer, e.g., triple-negative breast cancer, ovarian cancer (e.g., advanced ovarian cancer), lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutant NSCLC)), non-hematological malignancies).

[0368] 56. The method of 54, wherein the administering is performed in combination with administering an additional agent (e.g., a cancer therapeutic agent, e.g., a taxane, e.g., paclitaxel).

[0369] 57. A method of preparing a unit dosage form of a direct compression tablet comprising:

[0370] (a) Mixing (e.g., blending) by weight % on a dry weight basis:

[0371] (i) 5-50% by weight, based on dry weight, of VS-6063;

[0372] (ii) an excipient (e.g., a binder, e.g., a polymer, e.g., a precipitation inhibitor, e.g., HPMC, e.g., HPMCAS, e.g., HPMCAS-HF); and

[0373] (iii) at least one excipient selected from the group consisting of a filler, a disintegrant and a lubricant;

[0374] to form a VS-6063 formulation in the form of a tableting powder that can be directly compressed into tablets; and

[0375] (b) compressing the formulation prepared in step (a) to form compressed VS-6063 tablets in unit dosage form.

[0376] 58. The method of 57, wherein the filler is present in an amount of 30-60% by weight on a dry weight basis.

[0377] 59. The method of 57, wherein the disintegrant is present in an amount of 2.5-5% by weight on a dry weight basis.

[0378] 60. The method of 57, wherein the lubricant is present in an amount of 0.5-2% by weight on a dry weight basis.

Claims

1. Compound VS-6063 or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating cancer in a subject identified as having a mutation status in a gene selected from KRAS, INK4a / Arf and p53.

2. The compound for use according to claim 1, wherein the cancer is lung cancer.

3. The compound for use according to claim 2, wherein the lung cancer is non-small cell lung cancer (NSCLC).

4. The compound for use according to claim 3, wherein the NSCLC is KRAS mutant NSCLC.

5. The compound for use according to claim 3, wherein the NSCLC is INK4a / Arf mutant NSCLC.

6. The compound for use according to claim 3, wherein the NSCLC is p53 mutant NSCLC.

7. The compound for use according to claim 1, wherein the cancer is metastatic.

8. The compound for use according to claim 1, further comprising the use of one or more anti-tumor or anti-cancer agents.

9. The compound for use according to claim 8, wherein the one or more anti-tumor or anti-cancer agents are selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones and anti-androgens.

10. The compound for use according to claim 1, wherein the VS-6063 or a pharmaceutically acceptable salt thereof is administered 1, 2, 3 or 4 times a day.

11. The compound for use according to claim 1, wherein the VS-6063 or a pharmaceutically acceptable salt thereof is administered twice a day.

12. The compound for use according to claim 1, wherein 100 to 800 mg / day of VS-6063 or a pharmaceutically acceptable salt thereof is administered to the subject.

13. The compound for use according to claim 1, wherein 200 mg / day of VS-6063 or a pharmaceutically acceptable salt thereof is administered to the subject.

14. The compound for use according to claim 1, wherein 400 mg / day of VS-6063 or a pharmaceutically acceptable salt thereof is administered to the subject.

15. The compound for use according to claim 1, wherein VS-6063 or a pharmaceutically acceptable salt thereof is administered to the subject in a pharmaceutical composition comprising: 10 to 30% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per unit weight of the composition, and a pharmaceutically acceptable excipient.

16. The compound for use according to claim 15, wherein the pharmaceutically acceptable excipient is a mixture of two fillers.

17. The compound for use according to claim 16, wherein one filler is microcrystalline cellulose and the other is lactose.

18. The compound for use according to claim 15, wherein the pharmaceutically acceptable excipient is a disintegrant.

19. The compound for use according to claim 18, wherein the disintegrant is a modified starch.

20. The compound for use according to claim 15, wherein the pharmaceutically acceptable excipient is a lubricant.

21. The compound for use according to claim 20, wherein the lubricant is magnesium stearate.

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