Compositions and methods for treating abnormal cell growth

Abstract

To provide oral dosage forms and methods useful in treatment of abnormal cell growth such as cancer in mammals, in particular in humans.SOLUTION: In one aspect, the invention comprises a composition, e.g., pharmaceutical composition 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., Hydroxypropyl Methylcellulose. (HPMC) or Hypromellose (e.g., Hydroxypropyl Methylcellulose Acetate Succinate (HPMC-AS) or Hypromellose Acetate Succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF); e.g., polyol (e.g., mannitol-starch (e.g., Pearlitol Flash), mannitol, sorbitol)).SELECTED DRAWING: None

Description

Technical Field

[0001] Claims of Priority This application claims priority to U.S. Provisional Application No. 61 / 925,467, filed on January 9, 2014, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to compositions, such as oral dosage forms, and methods useful in the treatment of abnormal cell growth, such as cancer, in mammals, particularly humans.

Background Art

[0003] Focal adhesion kinase (FAK), a cytoplasmic non-receptor tyrosine kinase, has been shown by compelling evidence to play an essential role in cell-matrix signaling pathways (Clark and Brugge, 1995, Science 268:233-239) and its abnormal activation has been associated with increased tumor metastatic potential (Owens et al., 1995, Cancer Research 55:2752-2755). FAK was originally identified as a 125 kDa protein highly phosphorylated on tyrosine in cells transformed by v-Src. Subsequently, FAK was found to be a tyrosine kinase localized at focal adhesions, which are contact points between cultured cells and their substratum and sites of tyrosine phosphorylation concentration. FAK is phosphorylated and thus activated in response to the binding of the extracellular matrix (ECM) to integrins. Recently, studies have demonstrated that tumor cell apoptosis is induced by invasive transformation of tumors with increased FAK mRNA levels and attenuation of FAK expression (by use of antisense oligonucleotides) (Xu et al., 1996, Cell Growth and Diff. 7:413-418). FAK is expressed in most tissue types and is found at high levels in most human cancers, for example in very invasive metastases.

Prior Art Documents

Non-Patent Literature

[0004]

Non-Patent Literature 1

Non-Patent Literature 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] 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 inhibitors of non-receptor tyrosine kinase FAK for use in the treatment of abnormal cell growth. U.S. Patent No. 8,247,411 relates to a broad class of novel pyrimidine derivatives that are kinase inhibitors, and more particularly, inhibitors of FAK. Compounds such as these derivatives can be useful in the treatment of abnormal cell growth.

Means for Solving the Problems

[0006] In one aspect, the present invention includes, for example, a composition, such as VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride), which is mixed with an additive (e.g., a binder, e.g., a polymer, e.g., a precipitation inhibitor, e.g., hydroxypropyl methylcellulose (HPMC) or hypromellose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hypromellose 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, this additive is a binder. In some embodiments, this additive is a polymer. In some embodiments, this polymer is a precipitation inhibitor. In some embodiments, this precipitation inhibitor is HPMCAS. In some embodiments, this precipitation inhibitor is HPMCAS-HF. In some embodiments, this additive reduces precipitation (e.g., of VS-6063 in solution, e.g., in vivo) when administered orally. In some embodiments, this additive improves the bioavailability (e.g., 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 weight 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 to 1, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, or 1 to 9. In some embodiments, the above polymer is a precipitation inhibitor, such as hydroxypropyl methylcellulose (HPMC) or hypromellose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF).In some embodiments, 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) based on the amount of the polymer provided, e.g., the precipitation inhibitor, in the composition. In some embodiments, the present 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 weight of the composition. In some embodiments, the polymer is present as 25-55%, 35-45%, 38-43% or 40% by weight of the polymer per weight of the oral dosage form. In some embodiments, this polymer is a precipitation inhibitor such as hydroxypropyl methylcellulose (HPMC) or hypromellose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF). In some embodiments, this precipitation inhibitor is HPMCAS. In some embodiments, this precipitation inhibitor is HPMCAS-HF.

[0007] In some embodiments, the present composition is constituted by an oral dosage form. In some embodiments, this oral dosage form contains 5-50%, 5-30%, 10-30%, 10-20%, 12-15% or 13% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per weight of the oral dosage form. In some embodiments, VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) is present as 13% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per weight of the oral dosage form.

[0008] In some embodiments, this oral dosage form is a tablet. In some embodiments, this tablet is provided by direct compression of a physical blend or mixture. In some embodiments, this physical blend or mixture is provided by a dry granulation process.

[0009] 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, 6, 7, 8, 9, 10, 11, 12, 13 kP or more. 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 minutes or more.

[0010] In some embodiments, the pharmaceutical composition further comprises one or more fillers (e.g., microcrystalline cellulose (e.g., microcrystalline cellulose PH102, e.g., Avicel PH102), 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 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 PH102 (e.g., Avicel PH102). 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 weight of the oral dosage form. In some embodiments, these fillers are present in a ratio of 1:1 (w / w) to each other.

[0011] In some embodiments, the oral dosage form comprises a disintegrant (e.g., a polymer, e.g., a cross-linked polymer, e.g., cross-linked polyvinylpyrrolidone or crospovidone, carboxymethyl cellulose or croscarmellose sodium, starch, e.g., 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 weight of the oral dosage form.

[0012] In some embodiments, this oral dosage form contains a lubricant (e.g., talc, silica, fat, such as magnesium stearate). In some embodiments, this lubricant is magnesium stearate. In some embodiments, this lubricant is present at 0.1-2% or 0.2-1.5% by weight of the oral dosage form. In some embodiments, this lubricant is present at 1% w / w. In some embodiments, this lubricant is present at 0.5% w / w.

[0013] In one embodiment, the oral dosage form described herein has a greater C max value than a reference oral dosage form, e.g., a dosage form that does not contain an additive (e.g., a cellulose polymer and its derivatives, such as hydroxypropylmethylcellulose (HPMC) or hypromellose (e.g., hydroxypropylmethylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, such as HPMCAS-H, HPMCAS-M, HPMCAS-HF)) in the mixture. In one embodiment, the C max value of the oral dosage form described herein is at least 1.1-fold (e.g., at least 1.25-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 5-fold) greater than that of a reference dosage form of the same dosage (e.g., a dosage form having 100 mg of VS-6063 compared to a reference dosage form having 100 mg of VS-6063). In one embodiment, the C max value of the oral dosage form described herein is at least 1.6-fold greater, at least 1.7-fold greater, at least 1.8-fold greater, at least 1.9-fold greater, at least 2-fold greater, at least 3-fold greater, or at least 4-fold greater than that of a reference dosage form of the same dosage.

[0014] 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 contain additives (e.g., cellulose polymers and their derivatives, such as hydroxypropyl methylcellulose (HPMC) or hypromellose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, such as HPMCAS-H, HPMCAS-M, HPMCAS-HF)) in the mixture. In one embodiment, the difference in T max values between the fed and fasted states of a subject administered the oral dosage forms described herein is less than the difference in T max values between the fed and fasted states of a subject administered the same dose of a reference oral dosage form, e.g., a dosage form that does not contain additives (e.g., cellulose polymers and their derivatives, such as hydroxypropyl methylcellulose (HPMC) or hypromellose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, such as HPMCAS-H, HPMCAS-M, HPMCAS-HF)) in the mixture.

[0015] In one embodiment, the oral dosage forms described herein have a consistent exposure when administered to a subject. In one embodiment, the oral dosage forms described herein, when administered to a subject, result in an exposure with less than 50% variability associated with the exposure across multiple subjects compared to the exposure of the same dose of a reference oral dosage form. In one embodiment, the oral dosage forms described herein, when administered to a subject, result in an exposure with less than 40%, 30%, 20% or 10% variability associated with the exposure across multiple subjects compared to the exposure of the same dose of a reference oral dosage form.

[0016] In one aspect, the present invention provides an oral dosage form comprising, on a dry weight basis, an amount of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) of about 5 to 50% by weight, an amount of a pharmaceutically acceptable additive (e.g., a binder, e.g., a polymer, e.g., a precipitation inhibitor, e.g., hydroxypropylmethylcellulose (HPMC) or hypromellose (e.g., hydroxypropylmethylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF)) of about 25 to 55% by weight, an amount of a pharmaceutically acceptable filler (e.g., microcrystalline cellulose, e.g., microcrystalline cellulose PH102, e.g., Avicel PH102) of about 10 to 30% by weight, an amount of a second pharmaceutically acceptable filler (e.g., lactose, e.g., lactose monohydrate, e.g., FastFlo 316) of about 10 to 30% by weight, an amount of a pharmaceutically acceptable disintegrant (e.g., starch, e.g., modified starch, e.g., sodium starch glycolate) of about 0 to 5% by weight, and an amount of a pharmaceutically acceptable lubricant (e.g., magnesium stearate) of about 0.1 to 2% by weight, on a dry weight basis.In some embodiments, the present invention provides 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 dry weight, a pharmaceutically acceptable additive (e.g., a binder, e.g., a polymer, e.g., a precipitation inhibitor, e.g., hydroxypropyl methylcellulose (HPMC) or hypromellose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF)) in an amount of about 35-55% by dry weight, a pharmaceutically acceptable filler (e.g., microcrystalline cellulose, e.g., microcrystalline cellulose PH102, e.g., Avicel PH102) in an amount of about 15-25% by dry weight, a second pharmaceutically acceptable filler (e.g., lactose, e.g., lactose monohydrate, e.g., FastFlo 316) in an amount of about 15-25% by dry weight, 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 dry weight, and a pharmaceutically acceptable lubricant (e.g., magnesium stearate) in an amount of about 0.2-1.5% by dry weight. In some embodiments, the oral dosage form is a compressed pharmaceutical tablet or a direct compression pharmaceutical tablet.

[0017] In some embodiments, the additive is one or more binders (e.g., polyvinylpyrrolidone (e.g., polyvinylpyrrolidone vinyl acetate copolymer (PVP / VA), Copovidone), other copolymers (e.g., including polyethylene glycol, polyvinylcaprolactam, and polyvinyl acetate (e.g., Soluplus))). In some embodiments, the binder is a polymer, such as a precipitation inhibitor. In some embodiments, the binder is two binders (e.g., polyvinylpyrrolidone (e.g., polyvinylpyrrolidone vinyl acetate copolymer (PVP / VA), Copovidone), other copolymers (e.g., including polyethylene glycol, polyvinylcaprolactam, and polyvinyl acetate (e.g., Soluplus))). In some embodiments, the binder is a polymer, such as a precipitation inhibitor. In some embodiments, this binder is present at about 37.5% by weight of the binder per weight of the oral dosage form. In some embodiments, this binder is present at about 25% by weight of the binder per weight of the oral dosage form. In some embodiments, the filler is a polyol (e.g., mannitol-starch (e.g., Pearlitol Flash), mannitol, sorbitol).

[0018] In some embodiments, the disintegrant is polyvinylpolypyrrolidone (e.g., crospovidone). In some embodiments, this disintegrant is present at 0 - 30%, 5 - 25%, 5 - 20%, 5 - 15%, or 10% by weight of the disintegrant per weight of the oral dosage form.

[0019] In one embodiment, the oral dosage form described herein has a greater C value than a reference oral dosage form, e.g., a dosage form that does not contain an additive (e.g., a cellulose polymer and its derivatives, such as hydroxypropylmethylcellulose (HPMC) or hypromellose (e.g., hydroxypropylmethylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF)) in the mixture. max value. In one embodiment, the C of the oral dosage form described hereinmax 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 that of a reference dosage form of the same dosage amount (e.g., a dosage form having 100 mg of VS-6063 as compared to a reference dosage form having 100 mg of VS-6063). In one embodiment, the C of the oral dosage form described herein max The value is at least 1.6 times greater, at least 1.7 times greater, at least 1.8 times greater, at least 1.9 times greater, at least 2 times greater, at least 3 times greater, or at least 4 times greater than that of a reference dosage form of the same dosage amount.

[0020] In one embodiment, the oral dosage form described herein has a reduced food effect as compared to a reference oral dosage form, e.g., a dosage form that does not contain additives (e.g., cellulose polymers and their derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hypromellose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF)) in the mixture. In one embodiment, the difference in T between the fed state and the fasted state of a subject administered the oral dosage form described herein max is less than the difference in T between the fed state and the fasted state of a subject administered a reference oral dosage form of the same dosage amount, e.g., a dosage form that does not contain additives (e.g., cellulose polymers and their derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hypromellose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF)) in the mixture. max is smaller.

[0021] In one embodiment, the oral dosage form described herein has a certain exposure when administered to a subject. In one embodiment, the oral dosage form described herein, when administered to a subject, results in an exposure with less than 50% variability associated with the exposure across a plurality of subjects as compared to the exposure of a reference oral dosage form at the same dosage. In one embodiment, the oral dosage form described herein, when administered to a subject, results in an exposure with less than 40%, 30%, 20% or 10% variability associated with the exposure across a plurality of subjects as compared to the exposure of a reference oral dosage form at the same dosage.

[0022] In one aspect, the present invention provides 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 additive (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, a second pharmaceutically acceptable additive (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 on a dry weight basis, a pharmaceutically acceptable disintegrant (e.g., crospovidone) in an amount of about 5-15% 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.

[0023] In some embodiments, VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) is present at 10% by weight of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) per weight of the oral dosage form. In some embodiments, VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) is present at 25% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per weight of the oral dosage form. In some embodiments, VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) is present at 50% by weight of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride) per weight of the oral dosage form.

[0024] In some embodiments, this physical blend or mixture is provided by a spray-drying dispersion process. In some embodiments, the process results in 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 process results in 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 process results in 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, such as a polymer matrix (e.g., hydroxypropylmethylcellulose acetate succinate (HPMACS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M; hydroxypropylmethylcellulose phthalate (HPMCP) or hypromellose phthalate, e.g., HPMCP-HP55, HPMCP-HP55S, Methocol E3LV, PVP-VA, Soluplus, PVAP, polymethacrylic acid (e.g., Eudragit, e.g., 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, e.g., Eudragit L100-55)).

[0025] In one aspect, 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) for use in the treatment of a subject identified with a cancer disorder (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.

[0026] In one aspect, the present invention provides a method of treating a disorder 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 disorder. In some embodiments, the disorder is a cancer disorder (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.

[0027] In some embodiments, the administration is performed in combination with the administration of an additional agent (e.g., an anti-cancer or anti-tumor agent, e.g., a taxane, e.g., paclitaxel).

[0028] In one aspect, the present invention provides a method for preparing a directly compressed tablet in unit dosage form, comprising: (a) forming a VS-6063 formulation in the form of a tableting powder capable of being directly compressed into tablets by mixing (e.g., blending) (i) 5 to 50% by weight of VS-6063 on a dry weight basis, (ii) a pharmaceutically acceptable additive (e.g., a binder, e.g., a polymer, e.g., a precipitation inhibitor, e.g., HPMC, e.g., HPMC-AS, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF), and (iii) at least one pharmaceutically acceptable additive selected from a pharmaceutically acceptable filler, a pharmaceutically acceptable disintegrant, and a pharmaceutically acceptable lubricant, and (b) compressing the formulation prepared in step (a) to form a compressed VS-6063 tablet in unit dosage form. In some embodiments, the pharmaceutically acceptable filler is present at 30 to 60% by weight on a dry weight basis. In some embodiments, the pharmaceutically acceptable disintegrant is present at 2.5 to 5% by weight on a dry weight basis. In some embodiments, the pharmaceutically acceptable lubricant is present at 0.5 to 2% by weight on a dry weight basis.

[0029] In one aspect, the present invention provides a method for treating a subject having a mesothelioma, e.g., a malignant pleural mesothelioma, e.g., a surgically resectable malignant pleural mesothelioma (e.g., non-metastatic, unresectable), the method 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), thereby treating the subject. In some embodiments, the method comprises providing to the subject an effective cool 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).

[0030] In some embodiments, the subject has a mutation in a tumor suppressor gene. In some embodiments, the subject has a mutation in neurofibromin 2 (NF2). NF2 is a tumor suppressor gene that encodes the protein Merlin, which can function in the restriction of cell proliferation and the promotion of apoptosis. Merlin regulates FAK at least in part by attenuating the phosphorylation of FAK that disrupts the ability of FAK to interact with certain binding partners, resulting in inhibition of the FAK-mediated signaling pathway. Thus, a mutation in the NF2 gene that results in a decrease in the expression and / or activity of Merlin, or a decrease in the expression and / or activity of Merlin in the absence of an NF2 mutation, can result in increased sensitivity to a FAK inhibitor. Thus, a cancer patient having one or more changes in the NF2 gene, or a change in the level of Merlin expression and / or activity, such as a decrease in the level of Merlin expression, may have a cancer characterized by increased sensitivity to a FAK inhibitor and thus may benefit from treatment with the compounds 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 an abnormal level of NF2 and / or Merlin compared to, for example, 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 of the Merlin protein (e.g., the level is lower or at a dysfunctional level). In some embodiments, the method includes, for example, obtaining information regarding the status of NF2 and / or Merlin (i.e., the Merlin protein) in the subject, for example, directly or indirectly. In some embodiments, the status of NF2 and / or Merlin is determined by immunohistochemistry. In some embodiments, the status of NF2 and / or Merlin is determined by DNA sequence analysis. In some embodiments, the method includes testing the subject for the status of NF2 and / or Merlin in the subject.In some embodiments, the method comprises administering to the subject 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 response to the status of NF2 and / or Merlin, such as mutant NF2.

[0031] In some embodiments, the level of Merlin expression is low, decreased, or there is no Merlin expression. In some embodiments, the level of Merlin expression is compared to a reference standard. In some embodiments, the level of Merlin expression is low, decreased, or there is no Merlin expression compared to the reference standard. In some embodiments, the level of Merlin expression is evaluated by the level of Merlin RNA expression. In some embodiments, the level of Merlin expression is measured by evaluation of the level of RNA encoding Merlin. In some embodiments, the level of Merlin expression is evaluated by the level of Merlin protein expression. In some embodiments, the level of Merlin protein expression is assayed by immunohistochemistry or Western blot. Immunohistochemistry or IHC refers to the process of identifying the location of an antigen (e.g., a protein) in cells of a tissue section by utilizing the principle of an antibody that specifically binds to the antigen in biological tissue. In a preferred embodiment, the level of Merlin protein expression is assayed by immunohistochemistry.

[0032] In some embodiments, the patient has one or more alterations in the NF2 gene.

[0033] In some embodiments, alterations in the NF2 gene include mutations, chromosomal deletions, or alterations to the NF2 gene or NF2 promoter. In some embodiments, alterations to the NF2 promoter include alterations in methylation, such as hypermethylation. In some embodiments, the evaluation includes obtaining information regarding the patient's NF2 genotype. In some embodiments, the patient's NF2 genotype is compared to a reference standard.

[0034] In some embodiments, changes in the NF2 gene include mutations, chromosomal deletions, or changes to the NF2 gene. The NF2 gene includes any regulatory sequences, such as promoter sequences and enhancer sequences. In some embodiments, changes in the NF2 gene include mutations, chromosomal deletions, or changes to the NF2 gene. The NF2 gene includes any regulatory sequences, such as promoter sequences and enhancer sequences. In certain embodiments, the change in the NF2 gene is one or more mutations. In certain embodiments, the change is a single nucleotide polymorphism. In certain embodiments, the change is a point mutation. In certain embodiments, the change is an inactivating mutation. In certain embodiments, the change in the NF2 gene is a chromosomal deletion. In certain embodiments, the change is an inactivating chromosomal deletion. In certain embodiments, the change in the NF2 gene is hypermethylation of the promoter region of the gene.

[0035] Cancer patients having one or more changes in the NF2 gene, or changes in the level of merlin expression and / or activity, such as a decrease in the level of merlin expression, may have a cancer characterized by sensitivity or responsiveness to a FAK inhibitor and thus may benefit from treatment with a FAK inhibitor.

[0036] In some embodiments, the method includes a cool-down of a second treatment, such as a second anti-tumor treatment or anti-cancer treatment, such as co-administering one or more anti-tumor agents or anti-cancer agents. In some embodiments, the cool-down of the second treatment is provided after a diagnosis of mesothelioma. In some embodiments, the cool-down of the second treatment ends before initiation of a cool-down 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 first cool-down of the second treatment, 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), and providing a second cool-down of the second treatment. In some embodiments, the first cool-down is initiated before 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 cool-down replaces the first cool-down and is initiated before, at the same time as, or 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 number of administrations, the frequency of administration, the amount of the second therapeutic agent delivered by the administration, or the level of the second therapeutic agent in the subject, e.g., in the blood of the subject, is decreased in the second cool-down compared to the first cool-down. In some embodiments, the second agent is not administered to the subject 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 second agent is not administered to the subject during the cool 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 the 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).

[0037] In some embodiments, the subject has previously received a course of a second treatment, such as a second anti-cancer treatment or anti-tumor treatment, such as a course of one or more anti-cancer agents or anti-tumor agents. In some embodiments, the course of the second treatment is administered after diagnosis of mesothelioma. In some embodiments, the course of the second treatment ends before, at the same time as, or 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 second treatment 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 treatment. In some embodiments, the second course replaces the first course and is initiated before, at the same time as, or 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 second course is initiated before, at the same time as, or 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 number of administrations, the frequency of administration, the amount of the second therapeutic agent delivered by the administration, or the level of the second therapeutic agent in the subject, e.g., in the blood of the subject, is decreased in the second course as compared to the first course. In some embodiments, the second agent is not administered to the subject 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 second agent is not administered to the subject during the cool 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 the 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 second treatment includes administration of a therapeutic agent, such as an anti-tumor agent or an anti-cancer agent. In some embodiments, the second treatment includes administration of an additional agent, such as an anti-cancer agent or an anti-tumor agent, such as a mitotic inhibitor, an alkylating agent, an antimetabolite, intercalating antibiotics, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an antibody, a cytotoxic agent, an antihormonal agent, and an antiandrogen agent, which is selected from the group consisting of anti-cancer agents or anti-tumor agents. In some embodiments, the therapeutic agent includes a platin drug, such as cisplatin or carboplatin. In some embodiments, the therapeutic agent includes a drug other than a platin drug. For example, the therapeutic agent includes a taxane, such as docetaxel, paclitaxel; a plant-derived anti-tumor substance, such as an alkaloid, such as vinorelbine; an antimetabolite, such as gemcitabine; or a cytotoxic topoisomerase inhibitor, such as irinotecan. In some embodiments, the second treatment includes administration of a first and a second therapeutic agent. In some embodiments, the first and second therapeutic agents are each selected from the group consisting of additional therapeutic agents, such as anti-tumor agents or anti-cancer agents, such as a mitotic inhibitor, an alkylating agent, an antimetabolite, intercalating antibiotics, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an antibody, a cytotoxic agent, an antihormonal agent, and an antiandrogen agent, which is selected from the group consisting of anti-cancer agents or anti-tumor agents. In some embodiments, the therapeutic agent includes a platin drug, such as cisplatin or carboplatin. In some embodiments, the therapeutic agent includes a drug other than a platin drug. For example, the therapeutic agent includes a taxane, such as docetaxel, paclitaxel; a plant-derived anti-cancer or anti-tumor substance, such as an alkaloid, such as vinorelbine; an antimetabolite, such as gemcitabine; or a cytotoxic topoisomerase inhibitor, such as irinotecan.

[0039] In one aspect, the present invention is a method of treating a subject having cancer, such as lung cancer, such as non-small cell lung cancer (NSCLC), such as KRAS mutant NSCLC, 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), thereby treating the subject. In some embodiments, the method comprises providing to the subject an effective dose 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 a locally recurrent disease.

[0040] In one aspect, the present invention includes a method of evaluating a subject having cancer, such as lung cancer, such as 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 includes 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 group consisting of KRAS, INK4a / Arf, and p53. In some embodiments, the method includes obtaining the mutation status of KRAS in the NSCLC. In some embodiments, the method includes obtaining the mutation status of KRAS and INK4a / Arf in the NSCLC. In some embodiments, the method includes obtaining the mutation status of KRAS and p53 in the NSCLC. 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 selecting the subject in response to the mutation status 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 selecting the subject in response to a determination that the NSCLC contains a KRAS variant 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 selecting the subject in response to a determination that the NSCLC contains a KRAS variant and an INK4a / Arf variant 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 selecting a 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 response to a determination that the NSCLC contains a KRAS variant and a p53 variant. In some embodiments, the method comprises selecting a 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 response to a determination that the NSCLC contains a KRAS variant, an INK4a / Arf variant, and a p53 variant. In some embodiments, the method comprises testing a subject for mutations in genes in the NSCLC. In some embodiments, the method comprises testing a subject for mutations in genes from the group consisting of KRAS, INK4a / Arf, and p53 in the NSCLC. In some embodiments, the method comprises testing a subject for a mutation in KRAS in the NSCLC. In some embodiments, the method comprises testing a subject for mutations in KRAS and INK4a / Arf in the NSCLC. In some embodiments, the method comprises testing a subject for mutations in KRAS and p53 in the NSCLC. In some embodiments, the method comprises testing a subject for mutations in KRAS, INK4a / Arf, and p53 in the NSCLC. In some embodiments, cells of the subject (e.g., a subject having NSCLC) comprise a KRAS variant; a KRAS variant and an INK4a / Arf variant; or a KRAS variant, an INK4a / Arf variant, and a p53 variant. In some embodiments, the cancer is metastatic. In some embodiments, the subject has a locally recurrent disease.

[0041] In some embodiments, the method includes obtaining the mutation status of genes in the subject's NSCLC. In some embodiments, the genes are selected from the group consisting of KRAS, INK4a / Arf, and p53. In some embodiments, the method includes obtaining the mutation status of KRAS in the subject's NSCLC. In some embodiments, the method includes obtaining the mutation status of KRAS and INK4a / Arf in the subject's NSCLC. In some embodiments, the method includes obtaining the mutation status of the subject's KRAS and p53 in the subject's NSCLC. 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 selecting the subject in response to the mutation status 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 selecting the subject in response to a determination that the NSCLC contains a KRAS variant 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 selecting the subject in response to a determination that the NSCLC contains a KRAS variant and an INK4a / Arf variant 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 selecting the subject in response to a determination that the NSCLC contains a KRAS variant and a p53 variant 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 selecting a 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 response to a determination that the NSCLC contains a KRAS variant, an INK4a / Arf variant, and a p53 variant. In some embodiments, the method comprises testing a subject for mutations in genes in the NSCLC. In some embodiments, the method comprises testing a subject for mutations in genes from the group consisting of KRAS, INK4a / Arf, and p53 in the NSCLC. In some embodiments, the method comprises directly testing a subject for a KRAS mutation in the NSCLC. In some embodiments, the method comprises testing a subject for KRAS and INK4a / Arf mutations in the NSCLC. In some embodiments, the method comprises testing a subject for KRAS and p53 mutations in the NSCLC. In some embodiments, the method comprises testing a subject for KRAS, INK4a / Arf, and p53 mutations in the NSCLC. In some embodiments, cells in a subject (e.g., a subject having lung cancer, e.g., NSCLC) comprise a KRAS variant; a KRAS variant and an INK4a / Arf variant; or a KRAS variant, an INK4a / Arf variant, and a p53 variant.

[0042] In some embodiments, the method includes a cool-down of a second treatment, such as a second anti-tumor treatment or anti-cancer treatment, e.g., co-administering one or more anti-tumor agents or anti-cancer agents. In some embodiments, the cool-down of the second treatment is provided after the diagnosis of NSCLC. In some embodiments, the cool-down of the second treatment ends before starting the cool-down of VS-6063 or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition containing VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method includes providing a first cool-down of the second treatment, administering VS-6063 or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition containing VS-6063 or a pharmaceutically acceptable salt thereof), and providing a second cool-down of the second treatment. In some embodiments, the first cool-down is started before the administration of VS-6063 or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition containing VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the second cool-down replaces the first cool-down and is started before, simultaneously with, or 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 containing 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 by the administration, or the level of the second therapeutic agent in the subject, e.g., in the blood of the subject, is decreased in the second cool-down compared to the first cool-down. In some embodiments, the second agent is not administered to the subject 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 containing VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the second agent is not administered to the subject during the cool-down of VS-6063 or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, e.g., a composition containing 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).

[0043] In some embodiments, the subject has previously received a cool-down of a second treatment, such as a second anti-tumor treatment or anti-cancer treatment, such as one or more anti-tumor agents or anti-cancer agents. In some embodiments, the cool-down of the second treatment is administered after diagnosis of NSCLC. In some embodiments, the cool-down of the second treatment ends before, at the same time as, or after the first administration of VS-6063 or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, such as a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the second treatment 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, such as a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the method comprises providing a second cool-down of the second treatment. In some embodiments, the second cool-down replaces the first cool-down and begins before, at the same time as, or after the first administration of VS-6063 or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, such as a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof). In some embodiments, the second cool-down begins before, at the same time as, or after the first administration of VS-6063 or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, such as 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 by the administration, or the level of the second therapeutic agent in the subject, such as in the blood of the subject, is decreased in the second cool-down compared to the first cool-down. In some embodiments, the second agent is not administered to the subject after the first administration of VS-6063 or a pharmaceutically acceptable salt thereof, or a composition (e.g., a composition described herein, such as a composition comprising VS-6063 or a pharmaceutically acceptable salt thereof).In some embodiments, the second agent is not administered to the subject during the cool 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 the 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 second treatment comprises administration of a therapeutic agent, such as an anti-tumor agent or an anti-cancer agent. In some embodiments, the second treatment comprises administration of an additional agent, such as an anti-tumor agent or an anti-cancer agent, such as a mitotic inhibitor, an alkylating agent, an antimetabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an antibody, a cytotoxic agent, an anti-hormone agent, and an anti-androgen agent, selected from the group consisting of anti-tumor agents or anti-cancer agents. In some embodiments, the therapeutic agent comprises a platinum drug, such as cisplatin or carboplatin. In some embodiments, the therapeutic agent comprises a drug other than a platinum drug, for example, the therapeutic agent comprises a taxane, such as docetaxel, paclitaxel; a plant-derived anti-tumor substance, such as an alkaloid, such as vinorelbine; an antimetabolite, such as gemcitabine; or a cytotoxic topoisomerase inhibitor, such as irinotecan. In some embodiments, the second treatment comprises administration of a first and a second therapeutic agent. In some embodiments, the first and second therapeutic agents are each selected from the group consisting of additional therapeutic agents, such as anti-tumor agents or anti-cancer agents, such as a mitotic inhibitor, an alkylating agent, an antimetabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an antibody, a cytotoxic agent, an anti-hormone agent, and an anti-androgen agent, selected from the group consisting of anti-tumor agents or anti-cancer agents. In some embodiments, the therapeutic agent comprises a platinum drug, such as cisplatin or carboplatin. In some embodiments, the therapeutic agent comprises a drug other than a platinum drug, for example, the therapeutic agent comprises a taxane, such as docetaxel, paclitaxel; a plant-derived anti-tumor or anti-cancer substance, such as an alkaloid, such as vinorelbine; an antimetabolite, such as gemcitabine; or a cytotoxic topoisomerase inhibitor, such as irinotecan.

[0045] 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 over 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 over 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 over 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 over 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 over 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 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, 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 at 50 - 800, 50 - 600, 50 - 500, 50 - 400, 50 - 300 or 50 - 200 mg / 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 at 100 - 800, 100 - 600, 100 - 500, 100 - 400, 100 - 300 or 100 - 200 mg / 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 at 200 - 800, 200 - 600, 200 - 500, 200 - 400 or 200 - 300 mg / 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 at 250 - 800, 250 - 600, 250 - 500, 250 - 400 or 250 - 300 mg / day. In some embodiments, one or both endpoints are not included in these ranges, e.g., in this case, the lower endpoint is not included in these ranges. 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 at 100 + / - 50, 150 + / - 50, 200 + / - 50, 250 + / - 50, 300 + / - 50, 400 + / - 50, 500 + / - 50, 550 + / - 50 or 600 + / - 50 mg / 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 at 100 mg / day.In some embodiments, 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, 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.

[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 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 is 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., the 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 later cycle (e.g., the 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 a cycle is more 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 later cycle (e.g., the second cycle).

[0047] In some embodiments, a unit dosage formulation of 50+ / -25, 100+ / -50, 150+ / -50, 200+ / -50, 250+ / -50, 300+ / -50, 400+ / -50, 500+ / -50, 550+ / -50 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, 100+ / -25, 100+ / -10 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 dosage formulation of 100+ / -20, 100+ / -10 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 dosage 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, 200+ / -25, 200+ / -10, 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 dosage formulation of 200+ / -20, 200+ / -10 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 dosage 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, 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) at 400 + / - 50, 400 + / - 25, 400 + / - 10 or 400 + / - 5 mg / day is administered. In some embodiments, a unit dosage formulation 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) at 400 + / - 20, 400 + / - 10 or 400 + / - 5 mg is administered. In some embodiments, a unit dosage 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.

[0048] In one embodiment, the oral dosage form described herein has a greater C max value than a reference oral dosage form, e.g., a dosage form that does not contain an additive (e.g., a cellulose polymer and its derivatives, e.g., hydroxypropylmethylcellulose (HPMC) or hypromellose (e.g., hydroxypropylmethylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF)) in the mixture. max In one embodiment, the C max value of the oral dosage form described herein is at least 1.1-fold (e.g., at least 1.25-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 5-fold) greater than that of a reference dosage form at the same dose (e.g., a dosage form having 100 mg of VS-6063 relative to a reference dosage form also having 100 mg of VS-6063). In one embodiment, the C

[0049] In one embodiment, the oral dosage forms described herein have reduced food effect compared to a reference oral dosage form, e.g., a dosage form that does not contain additives (e.g., cellulose polymers and their derivatives such as hydroxypropyl methylcellulose (HPMC) or hypromellose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF)) in the mixture. In one embodiment, the difference in T max values between the fed and fasted states of a subject administered the oral dosage forms described herein is less than the difference in T max values between the fed and fasted states of a subject administered the same dose of a reference oral dosage form, e.g., a dosage form that does not contain additives (e.g., cellulose polymers and their derivatives such as hydroxypropyl methylcellulose (HPMC) or hypromellose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF)) in the mixture.

[0050] In one embodiment, the oral dosage forms described herein have a consistent exposure when administered to a subject. In one embodiment, the oral dosage forms described herein, when administered to a subject, result in an exposure with less than 50% variability associated with the exposure across multiple subjects compared to the exposure of a reference oral dosage form at the same dose. In one embodiment, the oral dosage forms described herein, when administered to a subject, result in an exposure with less than 40%, 30%, 20% or 10% variability associated with the exposure across multiple subjects compared to the exposure of a reference oral dosage form at the same dose.

[0051] In one aspect, the present invention includes a unit dosage form having 50 to 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 has 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 has 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 has 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 aspects, the present invention includes a unit dosage form having 100 to 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 has 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 has 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 has 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 has 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 has 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 has 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 has 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 has 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 has 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).

[0052] In one aspect, the present invention provides a method of treating a subject having ovarian cancer, such as advanced or metastatic ovarian cancer, the method 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, such as an anti-cancer agent or an anti-tumor agent, such as a mitotic inhibitor, such as a taxane, such as paclitaxel, wherein the amounts are effective, alone or in combination, to treat the subject, thereby treating the subject, and wherein the subject has received 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) during all cycles or courses 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, and wherein the subject has received 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 5, 10 or 15 days, and wherein the second therapeutic agent is provided, for example, in a different course regimen, on a day that is not necessarily the same as the day on which 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 provided.In some embodiments, the method comprises providing to the subject a cool 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), optionally providing to the subject 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, wherein the cool alone or in combination is effective to treat the subject.

[0053] In one aspect, the present invention provides a method of evaluating a subject having 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 selecting the subject in response to the mutation status 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 mutations in genes in the ovarian cancer.

[0054] In some embodiments, the method includes obtaining the mutation status of genes in the ovarian cancer of the subject. In some embodiments, the method includes selecting the subject in response to the mutation status 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 mutations in genes in the ovarian cancer of the subject. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is locally recurrent. In some embodiments, the cancer is progressive.

[0055] In some embodiments, the method includes a cycle of a second treatment, e.g., a second anti-cancer treatment or anti-tumor treatment, e.g., co-administering one or more anti-cancer agents or anti-tumor agents. In some embodiments, 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) is co-administered with a cycle of a second treatment, e.g., an anti-cancer agent or anti-tumor agent, e.g., a mitotic inhibitor, e.g., a taxane, e.g., paclitaxel. In some embodiments, 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) overlaps with a cycle of a second treatment, e.g., an anti-cancer agent or anti-tumor agent, e.g., a mitotic inhibitor, e.g., a taxane, e.g., paclitaxel. In some embodiments, the second treatment includes administration of paclitaxel. In some embodiments, the paclitaxel is administered at least twice per cycle, e.g., every 7+ / -3, 7+ / -2, 7+ / -1 or 7 days. In some embodiments, the paclitaxel is 80+ / -50, 80+ / -40, 180+ / -30, 80+ / -20, 80+ / -10 or 80 mg / m 2It is administered. In some embodiments, said cool-down of the second treatment is provided after the diagnosis of ovarian cancer. In some embodiments, the cool-down of the second treatment ends prior to the initiation of the provision 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), e.g., 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 the steps of providing a first cool-down of said second treatment, 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), and providing a second cool-down of said second treatment. In some embodiments, the first cool-down is initiated prior to the 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 cool-down replaces the first cool-down and is initiated before, at the same time as, or 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 number of administrations, the frequency of administration, the amount of the second therapeutic agent delivered by the administration, or the level of the second therapeutic agent in the subject, e.g., in the blood of the subject, is decreased in the second cool-down as compared to the first cool-down. In some embodiments, said second agent is not administered to the subject 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 second agent is not administered to the subject during the 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), i.e., during the cool-down of its administration. In some embodiments, the second agent is not administered to the subject during the 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).

[0056] In some embodiments, the subject has previously received a cool-down of a second treatment, e.g., a second anti-cancer treatment or anti-tumor treatment, e.g., a cool-down of one or more anti-cancer or anti-tumor agents. In some embodiments, the cool-down of the second treatment is administered after the diagnosis of ovarian cancer. In some embodiments, the cool-down of the second treatment ends before, at the same time as, or 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).

[0057] In some embodiments, the second treatment 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 cool of the second treatment. In some embodiments, the second cool replaces the first cool and is initiated before, simultaneously with, or 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 second cool is initiated before, simultaneously with, or 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 number of administrations, the frequency of administration, the amount of the second therapeutic agent delivered by the administration, or the level of the second therapeutic agent in the subject, e.g., in the blood of the subject, is decreased in the second cool as compared to the first cool. In some embodiments, the second agent is not administered to the subject 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 second agent is not administered to the subject during the cool 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 the 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).

[0058] In some embodiments, the second treatment comprises administration of a therapeutic agent, such as an anti-cancer agent or an anti-tumor agent. In some embodiments, the therapeutic agent comprises, for example, a mitotic inhibitor, such as a taxane, such as paclitaxel. In some embodiments, the second treatment comprises administration of a first and a second therapeutic agent. In some embodiments, the second treatment comprises administration of an additional agent, such as an anti-cancer agent or an anti-tumor agent, such as, a mitotic inhibitor, an alkylating agent, an antimetabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an antibody, a cytotoxic agent, an antihormonal agent, and an antiandrogen agent, an anti-cancer agent or an anti-tumor agent selected from the group consisting of.

[0059] 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 over cycles equal to or longer than 5, 10, 15, 20, 21, 25, 28, 30, 35, 40, 45 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 over cycles of 5 to 40, 10 to 40, 10 to 30 or 10 to 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 over cycles of 15 to 40, 15 to 30 or 15 to 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 over cycles 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 over a 21-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 over cycles of 28+ / -5, 28+ / -4, 28+ / -3, 28+ / -2 or 28+ / -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 over 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, 50 - 600, 50 - 500, 50 - 400, 50 - 300, 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, 100 - 600, 100 - 500, 100 - 400, 100 - 300, 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, 200 - 600, 200 - 500, 200 - 400, 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, 250 - 600, 250 - 500, 250 - 400, 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, these ranges (e.g., the ranges described herein) do not include one or both endpoints. For example, in this case, these ranges do not include the lower endpoint. 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 at 50+ / -25, 100+ / -50, 150+ / -50, 200+ / -50, 250+ / -50, 300+ / -50, 400+ / -50, 500+ / -50, 550+ / -50 or 600+ / -50 mg / 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 at 50 mg / 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 at 100+ / -50, 100+ / -25, 100+ / -10 or 100+ / -5 mg / 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 at 100 mg / 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 at 200+ / -50, 200+ / -25, 200+ / -10 or 200+ / -5 mg / 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 at 200 mg / 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 at 400 + / - 50, 400 + / - 25, 400 + / - 10 or 400 + / - 5 mg / 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 at 400 mg / day.

[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 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 is 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., the 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 later cycle (e.g., the 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 a cycle is more 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 later cycle (e.g., the second cycle).

[0061] In some embodiments, a unit dosage formulation of 50+ / -25, 100+ / -50, 150+ / -50, 200+ / -50, 250+ / -50, 300+ / -50, 400+ / -50, 500+ / -50, 550+ / -50 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, 200+ / -25, 200+ / -10 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 dosage formulation of 200+ / -20, 200+ / -10 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 dosage 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, 100+ / -25, 100+ / -10, 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 dosage formulation of 100+ / -20, 100+ / -10 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 dosage 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, 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) at 50 + / - 25, 50 + / - 10 or 50 + / - 5 mg / day is administered. In some embodiments, a unit dosage formulation 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) at 50 + / - 20, 50 + / - 10 or 50 + / - 5 mg is administered. In some embodiments, a unit dosage 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.

[0062] In one embodiment, the oral dosage form described herein has a greater C value than a reference oral dosage form, e.g., a dosage form that does not contain additives (e.g., cellulose polymers and their derivatives, e.g., hydroxypropylmethylcellulose (HPMC) or hypromellose (e.g., hydroxypropylmethylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF)) in the mixture. max In one embodiment, the C value of the oral dosage form described herein max 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 that of a reference dosage form of the same dosage (e.g., a dosage form having 100 mg of VS-6063 relative 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 max is at least 1.6 times greater, at least 1.7 times greater, at least 1.8 times greater, at least 1.9 times greater, at least 2 times greater, at least 3 times greater, or at least 4 times greater than that of a reference dosage form of the same dosage.

[0063] 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 contain additives (e.g., cellulose polymers and their derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hypromellose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF)) in the mixture. In one embodiment, the difference in T max values between the fed and fasted states of a subject administered the oral dosage forms described herein is less than the difference in T max values between the fed and fasted states of a subject administered the same dose of a reference oral dosage form, e.g., a dosage form that does not contain additives (e.g., cellulose polymers and their derivatives, e.g., hydroxypropyl methylcellulose (HPMC) or hypromellose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M, HPMCAS-HF)) in the mixture.

[0064] In one embodiment, the oral dosage forms described herein have a consistent exposure when administered to a subject. In one embodiment, the oral dosage forms described herein, when administered to a subject, result in an exposure with less than 50% variability associated with the exposure across multiple subjects compared to the exposure of a reference oral dosage form at the same dose. In one embodiment, the oral dosage forms described herein, when administered to a subject, result in an exposure with less than 40%, 30%, 20% or 10% variability associated with the exposure across multiple subjects compared to the exposure of a reference oral dosage form at the same dose.

[0065] In one aspect, the present invention includes a unit dosage form having 50 to 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 has 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 has 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 has 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 has 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 has 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 has 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 has 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 has 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 has 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). In certain embodiments, for example, the following are provided: (Item 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 additive (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., polyvinylpyrrolidone (e.g., polyvinylpyrrolidone vinyl acetate copolymer (PVP / VA), Copovidone), other copolymers (e.g., polyethylene glycol, polyvinylcaprolactam and polyvinyl acetate (e.g., Soluplus)))). (Item 2) The pharmaceutical composition according to item 1, wherein the additive is a polymer. (Item 3) The pharmaceutical composition according to item 2, wherein the polymer is a precipitation inhibitor. (Item 4) The pharmaceutical composition according to item 3, wherein the precipitation inhibitor is HPMCAS. (Item 5) The pharmaceutical composition according to item 3, wherein the precipitation inhibitor is HPMCAS-HF. (Item 6) The pharmaceutical composition according to item 1, wherein the additive reduces precipitation (e.g., of VS-6063 in vivo, e.g., in solution) when administered orally. (Item 7) When administered orally, the pharmaceutical composition according to item 1, wherein the additive improves 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). (Item 8) The pharmaceutical composition according to item 2, wherein the weight 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. (Item 9) The pharmaceutical composition according to item 8, wherein the polymer is a precipitation inhibitor (e.g., HPMC, e.g., HPMCAS, e.g., HPMCAS-HF). (Item 10) The pharmaceutical composition according to item 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, 30, 31, 32, 32.5, 33, 34, 35, 40, 45, 50% or more (w / w) relative to the amount of the polymer provided, e.g., the precipitation inhibitor. (Item 11) The pharmaceutical composition according to item 1, wherein 5 to 50%, 5 to 30%, 10 to 30%, 10 to 20%, 12 to 15%, 13% by weight of VS-6063 or a pharmaceutically acceptable salt thereof is mixed per weight of the composition. (Item 12) The pharmaceutical composition according to item 1, which is composed of an oral dosage form. (Item 13) The pharmaceutical composition according to item 1, wherein the oral dosage form contains 5 to 50%, 5 to 30%, 10 to 30%, 10 to 20%, 12 to 15%, 13% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per weight of the oral dosage form, and contains VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride). (Item 14) The pharmaceutical composition according to item 1, wherein the VS-6063 (for example, VS-6063 free base) or a pharmaceutically acceptable salt thereof (for example, VS-6063 hydrochloride) is present at 13% by weight of VS-6063 or a pharmaceutically acceptable salt thereof per weight of the oral dosage form. (Item 15) The oral dosage form according to item 12, which is a tablet. (Item 16) The oral dosage form according to item 15, wherein the tablet is provided by direct compression of a physical blend or mixture. (Item 17) The oral dosage form according to item 16, wherein the physical blend or mixture is provided by a dry granulation process. (Item 18) The oral dosage form according to item 2, wherein the polymer is present at 25 - 55%, 35 - 45%, 38 - 43%, 40% by weight of the polymer per weight of the oral dosage form. (Item 19) The oral dosage form according to item 18, wherein the polymer is a precipitation inhibitor (for example, HPMC, for example, HPMCAS, for example, HPMCAS-HF). (Item 20) The oral dosage form according to item 1, further comprising one or more fillers (for example, microcrystalline cellulose (for example, microcrystalline cellulose PH102, for example, Avicel PH102); lactose (for example, lactose monohydrate (for example, FastFlo 316))). (Item 21) The oral dosage form according to item 20, wherein the filler is present at 5 - 80%, 10 - 70%, 20 - 60%, 30 - 60%, 30 - 50%, 42% by weight of the filler per weight of the oral dosage form. (Item 22) The oral dosage form according to item 20, wherein the filler is a mixture of two fillers. (Item 23) The oral dosage form according to item 22, wherein one filler is microcrystalline cellulose PH102 (for example, Avicel PH102). (Item 24) The oral dosage form according to item 22, wherein the filler is lactose monohydrate (e.g., FastFlo 316). (Item 25) The oral dosage form according to item 23 or 24, wherein the filler is present in an amount of 10 - 30%, 15 - 25%, 20% by weight of the oral dosage form. (Item 26) The oral dosage form according to item 22, wherein the fillers are present in a ratio of 1:1 w / w to each other. (Item 27) The oral dosage form according to item 1, further comprising a disintegrant (e.g., a cross-linked polymer, e.g., cross-linked polyvinylpyrrolidone or crospovidone, carboxymethylcellulose or croscarmellose sodium, a modified starch, e.g., sodium starch glycolate). (Item 28) The oral dosage form according to item 27, wherein the disintegrant is sodium starch glycolate. (Item 29) The oral dosage form according to item 27, wherein the disintegrant is present in an amount of 0 - 5%, 1 - 5%, 2.5 - 5%, 3% by weight of the oral dosage form. (Item 30) The oral dosage form according to item 1, further comprising a lubricant (e.g., talc, silica, a fat, e.g., magnesium stearate). (Item 31) The oral dosage form according to item 30, wherein the lubricant is magnesium stearate. (Item 32) The oral dosage form according to item 30, wherein the lubricant is present in an amount of 0.1 - 2%, 0.2 - 1.5%, 1%, 0.5% by weight of the oral dosage form. (Item 33) 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, A pharmaceutically acceptable filler (e.g., microcrystalline cellulose, e.g., microcrystalline cellulose PH102, e.g., Avicel PH102) in an amount of about 10 - 30% by weight on a dry weight basis, About 10 to 30% by weight, on a dry weight basis, of a second pharmaceutically acceptable filler (e.g., lactose, e.g., lactose monohydrate, e.g., FastFlo 316), About 25 to 55% by weight, on a dry weight basis, of an additional pharmaceutically acceptable additive (e.g., precipitation inhibitor, e.g., HPMC-AS, e.g., HPMC-AS HF), About 0 to 5% by weight, on a dry weight basis, of a pharmaceutically acceptable disintegrant (e.g., starch, e.g., modified starch, e.g., sodium starch glycolate), and About 0.1 to 2% by weight, on a dry weight basis, of a pharmaceutically acceptable lubricant (e.g., magnesium stearate) An oral dosage form comprising. (Item 34) About 10 to 15% by weight, on a dry weight basis, of VS-6063 (e.g., VS-6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride), About 15 to 25% by weight, on a dry weight basis, of a pharmaceutically acceptable filler (e.g., microcrystalline cellulose, e.g., microcrystalline cellulose PH102, e.g., Avicel PH102), About 15 to 25% by weight, on a dry weight basis, of a second pharmaceutically acceptable filler (e.g., lactose, e.g., lactose monohydrate, e.g., FastFlo 316), About 35 to 55% by weight, on a dry weight basis, of an additional pharmaceutically acceptable additive (e.g., precipitation inhibitor, e.g., HPMC-AS, e.g., HPMC-AS HF), About 2.5 to 3.5% by weight, on a dry weight basis, of a pharmaceutically acceptable disintegrant (e.g., starch, e.g., modified starch, e.g., sodium starch glycolate), and About 0.2 to 1.5% by weight, on a dry weight basis, of a pharmaceutically acceptable lubricant (e.g., magnesium stearate) The oral dosage form according to item 33, comprising. (Item 35) The oral dosage form according to item 33 or 34, which is a compressed pharmaceutical tablet or a direct compression pharmaceutical tablet. (Item 36) The oral dosage form according to item 1, wherein the additive is one or more binders (e.g., polyvinylpyrrolidone (e.g., polyvinylpyrrolidone vinyl acetate copolymer (PVP / VA), Copovidone), other copolymers (e.g., polyethylene glycol, polyvinylcaprolactam, and polyvinyl acetate (e.g., Soluplus))). (Item 37) The oral dosage form according to item 36, wherein the binder comprises two binders (e.g., polyvinylpyrrolidone (e.g., polyvinylpyrrolidone vinyl acetate copolymer (PVP / VA), Copovidone), other copolymers (e.g., polyethylene glycol, polyvinylcaprolactam, and polyvinyl acetate (e.g., Soluplus))). (Item 38) The oral dosage form according to item 37, wherein the binder is present in an amount of about 37.5% by weight of the binder per weight of the oral dosage form. (Item 39) The oral dosage form according to item 37, wherein the binder is present in an amount of about 25% by weight of the binder per weight of the oral dosage form. (Item 40) The oral dosage form according to item 20, wherein the filler is a polyol (e.g., mannitol-starch (e.g., Pearlitol Flash), mannitol, sorbitol). (Item 41) The oral dosage form according to item 27, wherein the disintegrant is polyvinylpolypyrrolidone (e.g., crospovidone). (Item 42) The oral dosage form according to item 27, wherein the disintegrant is present in an amount of 0 - 30%, 5 - 25%, 5 - 20%, 5 - 15%, 10% by weight of the disintegrant per weight of the oral dosage form. (Item 43) 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 additive (e.g., a binder (e.g., polyvinylpyrrolidone (e.g., polyvinylpyrrolidone vinyl acetate copolymer (PVP / VA), Copovidone))) in an amount of about 15 to 25% by weight based on dry weight, A second pharmaceutically acceptable additive (e.g., a binder (e.g., polyvinyl acetate (e.g., Soluplus))) in an amount of about 15 to 25% by weight based on dry weight, A pharmaceutically acceptable filler (e.g., a polyol (e.g., mannitol - starch (e.g., Pearlitol Flash))) in an amount of about 30 to 40% by weight based on dry weight, A pharmaceutically acceptable disintegrant (e.g., crospovidone) in an amount of about 5 to 15% by weight based on dry weight, A pharmaceutically acceptable lubricant (e.g., magnesium stearate) in an amount of about 0.2 to 1.5% by weight based on dry weight An oral dosage form comprising. (Item 44) The oral dosage form according to item 1, wherein the VS - 6063 (e.g., VS - 6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS - 6063 hydrochloride) is present at 10% by weight of VS - 6063 or a pharmaceutically acceptable salt thereof per weight of the oral dosage form. (Item 45) The oral dosage form according to item 1, wherein the VS - 6063 (e.g., VS - 6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS - 6063 hydrochloride) is present at 25% by weight of VS - 6063 or a pharmaceutically acceptable salt thereof per weight of the oral dosage form. (Item 46) The oral dosage form according to item 1, wherein the VS - 6063 (e.g., VS - 6063 free base) or a pharmaceutically acceptable salt thereof (e.g., VS - 6063 hydrochloride) is present at 50% by weight of VS - 6063 or a pharmaceutically acceptable salt thereof per weight of the oral dosage form. (Item 47) The oral dosage form according to item 16, wherein the physical blend or mixture is provided by a spray - drying dispersion process. (Item 48) The oral dosage form according to item 47, wherein the process results in 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). (Item 49) The oral dosage form according to item 47, wherein the process results in 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). (Item 50) The oral dosage form according to item 47, wherein the process results in 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). (Item 51) The oral dosage form according to item 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). (Item 52) The oral dosage form according to item 51, wherein the dispersion further comprises a polymer, such as a polymer matrix (e.g., polymethacrylic acid (e.g., Eudragit L100-55)). (Item 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 use in the treatment of a subject identified with a cancer disorder (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). (Item 54) A method for treating a disorder 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) to treat said disorder. (Item 55) The method according to item 54, wherein said disorder is a cancer disorder (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). (Item 56) The method according to item 54, wherein said administration is performed in combination with the administration of an additional agent (e.g., a cancer therapeutic agent, e.g., a taxane, e.g., paclitaxel). (Item 57) A method for preparing a direct compression tablet of a unit dosage form, the method comprising: (a) As weight % on a dry weight basis (i) 5 - 50 wt% of VS-6063 on a dry weight basis, (ii) An additive (e.g., a binder, e.g., a polymer, e.g., a precipitation inhibitor, e.g., e.g., HPMC, e.g., HPMCAS, e.g., HPMCAS-HF), and (iii) At least one additive selected from a filler, a disintegrant, and a lubricant are mixed (e.g., blended) to form a VS-6063 formulation in the form of a tableting powder capable of being directly compressed into tablets, and (b) Compressing the formulation prepared during step (a) to form a compressed VS-6063 tablet of a unit dosage form. The method comprising. (Item 58) The method according to item 57, wherein the filler is present at 30 - 60 wt% on a dry weight basis. (Item 59) The method according to item 57, wherein the disintegrant is present at 2.5 - 5 wt% on a dry weight basis. (Item 60) The method according to item 57, wherein the lubricant is present in an amount of 0.5 to 2% by weight on a dry weight basis.

Brief Description of the Drawings

[0066]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Modes for Carrying Out the Invention

[0067] Detailed Description of the Invention The present disclosure is not limited to the application to the details of the composition, such as a formulation, such as an oral dosage form, or a specific order of preparation or administration of the composition, such as a formulation, such as an oral dosage form. The present composition, for example, the dosage forms described herein can be suitably prepared using other techniques or administered in various ways. Similarly, the expressions and terms used herein are for the purpose of description and should not be regarded as limiting.

[0068] Definition As used herein, the articles "a" and "an" refer to the grammatical object of the article being one or more (e.g., at least one).

[0069] "About" and "approximately" generally mean an acceptable degree of error of the measured quantity, taking into account the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, more typically within 5% of a given value or range of values.

[0070] As used herein, the amount of a compound, "effective amount" or "effective cool" effective for treating a disorder (e.g., a disorder described herein) is, when administered to a subject in a single or multiple doses, more than what would be expected in the absence of such treatment (e.g., placebo treatment), and refers to the amount of a compound effective to treat a subject or to cure, alleviate, mitigate or improve a subject having a disorder (a disorder described herein).

[0071] The term "pharmaceutically acceptable" as used herein refers to a compound or carrier (e.g., an additive) that can be administered to a subject together with a compound described herein (e.g., VS-6063, VS-6063 free base, VS-6063 hydrochloride), which does not destroy its pharmacological activity and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound.

[0072] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound described herein (e.g., VS-6063, e.g., the VS-6063 free base), where the compound is modified by converting the existing acid or base moiety to its salt form (e.g., VS-6063 hydrochloride). Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the compounds described herein (e.g., VS-6063) formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present disclosure can be synthesized from the compounds described herein (e.g., VS-6063, VS-6063 free base) containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water, or in an organic solvent (generally a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred), or in a mixture of the two. A listing of suitable salts can be found in Remington’s Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science, 66, No. 2 (1977), the entire disclosures of which are incorporated herein by reference in their entirety.

[0073] As used herein, the phrase "pharmaceutically acceptable derivative or prodrug" refers to any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of the compound VS-6063 that, when administered to a recipient, can (directly or indirectly) provide a therapeutic agent. In particular, advantageous derivatives and prodrugs are those that, when the compounds described herein (e.g., VS-6063, VS-6063 free base, VS-6063 hydrochloride) are administered to a mammal (by enabling more facile absorption of the orally administered compound into the bloodstream), improve the bioavailability of such compounds or enhance delivery to a biological compartment of the compounds described herein (e.g., VS-6063, VS-6063 free base, VS-6063 hydrochloride) as compared to, for example, such compounds. Preferred prodrugs include derivatives in which a group that enhances water solubility or active transport across the gastrointestinal membrane is attached to the structure of the formula described herein.

[0074] As used herein, the term "oral dosage form" refers to a composition or vehicle used to administer a drug, e.g., VS-6063, to a subject. Typically, an oral dosage form is administered via the mouth, but the "oral dosage form" is intended to encompass any substance that is administered to a subject and is absorbed across a membrane of the gastrointestinal tract, e.g., a mucosa, including, for example, the mouth, esophagus, stomach, small intestine, large intestine, and colon. For example, an "oral dosage form" includes a solution administered to the stomach via a feeding tube.

[0075] As used herein, the term "treating" or "treatment" refers to applying or administering a compound, alone or in combination with additional agents, to a subject, e.g., a subject having a disorder (e.g., a disorder described herein), a symptom of a disorder, or a predisposition to a disorder, for the purpose of curing, healing, alleviating, relieving, modifying, salvaging, ameliorating, improving, or affecting the disorder. Co - administration, co - administering, or co - providing, as used herein in the context of administration of a treatment, refers to the administration of one treatment either simultaneously, or prior to the administration of a secondary treatment (e.g., immediately before, less than 5, 10, 15, 30, 45, 60 minutes before, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72 hours or longer before).

[0076] The cool of a treatment, as referred to herein, includes one or more separate administrations of a therapeutic agent. The cool of a treatment can include one or more cycles of a therapeutic agent.

[0077] A cycle, as used herein in the context of a cycle of drug administration, refers to the period during which a drug is administered to a patient. For example, if a drug is administered over a 21 - day cycle, this cyclical administration is administered, for example, daily or twice a day for 21 days. A drug can be administered over more than one cycle. In some embodiments, the first and second, or subsequent cycles are the same with respect to one or both of the period and the cyclical administration. In embodiments, the first and second, or subsequent cycles are different with respect to one or both of the period and the cyclical administration. A rest period may be provided between each cycle. The rest cycle can be 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 1, 2, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more in length.

[0078] Various ranges, such as ranges of the amount of a drug administered per day, are presented herein. In some embodiments, the range includes both endpoints. In other embodiments, the range excludes one or both endpoints. By way of example, the range can exclude the lower endpoint. Thus, in such embodiments, the range of 250 - 400 mg / day excluding the lower endpoint includes amounts greater than 250 mg / day and less than or equal to 400 mg / day.

[0079] As used herein, the term "subject" is intended to include human and non-human animals. Exemplary human subjects include human subjects having a disorder, such as the disorders described herein. The term "non-human animal" of the present invention includes all vertebrates, such as non-mammals (e.g., chickens, amphibians, reptiles, etc.) and mammals such as non-human primates, domestic animals and / or agriculturally useful animals, e.g., sheep, dogs, cats, cows, pigs, etc.

[0080] Compound VS-6063 The present active agent (e.g., active ingredient) is the compound VS-6063 (e.g., VS-6063 free base) disclosed in U.S. Patent No. 7,928,109:

Chemical formula

[0081] VS-6063 is a potent inhibitor of the FAK protein tyrosine kinase and can be adapted for therapeutic use as an anti-proliferative agent (e.g., anti-cancer), anti-tumor (e.g., effective against solid tumors), anti-angiogenic (e.g., stopping or preventing blood vessel growth) in mammals, particularly humans. VS-6063 can be useful in the prevention and treatment of non-hematological malignancies. Furthermore, VS-6063 can be useful in the prevention and treatment of various human hyperproliferative disorders such as malignancies and benign tumors of the liver, kidney, bladder, chest, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, liver cancer, sarcoma, glioblastoma, head and neck, etc., and other hyperplastic 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 useful in the prevention and treatment of disorders such as mesothelioma.

[0082] 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.

[0083] Pharmaceutical Composition and Oral Dosage Form For example, a pharmaceutical composition may be provided in a form suitable for oral administration such as tablets, capsules, pills, powders, sustained release formulations, solutions and suspensions. The pharmaceutical composition may be in a unit dosage form suitable for single administration of an accurate dosage. The pharmaceutical composition may contain a pharmaceutically acceptable carrier in addition to VS-6063 or a pharmaceutically acceptable salt thereof, and may optionally further contain one or more pharmaceutically acceptable additives such as stabilizers (e.g., binders, e.g., polymers, e.g., precipitation inhibitors, e.g., hydroxypropyl methylcellulose (HPMC) or hypromellose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hypromellose acetate succinate, e.g., HPMCAS-H, HPMCAS-M)), excipients, binders and lubricants. In some embodiments, the composition provides a free-flowing, sticky tableting powder that can be directly compressed into tablets. Further, the tablets may contain other medical or pharmaceutical agents, carriers, and / or adjuvants. Exemplary pharmaceutical compositions include compressed tablets (e.g., directly compressed tablets) containing, for example, VS-6063 or a pharmaceutically acceptable salt thereof.

[0084] Tablets containing an active ingredient 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)) are also provided. In addition to the active ingredient or therapeutic ingredient, the tablets may contain some inert substances such as carriers. Pharmaceutically acceptable carriers can be sterilized liquids such as water and oil, including those of petroleum, animal, vegetable or synthetic origin (such as peanut oil, sesame oil, etc.). Saline solutions and aqueous dextrose can also be used as liquid carriers. Thus, the oral dosage forms for use according to the present invention can be formulated by conventional methods using one or more pharmaceutically acceptable carriers including additives and adjuvants, and these carriers facilitate the processing of the active ingredient into a preparation that can be used pharmaceutically.

[0085] Additives can impart good powder flow and compression characteristics to the material to be compressed. Desirable characteristics of additives include high compressibility regarding enabling strong tablets to be produced with low compression force, good powder flow properties that can improve the powder flow of other additives in the composition, and adhesiveness that can prevent, for example, tablets from breaking during processing, transportation, and handling. Such characteristics are imparted to these additives by pretreatment processes such as dry granulation (e.g., by roller compaction, slugging), wet granulation, spray drying spheronization (e.g., spray-dried dispersions, solid nanodispersions), or crystallization (e.g., salt form) of the pharmaceutical composition. They can be classified according to their roles in the final tablet. Some additives can function multifunctionally. For example, a filler can act as a binder and / or can function as a precipitation inhibitor. Other additives that impart physical characteristics to the finished tablet are colorants and flavoring and odor-masking agents (e.g., in the case of chewable tablets). Examples of additives are described, for example, in Handbook of Pharmaceutical Excipients (5th Edition), edited by Raymond C Rowe, Paul J. Sheskey, and Sian C. Owen; Publisher: Pharmaceutical Press.

[0086] In the case of oral administration, the active ingredient, for example the compounds 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 present invention to be formulated as tablets, pills, capsules, solutions, gels, syrups, slurries, powders or granules, suspensions or solutions in aqueous or non-aqueous media, etc., for oral ingestion by a subject. Pharmacological preparations for oral use can be obtained, for example, by using solid additives, optionally grinding the resulting mixture, and processing the mixture of granules, and adding suitable adjuvants if desired, to obtain tablets. Suitable additives such as excipients, binders or disintegrants may be desirable.

[0087] Tablets typically contain excipients or fillers, which are added, for example, to increase the bulk weight of the blend to provide a practical size for compression. Excipients or fillers that may be used include calcium salts such as dibasic calcium phosphate, and one or more of sugars such as lactose, sucrose, dextrose, microcrystalline cellulose, mannitol, and maltodextrin. Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable excipients include, but are not limited to, confectioner's sugar, compressible sugar, dextrate, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, and talc. In some embodiments, the excipient or filler is microcrystalline cellulose, which can be produced by the controlled hydrolysis of alpha-cellulose. Suitable microcrystalline cellulose has an average particle size of from about 20 nm to about 200 nm. Suitable microcrystalline cellulose includes, for example, Avicel PH101, Avicel PH102, Avicel PH103, Avicel PH105, and Avicel PH200, manufactured by FMC Corporation. In some embodiments, the excipient or filler is lactose. In some embodiments, lactose has an average particle size between about 50 μm and about 500 μm prior to formulation.

[0088] This pharmaceutical composition generally also contains a lubricant. Lubricants are usually added to prevent the tableting material from adhering to the punching die, to minimize friction during tablet compression, and to enable the removal of the compressed tablets from the die. Such lubricants are generally included in the final tablet mix in an amount of less than 1% by weight, per weight of the composition. Examples of lubricants include, but are not limited to, colloidal silica, magnesium trisilicate, talc, magnesium carbonate, magnesium oxide, glyceryl behaptate, polyethylene glycol, ethylene oxide polymers (e.g., Carbowax), sodium lauryl sulfate, magnesium stearate, aluminum stearate, calcium stearate, sodium stearyl fumarate, stearic acid, magnesium lauryl stearate, and mixtures 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%, preferably from about 0.5 to 1.5% w / w.

[0089] A glidant is a substance that can be added to a powder to improve its flowability. Examples of glidants include magnesium stearate, colloidal silicon dioxide (such as grades sold as Aerosil), starch and talc. Glidants can be present in the pharmaceutical composition at levels from 0 to about 5% w / w. Again, it should be noted that an additive can function multifunctionally. A lubricant, such as magnesium stearate, can also function as a glidant.

[0090] In addition to excipients / fillers and lubricants, other conventional additives may also be present in the pharmaceutical compositions of the present invention. Such additional additives include disintegrants, binders, flavoring agents, coloring agents and glidants. Some additives are multifunctional and can, for example, function both as a binder and a tablet disintegrant.

[0091] The disintegrant can be present in an amount necessary to promote dissolution (e.g., increase the tablet disintegration rate). A disintegrant is an additive that can counteract the physical forces of particle binding 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, starch, such as sodium starch glycolate, pregelatinized starch, clay, cellulose, alginate, gum, cross-linked polymers, such as cross-linked polyvinylpyrrolidone (e.g., polyvinylpolypyrrolidone, PVPP, crospovidone, crospolividone), cross-linked carboxymethylcellulose calcium and cross-linked carboxymethylcellulose sodium (croscarmellose sodium), and soybean polysaccharide. In some embodiments, the disintegrant used in the composition is sodium starch glycolate. Generally, the amount of the disintegrant can be 0 to about 25% w / w of the composition, more generally about 1% to about 15% w / w, and usually less than 15% w / w, less than 10% w / w or less than 5% w / w. In some embodiments, the amount of the disintegrant is about 10% w / w of the composition. In some embodiments, the amount of the disintegrant is about 3% w / w of the composition.

[0092] A binder is an additive that contributes to particle adhesion in a solid preparation. 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 methylcellulose (HPMC) or hypromellose (e.g., hydroxypropyl methylcellulose acetate succinate (HPMC-AS) or hypromellose 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, polymethacrylate (e.g., Eudragit , for example, Eudragit L100-55), polyvinylpyrrolidone (for example, polyvinylpyrrolidone vinyl acetate copolymer (PVP / VA), Copovidone), other copolymers (for example, polyethylene glycol, polyvinylcaprolactam and polyvinyl acetate (for example, polyvinyl phthalate (PVAP), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, Soluplus)), sorbitol, pregelatinized starch, alginic acid and its salts such as sodium alginate, magnesium aluminum silicate, polyethylene glycol and the like are included. Generally, the amount of the binder can vary widely, for example from 0% to 95% w / w of the composition. As described above, additives can act multifunctionally. For example, a tableting excipient can also act as a binder. In some embodiments, this binder is a precipitation inhibitor. A precipitation inhibitor is generally an additive that mediates supersaturation stabilization (for example, stabilization of a supersaturated solution) and / or delays and / or inhibits precipitation (for example, prevents rapid precipitation), for example in a solution or in the GI tract.In some embodiments, the binder is selected from the group consisting of starch (e.g., mannitol - starch, e.g., Pearlitol Flash), cellulose and its derivatives, such as microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose (HPMC) (e.g., hydroxypropyl methyl cellulose 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 such as lactose, sucrose, dextrose, glucose, maltodextrin, mannitol, xylitol, polymethacrylate (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 containing 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, e.g., Pearlitol Flash. In some embodiments, the binder is a copolymer (e.g., a copolymer containing 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).

[0093] In some embodiments, more than one type of binder is used in the composition. In some embodiments, the amount of binder is about 0 to 60% w / w of the composition. In some embodiments, the amount of binder present in the composition is 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80% weight or more per weight of the composition. In some embodiments, the amount of binder is about 20 to about 80% w / w of the composition. In some embodiments, the amount of binder is about 50% w / w of the composition. In some embodiments, the amount of binder is about 80% w / w of the composition.

[0094] Dosages can vary depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see, e.g., Fingl et al., "The Pharmacological Basis of Therapeutics", 1975). Dosages lower or higher than those listed above may be required. The specific dosage and treatment regimen for any particular subject depends on a variety of factors including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptom, the subject's predisposition to the disease, condition or symptom, and the judgment of the physician administering the treatment.

[0095] Tablets can be plain, film or sugar coated bisected, embossed, layered, or sustained release. They can be made in a variety of sizes, shapes and colors. Tablets can be swallowed, chewed, or dissolved in the mouth or sublingually.

[0096] Three processes: wet granulation, direct compression, and dry granulation are commonly used to make compressed tablets. The preparation method and type of additives are selected to impart the desired physical characteristics to the tablet formulation that enable rapid compression of the tablets. After compression, the tablets must have several additional attributes such as appearance, hardness, disintegration ability, and an acceptable dissolution profile. The selection of fillers and other additives depends on the chemical and physical properties of the drug, the behavior of the mixture during processing, and the properties of the final tablet. Prior formulation studies are conducted to determine the chemical and physical compatibility between the active ingredient and the proposed additives.

[0097] Direct compression is a relatively rapid method in which the powder material is directly compressed without changing the physical and chemical properties of the drug. The active ingredient (e.g., the compounds described herein, such as VS-6063, such as the VS-6063 free base or VS-6063 hydrochloride), direct compression additives, and other auxiliary substances such as glidants and lubricants are blended (e.g., in a twin shell blender or similar low shear device) before being compressed into tablets. This method typically consists of blending of the components, dry sieving, lubrication, and compression.

[0098] This dry granulation process can be used when one of the components, i.e., either the drug or an excipient, has sufficient adhesive properties to be tabletted. This method consists of blending of the components, slugging (or roller compaction of the components), dry sieving, lubrication, and compression. In some embodiments, dry granulation is used to improve the processability, e.g., flow characteristics, of a blend (e.g., the compositions described herein, such as compositions containing VS-6063).

[0099] The wet granulation method can be used, for example, to convert a powder mixture into granules with improved flow and adhesion properties for tableting. This procedure consists of, for example, the step of mixing the powder in a suitable blender and then adding a granulating solution to the mixed powder under shear to obtain granulated material. Next, the wet mass is sieved through a suitable sieve and dried by tray drying or fluidized bed drying. Alternatively, the moist mass may be dried and passed through a mill. The overall process includes weighing, blending of dry powders, wet granulation, drying, milling, blending, lubrication, and compression.

[0100] Oral dosage forms may, if desired, be presented in a pack or dispenser device such as a kit approved by the FDA, which may contain one or more unit dosage forms containing the active ingredient. The pack may include, for example, a metal or plastic foil such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may be accompanied by a cautionary statement with a container in a form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, and this cautionary statement reflects the approval of the composition form or human or veterinary administration by the government agency. Such cautionary statements can be, for example, labeling approved by the US Food and Drug Administration for prescription drugs, or an approved product insert.

[0101] Methods of treatment and administration The present invention relates, inter alia, to a method for treating abnormal cell growth, such as cancer, comprising the step of administering an oral dosage form comprising VS-6063 or a pharmaceutically acceptable salt thereof.

[0102] Abnormal cell growth As used herein, and unless otherwise indicated, abnormal cell growth refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes (1) tumor cells (tumors) that grow, for example, by expressing a mutated tyrosine kinase or by overexpressing a receptor tyrosine kinase, (2) benign and malignant cells of other proliferative diseases in which, for example, abnormal tyrosine kinase activation occurs, (3) any tumor that grows by a receptor tyrosine kinase, (4) any tumor that grows by abnormal serine / threonine kinase activation, and (5) benign and malignant cells of other proliferative diseases in which, for example, abnormal serine / threonine kinase activation occurs. Abnormal cell growth can refer to cell growth in epithelial (e.g., carcinoma, adenocarcinoma), mesenchymal (e.g., sarcoma (e.g., leiomyosarcoma, Ewing's sarcoma)), hematopoietic (e.g., lymphoma, leukemia, myelodysplasia (e.g., pre-malignant)), or other (e.g., melanoma, mesothelioma, and other tumors of unknown origin) cells.

[0103] 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, anal cancer, gastric 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 carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine 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 carcinoma, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma), or one or more combinations of the cancers described above. In some embodiments, the cancer is metastatic. In some embodiments, the abnormal cell growth is locally recurrent (e.g., the subject has a locally recurrent disease, e.g., cancer).

[0104] In some embodiments, the method includes administering to a mammal an oral dosage form of the invention effective to treat a non-blood-related malignant disease. In some embodiments, the method is effective to treat 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 genes for estrogen receptor, progesterone receptor, and Her2 / neu). In one embodiment, the lung cancer is non-small cell lung cancer (NSCLC), e.g., KRAS mutant NSCLC. In one embodiment, the ovarian cancer is advanced ovarian cancer (e.g., advanced or metastatic ovarian cancer).

[0105] In one embodiment, the method comprises administering to a mammal an oral dosage form of the invention effective to treat a composition, such as a mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma).

[0106] The inventive method contemplates administering a therapeutically effective amount of the compositions described herein, either singly or in multiple doses. The compositions, such as those described herein, can be administered at regular intervals, depending on the nature, severity and extent of the condition of the subject. In some embodiments, the compositions described herein are administered in a single dose. In some embodiments, the compositions described herein are administered in multiple doses. In some embodiments, a therapeutically effective amount of a composition, such as those described herein, can be administered orally and regularly (e.g., every 1, 2, 3, 4, 5 or 6 days, or every 1, 2, 3, 4, 5, 6, 7, 8 or 9 weeks, or every 1, 2, 3, 4, 5, 6, 7, 8, 9 months or more, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 times or more).

[0107] In some embodiments, the compositions described herein are administered at a predetermined interval (e.g., every 1, 2, 3, 4, 5 or 6 days, or every 1, 2, 3, 4, 5, 6, 7, 8 or 9 weeks, or every 1, 2, 3, 4, 5, 6, 7, 8, 9 months or more, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 times or more).

[0108] Combination The oral dosage forms and methods of the invention can be administered in combination with an additional (e.g., second, secondary) agent (e.g., therapeutic agent). This additional agent can include an anti-tumor agent or anti-cancer agent, such as an anti-mitotic agent, alkylating agent, antimetabolite, intercalating antibiotic, growth factor inhibitor, cell cycle inhibitor, enzyme, topoisomerase inhibitor, biological response modifier, antibody, cytotoxic drug, anti-hormone drug and anti-androgen drug. The anti-tumor agent can be selected from the group consisting of anti-tumor agents.

[0109] The oral dosage form of the present invention can be applied as a monotherapy or in combination with one or more other anti-tumor substances, such as, for example, mitotic inhibitors, such as taxanes, such as docetaxel (Taxotere), paclitaxel; alkaloids, such as vinblastine; alkylating agents, such as platinum coordination alkylating compounds, such as platinum-based, 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 interferon; and antihormonal drugs, such as antiestrogen drugs such as Nolvadex (tamoxifen) or antiandrogen drugs such as Casodex (4'-cyano-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide).

[0110] The oral dosage form of the present invention may be used alone or in combination with one or more of various anti-cancer agents or supportive care agents. For example, the oral dosage form of the present invention may be used with one or more selected from the group consisting of cytotoxic agents such as camptothecin, irinotecan HCl (Camptosar), edotecarin, SU-11248, epirubicin (Ellence); taxanes such as docetaxel (Taxotere), paclitaxel; rituximab (Rituxan), bevacizumab (Avastin), imatinib mesylate (Gleevac), Erbitux, gefitinib (Iressa) and combinations thereof. The present invention also contemplates using the oral dosage form of the present invention in combination with hormonal therapies such as exemestane (Aromasin), Lupron, anastrozole (Arimidex), tamoxifen citrate (Nolvadex), Trelstar and combinations thereof. Further, the present invention provides the oral dosage form of the present invention alone or in combination with a product selected from the group consisting of one or more supportive care products such as filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend or combinations thereof. Such co-treatments can be achieved by administering the individual components of those treatments simultaneously, sequentially or separately.

[0111] The oral dosage form of the present invention can be used in conjunction with the following, which are non-limiting lists of anti-tumor agents, anti-cancer agents, examples of additional or secondary agents that can be used in conjunction with the oral dosage form of the present invention. 〇 Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carbocon, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide and mitolactol; platinum coordination alkylating compounds, such as platinum-based (cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin or satrplatin, etc.) are included; 〇 Antimetabolites include, but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, gemcitabine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabine, 5-azacytidine, capecitabine, cladribine, clofarabine, decitabine, efloxatinib, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, ocfosfate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimethoprim, vidarabine, vincristine, vinorelbine; 〇 Antibiotics include, but are not limited to, aclarubicin, actinomycin D, amrubicin, annamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalammer, streptozocin, valrubicin or dinostatin; 〇 Hormone therapeutic agents, for example, exemestane (Aromasin), Lupron, anastrozole (Arimidex), doxercalciferol, fadrozole, formestane, anti-estrogen drugs such as tamoxifen citrate (Nolvadex) and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Femara), or anti-androgen drugs such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex (registered trademark) (4'-cyano-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide), and combinations thereof; 〇 Anti-tumor substances derived from plants include, for example, mitosis inhibitors such as alkaloids such as vinblastine; taxanes such as those selected from docetaxel (Taxotere) and paclitaxel; 〇 The cytotoxic topoisomerase inhibitors include one or more drugs selected from the group consisting of aclarubicin, amonafide, belotecan, camptothecin and camptothecin derivatives (including, but not limited to, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan, irinotecan HCl (Camptosar)), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide and topotecan, and combinations thereof; 〇 The immunotherapeutic agents include interferon and a number of other immunopotentiators. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a or interferon gamma-n1. Other agents include filgrastim, lentinan, sizofiran, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, OncoVAX-CL, sargramostim, tasnemermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitsumomab, oregovomab, pemtumomab and Provenge; 〇 Biological response modifiers are agents that modify the defense mechanisms of living organisms or biological responses such as survival, growth, or differentiation of tissue cells, and induce them to have antitumor activity. Such agents include krestin, lentinan, sizofuran, picibanil, or ubenimex; 〇 Other anticancer agents include alitretinoin, ampligen, atrasentan, bexarotene, bortezomib, bosentan, calcitriol, exisulind, finasteride, fotemustine, ibandronic acid, miltefosine, mitoxantrone, 1-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotene, TLK-286, Velcade, Tarceva, tretinoin, CTLA4 inhibitors, or farnesyl protein transferase inhibitors; 〇 Other anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, remo-bab, Revlimid, squalamine, ukrain, and Vitaxin; 〇 Platinum coordination compounds include, but are not limited to, cisplatin, carboplatin, nedaplatin, or oxaliplatin; 〇 The tyrosine kinase inhibitors are Iressa or SU5416; 〇 Antibodies include Herceptin, Erbitux, Avastin, rituximab, or cytotoxic lymphocyte antigen 4 (CTLA4); and 〇 Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, or interferon gamma-n1.

Examples

[0112] The present disclosure is further described in the following examples, which do not limit the scope of the claims.

[0113] Example 1 Dry Granulation of VS-6063 Formulation The VS-6063 immediate release (IR) formulation was prepared using a dry granulation technique. The composition of this formulation is shown in Table 1.

[0114] [Table 1]

[0115] The in-granule blend was prepared by sieving all of the VS-6063 and additives through a 600 μm sieve before use. The required amounts of the functional additives and VS-6063 were weighed and pre-blended for 1 minute using a large plastic spatula, and then mixed in a Turbula mixer set at 32 rpm for 5 minutes. The remaining sieved components (excluding magnesium stearate) were added to the above pre-blend, mixed for 1 minute using a large plastic spatula, and then mixed in a Turbula mixer set at 32 rpm for 15 minutes. After the addition of magnesium stearate, the final blend was performed in a Turbula mixer set at 32 rpm for 3 minutes. Next, the in-granule blend was roller-compacted. The granule properties for two IR tablet formulations were characterized and compared with a direct compression batch of the same composition. Shown in Table 2.

[0116] [Table 2]

[0117] The particle size analysis data shows a bimodal particle size distribution with a particle size distribution >710 μm of about 20% and a particle size distribution <75 μm of about 20%.

[0118] The physical properties of these blends were determined and compared to direct compression formulations (HPMC-AS formulations only) (Table 2). The Hausner ratios for the blends tested were >1.3 and Carr's indices were >23%, indicating that these blends may have poor powder flow, be sticky, and have high interparticle friction. However, the angle of repose indicates reasonable powder flow.

[0119] In comparison to direct compression methods, higher compression forces may be required to achieve the desired tablet hardness in dry granulated blends.

[0120]

Table 3

[0121] Figure 1 shows that for HPMC-AS formulations, dry granulation can result in slower dissolution after a change in pH (e.g., from gastric pH to intestinal pH) compared to tablets prepared using direct compression methods.

[0122] For PVP VA / Soluplus formulations, the dissolution profile of tablets prepared by dry granulation methods can be even slower compared to tablets prepared using direct compression methods. The resulting dissolution profile was very similar to that of the VS-6063 reference product (e.g., unformulated product).

[0123] Dry Granulation of Example 2 VS-6063 Immediate Release Formulation One batch of the VS-6063 IR formulation was prepared using dry granulation methods (Table 4).

[0124]

Table 4

[0125] The in - granule blend was prepared by sieving all of VS - 6063 and the additives through a 600 - μm sieve before use. The required amounts of the functional additives and VS - 6063 were weighed, pre - blended for 1 minute using a large plastic spatula, and then mixed with a Turbula mixer set at 32 rpm for 5 minutes. The remaining sieved components (excluding magnesium stearate) were added to the above pre - blend, mixed for 1 minute using a large plastic spatula, and then mixed with a Turbula mixer set at 32 rpm for 15 minutes. After the addition of magnesium stearate, the final blend was carried out with a Turbula mixer set at 32 rpm for 3 minutes. Next, the in - granule blend was roller - consolidated.

[0126] After completion of the dry granulation process, the consolidated ribbon was passed through sieves of 1.4 mm, 1.18 mm, and 850 μm. Next, a tablet blend was prepared by mixing the granules and magnesium stearate using a Turbula mixer at 32 rpm for 3 minutes.

[0127]

Table 5

[0128] Particle size analysis data showed that a larger portion of the blend consisted of fine particles (about 45% being < 150 μm), compared to the roller - consolidated PVP VA / Soluplus formulation (about 35% being < 150 μm) that produced a harder ribbon.

[0129] The physical properties of the blend before and after roller consolidation were also determined, and it was shown that the fluidity might not be significantly improved by using the dry granulation technique (Table 5). These data also indicate that the powder flow properties might not be improved by the formation of a softer ribbon compared to granules formed from a harder ribbon (Table 5).

[0130] Compared to direct compression methods, higher compression forces, such as 8000 lbs, may be required to achieve the desired tablet hardness necessary for dry granulation formulations. However, this is likely to be lower compared to the 10000 lbs compression force that may be required for the manufacture of tablets derived from granules prepared from harder ribbons.

[0131]

Table 6

[0132] To determine whether the disintegration time is improved by adding additional crospovidone to the formulation, the crospovidone content was further increased (3% was added to the extragranular blend) so that the total content of the disintegrant was 13%. The tablets were compressed using a Carver tablet press with an 18.97×10.41 mm elliptical tool, which is tablet tooling. The compression force was adjusted to achieve a tablet hardness of 10 - 14 kP. The tablet compression data are shown in Table 6.

[0133]

Table 7

[0134] Compared to direct compression, granules produced by dry granulation may not have improved compressibility or powder flow. The use of softer ribbons may not improve the disintegration time of the resulting tablets, and their dissolution profiles are not improved compared to the reference product (Figure 2), indicating that the function of the precipitation inhibitor in the PVP VA / Soluplus formulation may be lost during dry granulation.

[0135] Dry Granulation of Example 3 VS - 6063 Formulation One batch of the VS - 6063IR formulation was prepared using the dry granulation method (Table 8).

[0136]

Table 8

[0137] The in - granule blend preparation was carried out by sieving all of VS - 6063 and the additives through a 600 - μm sieve before use. The required amounts of the functional additives and API (e.g., VS - 6063) were weighed, pre - blended for 1 minute using a large plastic spatula, and then mixed with a Turbula mixer set at 32 rpm for 5 minutes. The remaining sieved components (excluding magnesium stearate) were added to the above pre - blend, mixed for 1 minute using a large plastic spatula, and then mixed with a Turbula mixer set at 32 rpm for 15 minutes. After the addition of magnesium stearate, the final blend was carried out with a Turbula mixer set at 32 rpm for 3 minutes. Next, the in - granule blend was roller - compacted.

[0138] The granule properties of the IR tablet formulation are shown in Table 9 and compared with a direct - compression batch of the same composition.

[0139]

Table 9

[0140] Particle size analysis data showed that for both batches, a bimodal particle size distribution was present.

[0141] The physical properties of these blends were determined and compared with direct - compression formulations (only the HPMC - AS formulation). The data showed that the use of the dry - granulation technique can improve the flowability (Table 9). However, the Hausner ratio for these experiments was > 1.3 and Carr's index was > 23%, indicating that these may have poor powder flow, be sticky, and have high inter - particle friction. The data for the angle of repose still indicate fair powder flow.

[0142] For both dry - granulation formulations, when compared with the direct - compression method, a higher compression force may be required to achieve the desired tablet hardness.

[0143]

Table 10

[0144] Data from Figure 3 suggest that for HPMC-AS formulations, by introducing a dry granulation technique, the dissolution profiles of all batches after pH modification are equivalent to those of tablets prepared using a direct compression technique.

[0145] Example 4 In Vivo Evaluation of the Pharmacokinetics of VS-6063 in Various Formulations Abbreviations used: Relative bioavailability = AUC inf Test formulation / AUC inf Reference formulation C max Observed maximum concentration T max Time to maximum concentration t 1 / 2 Terminal half-life AUC inf Area under the concentration-time curve extrapolated from time 0 to infinity AUC last Area under the concentration-time curve from time 0 to the final quantifiable concentration.

[0146] Study design In a 4-session crossover design with a washout period of at least 3 days between dosing sessions, oral nutritional doses of VS-6063 in various formulations were administered to 4 groups consisting of 1 male beagle dog per group. In each session, VS-6063, VS-6063-25% SDD in Soluplus / PVP-A, a physical mixture of VS-6063-25% 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: K 2EDTA was scheduled to be collected from each animal before dosing and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after dosing in each dosing session. For plasma, blood samples were processed and for VS-6063, this plasma was analyzed by LC-MS / MS. Plasma concentration-time data for individual animals were analyzed to determine the pharmacokinetic profile of VS-6063.

[0147] In a 4-session crossover design with a washout period of at least 3 days between dosing sessions, oral nutritional doses of VS-6063 in various formulations were administered to 4 groups consisting of 1 male beagle dog per group. In each session, a physical mixture of VS-6063-25% 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 a physical mixture of VS-6063-50% with Soluplus / PVP-A was administered at target dose levels of 10 and 20 mg API / kg. Blood samples (anticoagulant: K 2 EDTA was scheduled to be collected from each animal before dosing and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after dosing in each dosing session. For plasma, blood samples were processed and for VS-6063, this plasma was analyzed by LC-MS / MS. Plasma concentration-time data for individual animals were analyzed to determine the pharmacokinetic profile of VS-6063.

[0148] Dose formulation VS-6063 was formulated at a target concentration of 10 mg API / mL in 0.5% (w / v) Methocel A4M in water containing 0.1% (v / v) Tween 80 (correction factor 0.934). 10 mg in 0.5% (w / v) Methocel A4M in water VS-6063-25% SDD in Soluplus / PVP-A was formulated at the target concentration of API / mL (correction factor 0.25). A physical mixture of VS-6063-25% with Soluplus / PVP-A was formulated at the target concentration of 10 mg API / mL in 0.5% (w / v) Methocel A4M in water (correction factor 0.25). VS-6063-10% SDD in EUDRAGIT L100-55 was formulated at the target concentration of 10 mg API / mL in 0.5% (w / v) Methocel A4M in water (correction factor 0.10).

[0149] A physical mixture of VS-6063-25% with Soluplus / PVP-A and VS-6063-25% SDD in Soluplus / PVP-A were formulated at the target concentration of 10 mg API / mL in 0.5% (w / v) Methocel A4M in water (correction factor 0.25). A physical mixture of VS-6063-50% with Soluplus / PVP-A was formulated at the target concentrations of 5 mg API / mL and 10 mg API / mL in 0.5% (w / v) Methocel A4M in water (correction factor 0.50).

[0150] Dosing In a 4-session crossover design with a washout period of at least 3 days between dosing sessions, oral nutritional doses of VS-6063 in various formulations were administered to 4 groups consisting of 1 male beagle dog per group. In each session, VS-6063, VS-6063-25% SDD in Soluplus / PVP-A, a physical mixture of VS-6063-25% with Soluplus / PVP-A, and VS-6063-10% SDD in EUDRAGIT L100-55 were administered at the target dose level of 10 mg API / kg. The animals were fasted overnight before dosing. Water was not withheld. Food was returned 4 hours after dosing.

[0151] Before dosing, the body weight of each animal was recorded. The dose (rounded to the nearest 0.01 mL) was calculated based on the pre-treatment body weight (kg) and a dose volume of 1 mL / kg. After the enteral nutrition dose, before removing the feeding tube, 10 - 20 mL of water was flushed vigorously through this tube. Before and immediately after dosing each animal, the dosing syringe was weighed, and the amount of formulation administered to each animal was determined from the difference in syringe weights.

[0152] In a 4 - session crossover design including a washout period of at least 3 days between dosing sessions, four groups consisting of one male beagle dog per group were given enteral nutrition doses of VS - 6063 in various formulations. In each session, a physical mixture of VS - 6063 - 25% 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 a physical mixture of VS - 6063 - 50% with Soluplus / PVP - A was administered at target dose levels of 10 and 20 mg API / kg. The animals were fasted overnight before dosing. Water was not withheld. Food was returned 4 hours after dosing.

[0153] Before dosing, the body weight of each animal was recorded. The dose (rounded to the nearest 0.01 mL) was calculated based on the pre-treatment body weight (kg) and a dose volume of 2 mL / kg. After the enteral nutrition dose, before removing the feeding tube, 10 - 20 mL of water was flushed vigorously through this tube. Immediately before and immediately after dosing each animal, the dosing syringe was weighed, and the amount of formulation administered to each animal was determined from the difference in syringe weights.

[0154] VS - 6063 concentration in plasma The mean (n = 4) plasma concentration - time profile is shown in Figure 5 (linear scale).

[0155] Over 4 sessions, after a single oral dose of VS-6063 at a target dose of 10 mg / kg, plasma concentrations increased at a fairly rapid rate and reached maximum concentration for each individual animal within 2 to 4 hours (mean 2.50 hours) after dosing. Next, the mean concentration decreased in an apparent first-order manner. The concentration of VS-6063 was quantifiable in all animals up to 24 hours after dosing (final time point).

[0156] Over 4 sessions, after a single oral dose of VS-6063-25% SDD in Soluplus / PVP-A, a physical mixture of VS-6063-25% with Soluplus / PVP-A, and VS-6063-10% SDD in EUDRAGIT L100-55 at a target dose of 10 mg API / kg, plasma concentrations increased at a fairly rapid rate and reached maximum concentration for each individual animal within 0.5 to 4 hours (mean 1.75 to 1.88 hours) after dosing. Next, the mean concentration decreased in an apparent first-order manner. The concentration of VS-6063 was quantifiable in all animals up to 24 hours after dosing (final time point).

[0157] Plasma pharmacokinetics of VS-6063 Plasma pharmacokinetic parameters for VS-6063 are shown in Tables 13 and 14.

[0158] For VS-6063 at a target dose of 10 mg / kg over 4 sessions, the mean estimated half-life was approximately 3.9 hours. Mean C max and mean T max were 614 ng / mL and 2.50 hours, respectively. Mean AUC last was 3100 ng * h / mL, and mean AUC inf was 3120 ng * h / mL (Table 17).

[0159] For VS-6063-25% SDD in Soluplus / PVP-A at a target dose of 10 mg API / kg over 4 sessions, the mean estimated half-life was approximately 3.2 hours. Mean C max and mean Tmax were 1770 ng / mL and 1.75 hours, respectively. The average AUC last was 8130 ng * ·h / mL, and the average AUC inf was 8170 ng * ·h / mL (Table 18).

[0160] For the physical mixture of VS-6063-25% with Soluplus / PVP-A at a target dose of 10 mg API / kg over 4 sessions, the average estimated half-life was approximately 3.7 hours. The average C max and average T max were 1460 ng / mL and 1.75 hours, respectively. The average AUC last was 7320 ng * ·h / mL, and the average AUC inf was 7410 ng * ·h / mL (Table 19).

[0161] For the VS-6063-10% SDD in EUDRAGIT L100-55 at a target dose of 10 mg API / kg over 4 sessions, the average estimated half-life was approximately 2.9 hours. The average C max and average T max were 1800 ng / mL and 1.88 hours, respectively. The average AUC last was 8720 ng * ·h / mL, and the average AUC inf was 8740 ng * ·h / mL (Table 20).

[0162] Based on the average pharmacokinetic data, when comparing the test formulations (VS-6063-25% SDD, VS-6063-25% physical mixture, and VS-6063-10% SDD) with the reference formulation (VS-6063), the relative bioavailability is improved, but there is significant variability among animals. The estimated values of the average relative bioavailability were 2.97 (CV 72.7%) for the 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 comparing the crossover data, animal number 4001 was the least exposed to the reference formulation (VS-6063), contributing to the overall variability among the treated animals (CV 52.8% for the average AUC inf ), and having the highest relative bioavailability among the test formulations.

[0163] Vomiting was observed in 3 out of 4 subjects administered the VS-6063-25% physical mixture, but the average relative bioavailability was similar to that of the other test formulations compared to the reference formulation.

[0164] VS-6063 concentration in plasma The average plasma concentration-time profile is shown in Figure 6 (linear scale).

[0165] After a single oral dose of the VS-6063-25% physical mixture at a target dose of 20 mg API / kg over 4 sessions, the plasma concentration increased rapidly and reached the maximum concentration within 0.25 to 1 hour (average 0.688 hours) after dosing. Subsequently, the average concentration decreased in an apparent first-order manner. The concentration of VS-6063 was quantifiable in all animals up to 24 hours after dosing (final time point).

[0166] Over 4 sessions, after a single oral dose of VS-6063-25% SDD at a target dose of 20 mg API / kg, plasma concentrations increased at a fairly rapid rate and reached maximum concentration within 0.25 to 2 hours (mean 1.31 hours) after dosing. Next, the mean concentration decreased in an apparently first-order manner. VS-6063 concentrations were quantifiable in all animals up to 24 hours after dosing (final time point).

[0167] Over 4 sessions, after a single oral dose of a physical mixture of VS-6063-50% at target doses of 10 mg API / kg and 20 mg API / kg, plasma concentrations increased at a fairly rapid rate and reached maximum concentration within 0.5 to 2 hours (mean 1.38 hours) after dosing for the 10 mg API / kg dose and within 0.5 to 4 hours (mean 2.13 hours) after dosing for the 20 mg API / kg dose. Next, the mean concentration decreased in an apparently first-order manner. VS-6063 concentrations were quantifiable in all animals up to 24 hours after dosing (final time point).

[0168] Plasma pharmacokinetics of VS-6063 Plasma pharmacokinetic parameters for VS-6063 are shown in Tables 15 and 16.

[0169] For the physical mixture of VS-6063-25% with Soluplus / PVP-A at a target dose of 20 mg API / kg over 4 sessions, the mean estimated half-life was approximately 3.0 hours. The mean C max and mean T max were 1670 ng / mL and 0.688 hours, respectively. The mean AUC last was 8670 ng * h / mL, and the mean AUC inf was 8700 ng * h / mL (Table 21).

[0170] For VS-6063-25% SDD in Soluplus / PVP-A at a target dose of 20 mg API / kg over 4 sessions, the mean estimated half-life was approximately 3.1 hours. The mean Cmax and mean T max were 1300 ng / mL and 1.31 hours, respectively. Mean AUC last was 5920 ng * ·h / mL, and mean AUC inf was 5940 ng * ·h / mL (Table 22).

[0171] For the physical mixture of VS-6063-50% with Soluplus / PVP-A at a target dose of 10 mg API / kg over 4 sessions, the mean estimated half-life was approximately 3.0 hours. Mean C max and mean T max were 680 ng / mL and 1.38 hours, respectively. Mean AUC last was 3390 ng * ·h / mL, and mean AUC inf was 3400 ng * ·h / mL (Table 23).

[0172] For the physical mixture of VS-6063-50% with Soluplus / PVP-A at a target dose of 20 mg API / kg over 4 sessions, the mean estimated half-life was approximately 3.5 hours. Mean C max and mean T max were 1160 ng / mL and 2.13 hours, respectively. Mean AUC last was 6900 ng * ·h / mL, and mean AUC inf was 6930 ng * ·h / mL (Table 24).

[0173] Observation of vomiting was consistent with lower exposure, while in other cases, there was no correlation.

[0174] Pharmacokinetic data suggest that the physical mixtures of VS-6063-50% at target doses of 10 mg API / kg and 20 mg API / kg are dose-proportional. AUC inf and C max normalized by mean dose may be similar.

[0175] Comparing the data from both studies, as summarized in Table 11 below, the physical mixture of VS-6063-25% (20 mg API / kg) and VS-6063-25% SDD (20 mg API / kg) had a mean AUC normalized by dose that was not proportional to dose compared to the physical mixture of VS-6063-25% (10 mg API / kg) and VS-6063-25% SDD (10 mg API / kg). inf and C max was not proportional to dose.

[0176]

Table 11

[0177]

Table 12

[0178] Conclusion Mean pharmacokinetic data suggest that the relative bioavailability can be improved when comparing VS-6063-25% SDD in Soluplus (10 mg API / kg), the physical mixture of VS-6063-25% with Soluplus (10 mg API / kg), and VS-6063-10% SDD in Eudragit L100-55 (10 mg API / kg) to VS-6063 (10 mg / kg), but there was variability among animals. The estimated mean relative bioavailability values were 2.97 (CV 72.7%) for the physical mixture of VS-6063-25%, 3.21 (CV 43.3%) for VS-6063-10% SDD, and 3.78 (CV 89.9%) for VS-6063-25% SDD.

[0179] Based on the average pharmacokinetic data, it is suggested that the physical mixtures of VS-6063-50% with Soluplus / PVP-A at target doses of 10 mg API / kg and 20 mg API / kg are proportional to the dose. The average AUC normalized by the average dose inf and the average C max can generally be similar.

[0180] Comparing the data from both studies, the physical mixtures of VS-6063-25% (20 mg API / kg) and VS-6063-25% SDD (20 mg API / kg) show less proportionality to the dose when compared with the average AUC normalized by the dose of the physical mixtures of VS-6063-25% (10 mg API / kg) and VS-6063-25% SDD (10 mg API / kg). Comparing the physical mixtures of VS-6063-50% at target doses of 10 mg API / kg and 20 mg API / kg with VS-6063 (10 mg / kg) based on the average pharmacokinetic data normalized by the dose, it is suggested that the relative bioavailability can be similar. inf and the average C max When compared, they are not as proportional to the dose. Based on the average pharmacokinetic data normalized by the dose, comparing the physical mixtures of VS-6063-50% at target doses of 10 mg API / kg and 20 mg API / kg with VS-6063 (10 mg / kg), it is suggested that the relative bioavailability can be similar.

[0181]

Table 13

[0182]

Table 14

[0183]

Table 15

[0184]

Table 16

[0185]

Table 17

[0186]

Table 18

[0187]

Table 19

[0188]

Table 20

[0189]

Table 21

[0190]

Table 22

[0191]

Table 23

[0192]

Table 24

[0193] Example 5 Clinical Study Protocol: Phase I Trial of the Safety, Bioavailability, and Pharmacodynamics of the Selected VS-6063 Formulation Study Design In a Phase I, non-blind, single-site, single-dose, partially randomized trial, the safety, bioavailability, and pharmacodynamics of the VS-6063 prototype and reference formulations were studied in healthy male subjects. This study consisted of four periods, each of which adhered to the same study design, with an age between 40 and 65 years and a body mass index between 18.0 and 35.0 kg / m 2Included were 24 healthy male subjects with a body mass index between . After a 28-day screening period, on the morning of the day before the dosing day (-1 day), they were admitted to the medical unit and dosed on the morning of day 1. Subjects in Regimens A and B were administered VS-6063 after an overnight fast of approximately 10 hours, while subjects in Regimens C and D were administered VS-6063 within 30 minutes of starting a high-fat breakfast (consumed within 25 minutes). The subjects remained on-site until 36 hours after dosing. There was a minimum washout period of 7 days between administrations of each regimen. Follow-up calls were made during Periods 3 and 4, on days 7 to 10 after the final dose, to confirm that the subjects were in good condition.

[0194]

Table 25

[0195] Statistical methods The pharmacokinetic (PK) parameter AUC, which is corrected for dose last , AUC inf and C max were subjected to formal statistical analysis to evaluate relative bioavailability and the presence of food effects. The natural logarithm transformation was applied to this PK parameter and analyzed using the mixed model technique. To compare the various regimens, the adjusted geometric mean ratio (GMR) and the 90% confidence interval (CI) for the adjusted GMR were calculated. The CI is based on the t-distribution, and its variability was estimated by a model using the Kenward-Roger method for calculating degrees of freedom.

[0196] Study results After administration of either 200 mg of the VS-6063 reference formulation tablets (containing VS-6063, microcrystalline cellulose PH102, Fastflo 316, sodium starch glycolate, and magnesium stearate) or 100 mg of the VS-6063 prototype formulation tablets (containing VS-6063, HPMCAS-HF, microcrystalline cellulose PH102, Fastflo 316, sodium starch glycolate, and magnesium stearate) in the fed and fasted states, the plasma concentration increased to the maximum level immediately after dosing. Thereafter, as VS-6063 was distributed and eliminated from the systemic circulation, a biphasic decline in plasma levels continued over the 24-hour sampling period. No actual difference in half-life could be determined between the reference and prototype formulations in either the fed or fasted state.

[0197] In the fasted state, the 100 mg prototype formulation administered in Regimen B resulted in considerably higher exposure compared to the 200 mg reference formulation in Regimen A. C max and AUC last The adjusted GMR and 90% CI for Regimen B / Regimen A based on Cmax and AUC were 421.33 (348.4%, 509.5%) and 433.05 (366.8%, 511.3%), respectively, and as a result of the change in formulation, the exposure was equal to a 4-fold increase. In addition to the improvement in bioavailability, there was evidence that the variability associated with the exposure parameters observed upon administration of the prototype formulation decreased from approximately 70% to 30%.

[0198] The comparison of the time taken to reach the maximum plasma concentration of VS-6063 was 2 to 4 times longer in the fed state than in the fasted state (C max and AUC last(evaluated by) indicating that food affects the absorption rate. Furthermore, determination of exposure after administration of 200 mg of the VS-6063 reference formulation in both fed and fasted states showed that exposure levels were higher in the fed state compared to the fasted state, which means that there is an effect of food on the reference formulation. Despite these effects, an increase in VS-6063 exposure was still observed when the prototype formulation was administered and compared to the reference formulation in the fed state. C max and AUC last The adjusted GMR and 90% CI for Regimen C / Regimen D based on inf were 129.8 and 125.1, respectively.

[0199] Overall, maximum exposure was achieved using the prototype formulation administered in the fasted state. Equal exposure with respect to AUC inf was also achieved using the prototype formulation in the fed state.

[0200] VS-6063 was well tolerated when administered in both fed and fasted states with both the reference and prototype formulations. There were no serious adverse events (AEs) or severe AEs reported during the study, and no subjects were discontinued as a result of an AE. The overall incidence of total AEs was low, with 12 AEs reported by 9 subjects. The incidence of AEs was highest for Regimen C (5 subjects) compared to Regimens A, B, and D (3 subjects, 2 subjects, and 1 subject, respectively). The most common AE was headache, which was reported by 3 subjects. All other AEs were reported by 1 subject. There were no subjects who reported AEs related to VS-6063, and almost all AEs were of moderate severity. There were no clinically significant findings in any laboratory evaluations, vital sign measurements, ECGs, or physical examinations.

Claims

1. 1. A composition comprising VS-6063 or a pharma- ceutically acceptable salt thereof for use in a method of treating cancer in a subject identified as having a mutational status in a gene selected from the group consisting of KRAS, INK4a / Arf, and p53, the method comprising the step of administering to the subject an effective amount of VS-6063 or a pharma- ceutically acceptable salt thereof, the composition comprising 10-30% by weight of VS-6063 or a pharma- ceutically acceptable salt thereof per weight of the composition.

2. The composition of claim 1 , wherein the cancer is lung cancer.

3. The composition of claim 2 , wherein the lung cancer is non-small cell lung cancer (NSCLC).

4. The composition of claim 3 , wherein the NSCLC is a KRAS mutated NSCLC.

5. The composition of claim 3, wherein the NSCLC is an INK4a / Arf mutated NSCLC.

6. The composition of claim 3 , wherein the NSCLC is a p53 mutated NSCLC.

7. The composition of any one of claims 1 to 6, wherein the cancer is metastatic.

8. The composition of any one of claims 1 to 7, further comprising the step of administering to the subject one or more anti-tumor or anti-cancer agents.

9. The one or more anti-tumor or anti-cancer agents may be 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, cytotoxic agents, antihormonal agents, and anti-cancer agents. The composition of claim 8, selected from the group consisting of androgenic drugs.

10. The composition according to any one of claims 1 to 9, wherein the VS-6063 or a pharma- ceutically acceptable salt thereof is administered 1, 2, 3 or 4 times per day.

11. The composition according to any one of claims 1 to 10, characterized in that the VS-6063 or a pharma- ceutically acceptable salt thereof is administered twice a day.

12. The composition according to any one of claims 1 to 11, characterized in that 100 to 800 mg of VS-6063 or a pharma- ceutically acceptable salt thereof is administered to the subject per day.

13. The composition according to any one of claims 1 to 12, characterized in that 200 mg of VS-6063 or a pharma- ceutically acceptable salt thereof is administered to the subject per day.

14. The composition according to any one of claims 1 to 12, characterized in that 400 mg of VS-6063 or a pharma- ceutically acceptable salt thereof is administered to the subject per day.

15. The composition according to any one of claims 1 to 14, further comprising a pharma- ceutically acceptable excipient.

16. The composition of claim 15, wherein the pharma- ceutically acceptable excipient is a mixture of two fillers.

17. 17. The composition of claim 16, wherein one filler is microcrystalline cellulose and the other filler is lactose.

18. The composition of claim 15, wherein the pharma- ceutically acceptable excipient is a disintegrant.

19. 20. The composition of claim 18, wherein the disintegrant is a modified starch.

20. The composition of claim 15, wherein the pharma- ceutically acceptable excipient is a lubricant.

21. 21. The composition of claim 20, wherein the lubricant is magnesium stearate.

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