High drug loading formulations of encorafenib

Abstract

This invention relates to high drug loading formulations comprising solid amorphous dispersions of encorafenib, together with one or more surfactants and polymers, and to methods of using such solid forms and pharmaceutical compositions in the treatment of proliferative diseases such as cancer.

Description

[0001] HIGH DRUG LOADING FORMULATIONS OF ENCORAFENIB

[0002] FIELD OF THE INVENTION

[0003] This invention relates to high drug loading amorphous solid dispersion forms of encorafenib, and to methods of using such solid forms in formulations for the treatment of proliferative diseases such as cancer.

[0004] BACKGROUND OF THE INVENTION

[0005] Encorafenib is an orally available, highly selective ATP-competitive small molecule RAF kinase inhibitor, which suppresses the RAF / MEK / ERK pathway in tumor cells expressing BRAF V600E mutations, including melanoma and colorectal cancer cell lines. The compound encorafenib, which is described by the chemical names “methyl N-{(2S)- 1 -[(4-{3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1 -(propan-2-yl)-1 H-pyrazol- 4-yl}pyrimidin-2-yl)amino]propan-2-yl}carbamate” and “methyl N-[(2S)-1-({4-[3-(5-chloro- 2-fluoro-3-methanesulfonamidophenyl)-1 -(propan-2-yl)-1 H-pyrazol-4-yl]pyrimidin-2- yl}amino)propan-2-yl]carbamate” (and is also referred to as “PF-07263896”, “LGX818”, and “ONO-7702”) has the structure:

[0006] Encorafenib

[0007] Encorafenib, and pharmaceutically acceptable salts thereof, and methods of treating cancer using encorafenib, are disclosed in International Publication No. WO 2011 / 025927 published March 3, 2011. Additional methods of treating cancer using encorafenib, and pharmaceutically acceptable salts thereof, are disclosed in International Publication Nos. WO 2013 / 070996 published May 16, 2013, WO 2014 / 018725 published January 30, 2014, WO 2014 / 025688 published February 13, 2014, WO 2014 / 072493 published May 15, 2014, WO 2014 / 147573 published September 25, 2014, WO 2017 / 210538 published December 7, 2017, and WO 2013 / 078264 published May 30, 2013.

[0008] BRAFTOVI® (encorafenib) is indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation (BRAFTOVI® (encorafenib), United States Prescribing Information, 2018, Colorado, Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc., the contents of which are incorporated herein by reference in their entirety). BRAFTOVI® (encorafenib) also indicated in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, after prior therapy (BRAFTOVI® (encorafenib), United States Prescribing Information, 2020, Colorado, Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc., the contents of which are incorporated herein by reference in their entirety).

[0009] The current dosage formulation for encorafenib comprises up to six capsules of 00 size for 450 mg or four capsules for 300 mg dosing. A more patient-centric dosage form would reduce the unit dose size and potentially the number of individual dosage forms required to be administered. Additionally, there is a need to ensure correct dosing by avoiding the opening of capsules due to large 00 capsule size for some patients.

[0010] BRIEF SUMMARY OF THE INVENTION

[0011] Each of the embodiments described below can be combined with any other embodiment described herein not inconsistent with the embodiment with which it is combined.

[0012] In one aspect, the invention provides high drug loading formulations having an inner phase and an external phase, in which the inner phase comprises amorphous solid dispersion (ASD) forms of encorafenib, or “methyl N-{(2S)-1 -[(4-{3-[5-chloro-2-fluoro-3- (methanesulfonamido)phenyl]-1 -(propan-2-yl)-1 H-pyrazol-4-yl}pyrimidin-2- yl)amino]propan-2-yl}carbamate” and “methyl N-[(2S)-1 -({4-[3-(5-chloro-2-fluoro-3- methanesulfonamidophenyl)-1 -(propan-2-yl)-1 H-pyrazol-4-yl]pyrimidin-2- yl}amino)propan-2-yl]carbamate” (and is also referred to as “PF-07263896”, “LGX818”, and “ONO-7702”) having the structure: with one or more pharmaceutically acceptable surfactants and polymers.

[0013] In one aspect, the invention provides an inner phase of amorphous solid dispersions (ASD) forms of encorafenib: and one or more surfactants and one or more polymers, wherein encorafenib is present in an amount of about 25%, 26%, 27%, 28%, 29%, 30%, 31 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41 %, 42%, 43%, 44% or 45%, 50% by weight of the inner phase amorphous solid dispersion (‘high drug loading formulations’). In one aspect of the invention encorafenib is present in the inner phase in a range from about 25% to about 50% by weight of the amorphous solid dispersion (ASD) (w / w), or in ranges therein. In an alternate aspect, the encorafenib is present in an amount from about 25% to about 40% by weight of the ASD. In an alternate aspect, the encorafenib is present in an amount from about 30% to about 40% by weight of the ASD. In still an alternate aspect, the encorafenib is present in an amount from about 33% to about 39% by weight of the ASD.

[0014] In another aspect of the high drug loading formulations of encorafenib, the one or more surfactants in the inner phase ASD are selected from the group consisting of low molecular weight surfactants (less than 2000 g / mol, <2 kDa) including sodium lauryl sulfate (SLS), Tween 20, Tween 80 (polyethylene glycol sorbitan monooleate), sorbitan monolaurate, sorbitan trioleate, docusate sodium, D-alpha-tocopheryl polyethyleneglycol succinate, cetyl trimethyl ammonium bromide, SPAN 85 and other pharmaceutically acceptable surfactants which are present in a total weight % (w / w) of the inner phase ASD in about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%, and ranges therein. In another preferred embodiment, the one or more surfactants are present in a total weight % (w / w) of the inner phase ASD in about 0.5%, 1 %, 2%, 3%, 4%, or less than about 5%. Preferred surfactants have been observed to function more advantageously than larger molecular weight surfactants such as polaxomer 188 which likely function on balance more as a process aid than as a dissolution enhancer.

[0015] In another aspect of the high drug loading formulations of encorafenib, the one or more polymers in the inner phase ASD include, but are not limited to, polyvinylpyrrolidine / vinyl acetate (e.g. PVP VA64), cellulose ethers, cellulose esters, polyacrylates, polymethacrylates, homopolymers of N-vinyl lactams, copolymers of N- vinyl lactams, polyacrylamides, and polyalkylene oxides; and mixtures thereof. In a further aspect of the high drug loading formulations of the invention, certain polymers of the invention include but are not limited to poly(methacylic acid-co-methyl methacrylate) (1 :1 ) (Eudragit L 100, and Eudragit L100-55 Evonik, Germany), Hypromellose acetate succinate, Hypromellose, Hypromellose phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (PEG 6000 / vinylcaprolactam / vinyl acetate copolymer in the ratio 13 / 57 / 30, marketed as Soluplus®, BASF, Ludwigshafen, Germany). In one aspect of the invention the one or more polymers are present in the inner phase ASD in a total weight amount of about 40% to about 79.5% w / w. In other aspects of the invention the one or more polymers are present in the inner phase ASD in an amount of about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, up to a maximum of about 79.5% w / w, and ranges therein.

[0016] In a further aspect, the high drug loading formulations of encorafenib have a reduced size of unit dose wherein the size of unit dose is less than about 20 mm, 15 mm or 10 mm in length. In a further aspect of the invention the high drug loading formulations of encorafenib have a reduced size of unit dose of about 8 mm for a round tablet, or about 13 mm to about 20 mm in length for an oval tablet (FIG 1 ). In a still further aspect of the invention the high drug loading formulations of encorafenib have a reduced size of unit dose of about 8 mm for a 50 mg round tablet, or about 13 mm to about 15 mm in length for a 75 mg oval tablet, or about 18 mm to about 20 mm in length for a 150 mg oval tablet (FIG 1 ). In a still further aspect, the reduced size of unit dose is about 13 mm or about 14 mm in length for a 75 mg oval tablet, or about 18 mm or about 19 mm in in length for a 150 mg oval tablet (FIG 1 ).

[0017] Tablet embodiments of the invention include 25 mg, 50 mg, 75 mg or 150 mg forms to replace the 50 and 75 mg capsule form to decrease size or number of doses for patient acceptance. The patient-centric size attributes of the tablets of the current invention are enabled through the use of increased drug load in hot melt extrusion (HME) while also maintaining performance and stability.

[0018] In one aspect, encorafenib ASD is further processed into particle sizes having a diameter size Dso of 100 - 200 pm and diameter size 90%, D90, of 200 - 350 pm.

[0019] The high drug loading formulations of the invention include an external phase which comprises excipients such as:

[0020] High drug loading amorphous solid dispersions of encorafenib are further formulated into solid oral dosage forms (tablets or capsules) by inclusion of the below additional excipients, which form the external phase of such a formulation:

[0021] • Compression aid / Ductile filler - Microcrystalline cellulose

[0022] • Compression aid / Brittle filler - Mannitol, lactose monohydrate or Dibasic calcium phosphate

[0023] • Flow aid or enhancer - Colloidal silicon dioxide or talc

[0024] • Disintegrant - Crospovidone, Croscarmellose sodium, low-sub hydroxypropyl cellulose, starch 1500 or Sodium starch glycolate

[0025] • Lubricant - glyceryl behenate, magnesium stearate or sodium stearyl fumarate

[0026] In different embodiments of the present invention, the external phase comprises various ranges of %w / w of acidifier, filler, disintegrant, flow aid or enhancer and lubricant. For instance, the present external phase can comprise 0-40% acidifier, 20-70% filler, 0-30% disintegrant, 0-10% flow enhancer and 0-10% lubricant, preferably 30-70% filler, 5-20% disintegrant, 0-5% flow enhancer and 0.1 -5% lubricant, more preferably 20-50% filler, 1 -15% disintegrant and 0.1 -5% lubricant. In one embodiment, neither the external phase nor internal phase comprises an acidifier. In another embodiment where a lubricant is present, neither the external phase nor internal phase comprises a flow aid. In different embodiments of the present invention, the solid oral dosage form, for example, capsules or tablets, are a blend of the internal and external phases in a ratio of from 100:0 to 30:70, preferably 80:20 to 40:60, most preferably 75:25 to 50:50.

[0027] In one aspect, the high drug loading formulations of the invention provides amorphous solid dispersions of encorafenib with impurities less than 0.5% w / w after 13 weeks of storage at 25°C / 60% relative humidity or at 40 °C / 75% relative humidity.

[0028] In one aspect, the invention provides a high drug loading pharmaceutical formulations comprising amorphous solid dispersions of encorafenib, one or more surfactants and one or more polymers and one or more pharmaceutically acceptable tablet excipients including a binder, a filler, a flow aid, a disintegrant, a glidant, and a lubricant in ranges.

[0029] In one aspect, the invention provides a high drug loading tablet formulation comprising an amorphous solid dispersion of encorafenib.

[0030] In a further embodiment, the high drug loading formulations of the invention are used in methods or medicaments to treat a proliferative disease, wherein the proliferative disease is a cancer. In another embodiment, the cancer is a B-RAF-associated cancer.

[0031] In yet another aspect, the high drug loading formulations of amorphous solid dispersion of encorafenib, according to the aspects or embodiments described herein, are used in the manufacture of a medicament for the treatment of cancer.

[0032] In one embodiment, the B-RAF associated cancer is associated with a BRAF V600E or V600K mutation.

[0033] In one embodiment, the method of treating a proliferative disease further comprises administration of a therapeutically effective amount of one or more additional anticancer agents.

[0034] In one embodiment, the invention relates to administration of the high drug loading formulations of amorphous dispersion of encorafenib, in a method of treating a BRAF cancer in combination with a MEK inhibitor, including but not limited to binimetinib.

[0035] In a still further embodiment, the cancer is non-small cell lung cancer. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter. The present invention may be understood more readily by reference to the following description of the embodiments of the invention and the Examples included herein. It is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0036] E1 A pharmaceutical formulation of the invention comprisin an inner phase of

[0037] (a) an amorphous solid dispersion comprising about 25 mg, 50 mg, 75 mg, 100 mg or 150 mg of encorafenib:

[0038] (b) one or more surfactants,

[0039] (c) one or more polymers; and optionally an external phase comprising (d) one or more pharmaceutically acceptable excipients; wherein the encorafenib is present in an amount of about 25% to about 45% w / w, and the surfactant is selected from the group consisting of sodium lauryl sulfate, Tween 80, sorbitan monolaurate, sorbitan trioleate, docusate sodium, D-alpha-tocopheryl polyethyleneglycol succinate, and cetyl trimethyl ammonium bromide.

[0040] E2 The formulation of E1 , wherein encorafenib is present in an amount of about 30% to about 45% w / w.

[0041] E3 The formulation of any of the above embodiments, wherein encorafenib is present in an amount of about 33% to about 39% w / w. E4 The formulation of any of the above embodiments, wherein the surfactant is sodium lauryl sulfate.

[0042] E5 The formulation of any of the above embodiments, wherein the formulation is present in a unit dose which is less than about 20 mm in length.

[0043] E6 The formulation of any of the above embodiments, wherein the formulation is present in a unit dose which is less than about 15 mm in length.

[0044] E7 The formulation of any of the above embodiments, wherein the size of the unit dose is less than 10 mm.

[0045] E8 The formulation of any of the above embodiments, wherein the surfactant is present in an amount of about 0.5% to about 20% w / w.

[0046] E9 The formulation of any of the above embodiments, wherein the surfactant is present in an amount of about 2% to about 15% w / w.

[0047] E10 The formulation of any of the above embodiments, wherein the surfactant is present in an amount of about 2% to about 7% w / w.

[0048] E11 The formulation of any of the above embodiments, wherein the polymer is present in an amount of about 40% to about 79.5% w / w.

[0049] E12 The formulation of any of the above embodiments, wherein the polymer is present in an amount of about 50% to about 65% w / w.

[0050] E13 The formulation of any of the above embodiments, wherein the polymer is present in an amount of about 55% to about 60% w / w.

[0051] E14 The formulation of any of the above embodiments, wherein the polymer is selected from the group consisting of vinyl acetate polymers, graft polymers of polyethylene glycol, polyvinyl caprolactam, polyvinyl acetate, high molecular weight polyalkylene oxides, cellulose polymers or HPMCAS polymers.

[0052] E14a The formulation of any of the above embodiments, wherein the polymer is selected in the group comprising a copolymer of vinyl acetate and vinylpyrrolidone.

[0053] E15 The formulation of any of the above embodiments, wherein the polymer is polyvinylpyrrolidone vinyl acetate 6:4 co-polymer.

[0054] E16 The formulation of any of the above embodiments, wherein the pharmaceutically acceptable excipient is selected from a binder, filler, disintegrant, glidant or lubricant.

[0055] E17 The formulation of any of the above embodiments, wherein the external phase comprises excipients, such as a compression aids (ductile fillers or brittle fillers), flow aids, disintegrants and lubricants;

[0056] E18 The formulation of any of the above embodiments, wherein the pharmaceutically acceptable excipients include one or more of microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide or magnesium stearate.

[0057] E19 The formulation of any of the above embodiments, wherein the formulation does not include an acidifier.

[0058] E20 The formulation of any of the above embodiments, wherein the formulation does not include a flow aid.

[0059] E21 The formulation of any of the above embodiments, wherein the pharmaceutically acceptable excipients are present in the amounts of

[0060] (a) 14% to 50% of microcrystalline cellulose;

[0061] (b) 14% to 50% of lactose monohydrate;

[0062] (c) 1 % to 6% of croscarmellose sodium;

[0063] (d) 0.1 % to 1.25% of colloidal silicon dioxide; and

[0064] (e) 0.25% to 1 .25% of magnesium stearate. E22 The formulation of any of the above embodiments, wherein the formulation is a tablet or capsule.

[0065] E23 The formulation of any of the above embodiments, wherein the formulation is a tablet.

[0066] E24 The formulation of any of the above embodiments, wherein the amorphous solid dispersion comprises about 50 mg, 75 mg, or 150 mg of encorafenib.

[0067] E25 The formulation of any of the above embodiments, wherein the amorphous solid dispersion comprises about 50 mg of encorafenib.

[0068] E26 The formulation of any of the above embodiments, wherein the amorphous solid dispersion comprises about 75 mg of encorafenib.

[0069] E27 The formulation of any of the above embodiments, wherein the amorphous solid dispersion comprises about 150 mg of encorafenib.

[0070] EM1 A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical formulation according to any one of the above E embodiments.

[0071] EM2 The method according to EM1 , wherein said cancer is a BRAF-associated cancer.

[0072] EM3 The method according to any of the above EM embodiments, wherein said cancer expresses a BRAF V600 mutation.

[0073] EM4 The method according to any of the above EM embodiments, wherein the method further comprises administration of a MEK inhibitor.

[0074] EM5 The method according to any of the above EM embodiments, wherein the method further comprises administration of binimetinib. EM6 The method according to any of the above EM embodiments, wherein the cancer is non-small cell lung cancer.

[0075] EMF1 A pharmaceutical formulation comprising an amorphous solid dispersion of encorafenib according to any one of the above E embodiments, for use in the manufacture of a medicament for the treatment of cancer.

[0076] EMF2 The pharmaceutical formulation of EMF1 , wherein the cancer is non-small cell lung cancer.

[0077] BRIEF DESCRIPTION OF THE DRAWINGS

[0078] FIG. 1A. Tablet Components of Current Formulation Versus High Drug Loading Formulation.

[0079] FIG. 1 B. Side-by-side Current Commercial Capsule versus High Drug Loading Tablet Embodiments.

[0080] FIG. 2. Summary of tablet formulation process characteristics.

[0081] FIG. 3. Design of high drug load tablet formulations comprising sodium lauryl sulfate (SLS) by 18 mm hot melt extrusion (HME) A.

[0082] FIG. 4. Compression plan for tablet formulations (HME Formulation B) comprising 4.76% SLS by HME: AQ-21 -0043A; 43B; 43C; 43D.

[0083] FIG. 5. Dissolution data for tablet formulation (HME Formulation B); AQ-21 - 0043A; 43B; 43C; 43D.

[0084] FIG. 6. Intrinsic dissolution of with polymer PVPVA64 with variable drug loading of encorafenib at about 23%, 30%, 35%, 40%, 50% w / w in acetate buffer pH 4.5. FIG. 7. Intrinsic dissolution of with polymer PVPVA64 with variable drug loading of encorafenib and Intra-HME Additives: 221 A (27.3% DL / Poloxamer188 9%), 222A (43.5% DL / P188 13%), 223A (16.7% DL / succinic acid16.7%), 224A (37.5%DL / succinic acid 25%), 224A (37.5% DL / SLS 4.8%), 225A (28.6% DL / SLS 4.8%), 226A (47.6%DL / 4.8% SLS) w / w in dissolution medium acetate buffer pH 4.5.

[0085] FIG. 8. Kinetic solubility of encorafenib with PVPVA64 HMEs with Variable Drug Loading and Intra-HME Additives in dissolution medium acetate buffer pH 4.5: encorafenib drug substance compared to milled extrudates 45.45% DL / 9.1 % SLS; 36.40% DL / 9.1 % SLS; 45.45%DL / 7.5% SLS, all w / w.

[0086] FIG. 9. Kinetic solubility of encorafenib with PVPVA64 HMEs with Variable Drug Loading and Intra-HME Additives in dissolution medium reflecting Fasted State Simulated Intestinal Fluid (FaSSIE, pH 6.5): encorafenib drug substance compared to milled extrudates 45.45% DL / 9.1 % SLS; 36.4%DL / 9.1%SLS, 37.5%DL / 7.5% SLS; 17.5 Succinic Acid; 37.5%DL / 7.5% SLS; 37.5% DL / 17.5% Succinic Acid, all w / w.

[0087] FIG. 10. USPII Dissolution Testing of Encorafenib: PVPVA64 with Variable Drug Loading and Intra-HME Additives formulated in Tablets 221 A - 227A: 221 A (27.3% DL / Poloxamer188 9%), 222A (43.5% DL / P188 13%), 223A (16.7% DL / succinic acid16.7%), 224A (37.5%DL / succinic acid 25%), 224A (37.5% DL / SLS 4.8%), 225A (28.6% DL / SLS 4.8%), 226A (47.6%DL / 4.8% SLS); 227A (37.5%DL / succinic acid + 15 mg extragranular succinic acid); all w / w in dissolution medium acetate buffer pH 4.5.

[0088] FIG. 11. USPII Dissolution Testing of Encorafenib: PVPVA64 with Variable Drug Loading and Intra-HME Additives formulated in Tablets 231A - 233A in dissolution medium acetate buffer pH4.5: 231 A (45.5% DL / 9.1 %SLS); 232A (36.4%DL / 9.1 %SLS); 233A (37.5%DL, 7.5%SLS,17.5% succinic acid), all w / w.

[0089] FIG. 12. Schematic of Manufacturing Process Flow for Relative Bioavailability Study Batches FIG. 13. USPII Dissolution Testing of encorafenib PVPVA64 HMEs with Variable SLS Levels Formulated into Tablets Containing MCC as the Diluent in Dissolution Medium Acetic Buffer pH 4.5.

[0090] FIG. 14. USPII Dissolution Testing of encorafenib PVPVA64 HMEs with Variable SLS Levels Formulated into Tablets Containing MCC and Lactose as the Diluent in Dissolution Medium Acetic Buffer pH 4.5.

[0091] FIG. 15. USPII Dissolution Testing of encorafenib PVPVA64 HMEs with Variable SLS Levels and HME PSD (d90) Formulated into Tablets Containing MCC (no Lactose) as the Diluent in Dissolution Medium Acetic Buffer pH 4.5.

[0092] FIG. 16A, 16B and 16C. USPII Dissolution Performance in Multi-Media of High Drug Loaded Encorafenib PVPVA64 HMEs Formulated into Tablets as Compared Against Commercial Capsule Formulation with Low HME Drug Loading.

[0093] DETAILED DESCRIPTION OF THE INVENTION

[0094] It is to be understood that the terminology used herein is to be given its traditional meaning as known in the relevant art.

[0095] As used herein, the singular form “a”, “an”, and “the” include plural references unless indicated otherwise.

[0096] The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (‘glass transition’). In certain embodiments, an amorphous form of a substance may be substantially free of crystalline forms. As used herein, the term “substantially free of crystalline forms” means an amorphous form of a substance may contain less than about 1 %, 2%, 3%, 4%, 5% of one or more crystalline forms on a weight basis. The term “anhydrous” as used herein, refers to a crystalline form that only contains the compound as part of its crystalline lattice.

[0097] The term “solvate” describes a molecular complex comprising a compound (e.g., the active pharmaceutical ingredient (API) of a drug product) and a stoichiometric or non- stoichiometric amount of one or more solvent molecules (e.g., water or ethanol). When the solvent is tightly bound to the compound, the resulting complex will have a well- defined stoichiometry that is independent of humidity. When, however, the solvent is weakly bound, as in channel solvates and hygroscopic compounds, the solvent content will be dependent on humidity and drying conditions. In such cases the complex will often be non-stoichiometric.

[0098] The term "hydrate" describes a solvate comprising the compound and a stoichiometric or non-stoichiometric amount of water. A “monohydrate” is a hydrate comprising one molecule of water per molecule of compound (i.e. , a 1 :1 stoichiometry of water to compound).

[0099] The term “substantially pure” means a particular crystalline form includes less than 10%, for example less than 5%, for example less than 3%, for example less than 1 % by weight of any other physical forms of the compound.

[0100] The term “polymer” refers to a compound comprising repeating structural units (monomers) connected by covalent chemical bonds. Polymers may be further derivatized, crosslinked, grafted or end-capped. Non-limiting examples of polymers include copolymers, terpolymers, quaternary polymers, and homologues.

[0101] The term “copolymer” refers to a polymer consisting essentially of two or more different types of repeating structural units (monomers).

[0102] The term “solid dispersion” refers to a solid state which comprises at least two constituents, wherein one constituent is homogenously dispersed significantly evenly throughout the other constituent or constituents. It includes solid or glassy solutions, i.e., the dispersion of the constituents is in such a way that the composition is chemically and physically homogenous in nature. In one embodiment, the first constituent is an active pharmaceutical ingredient (API), (i.e., encorafenib), and the second constituent is a matrix that comprises one or more surfanctants and one or more polymers, wherein the API is dispersed significantly uniformly within the matrix (the polymer). Without limitation, solid dispersions may be physically classified as a eutectic mixture, a solid solution, a glass solution or suspension, an amorphous precipitate in a glassy or crystalline carrier, a complex, a complexed formation, or a combination of the different systems. In addition, solid dispersions may be prepared using various techniques known to those skilled in the art, such as by co-dissolving the API (i.e. , encorafenib) and surfactant and / or polymer in a solvent, then spray-drying, spray-congealing, evaporating, curing or microwaving, blending and direct compression, co-precipitating or mechanical admixture at an elevated but non-melting temperature, wet granulation, extrusion-spheronization, melt fusion, hot melt extrusion (HME) and the like.

[0103] The term “amorphous solid dispersion” refers to a solid dispersion as defined herein, wherein encorafenib is in amorphous form.

[0104] Amorphous solid dispersions

[0105] In one embodiment, the invention provides an amorphous solid dispersion formulation comprising encorafenib, one or more pharmaceutically acceptable surfactants and polymers.

[0106] The amorphous solid dispersion formulations provided herein have advantages over current formulations of encorafenib by providing improved, smaller dosage forms for enhanced patient experience. The current dosage forms are in capsule forms, with some patients commenting that the number of capsules, as much as six, has negatively impacted the patient experience.

[0107] Additional drivers for the improved tablet formulations include improved physical stability for primary packaging flexibility. The commercial capsule formulation can more easily break during transport and storage.

[0108] Suitable polymers for use in the subject solid dispersions include, but are not limited to, cellulose esters; cellulose ethers; polyacrylates; polymethacrylates; homopolymers and copolymers of N-vinyl lactams; polyacrylamides; vinyl acetate polymers; graft copolymers of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate; and polyalkylene oxides; and mixtures thereof.

[0109] In some embodiments, the polymer is a cellulose ether polymer. For example, the polymer may be selected from methyl cellulose, ethyl cellulose, (hydroxyalkyl)cellulose (e.g., hydroxyethyl cellulose (HEC) or hydroxypropyl cellulose (HPC)), or (hydroxyalkyl)alkyl-cellulose (e.g., hydroxypropyl methyl cellulose (HPMC or hypromellose)). In some embodiments, the polymer is methyl cellulose. In some embodiments, the polymer is ethyl cellulose. In some embodiments, the polymer is HEC. In some embodiments, the polymer is HPC. In some embodiments, the polymer is HPMC.

[0110] In some embodiments, the polymer is a cellulose ester polymer. In some embodiments, the cellulose ester polymer is cellulose phthalate (e.g., cellulose acetate phthalate or hypromellose phthalate (HPMCP)) or cellulose succinate (e.g., hypromellose succinate (HPMCS) or hypromellose acetate succinate (HPMCAS)). In some embodiments, the cellulose ester polymer is HPMCP. In some embodiments, the cellulose ester polymer is HPMCAS.

[0111] Cellulose ester polymers described herein may be further defined by a particular grade. For example, an HPMC polymer may be selected from HPMC E3, HPMC E5, HPMC E6, HPMC El 5, HPMC K3, HPMC A4, or HPMC A 15. In some embodiments, the HPMCAS is HPMCAS-L, HPMCAS-M, HPMCAS-H, HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LG, HPMCAS-MG, or HPMCAS-HG. In one embodiment, the HPMCP is HPMCP 50 or HPMCP 55. In one embodiment, the cellulose ester polymer is HPMCP. In one embodiment, the cellulose ester polymer is HPMCP 50. In one embodiment, the cellulose ester polymer is HPMCAS-L, HPMCAS-M, or HPMCAS-H. In one embodiment, the cellulose ester polymer is HPMCAS-L. In one embodiment, the cellulose ester polymer is HPMCAS-LG.

[0112] In one embodiment, the polymer is a polyacrylate or polymethacrylate. In one embodiment, the polymer is methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylates), or poly(hydroxyalkyl methacrylates). Suitable polyacrylate or polymethacrylate include, without limitation, methacrylic acid-methyl methacrylate copolymer (1 :1 ) sold under the Eudragit™ trademark of Rohm GmbH as Eudragit RS 100, Eudragit L 100, Eudragit L 100-55, and Eudragit S 100, products of other manufacturer’s equivalent thereto, and mixtures thereof. In one embodiment, the polymer is Eudragit RS 100. In one embodiment, the polymer is Eudragit S 100.

[0113] In one embodiment, the polymer is a homopolymer or copolymer of N-vinyl lactams. In one embodiment, the polymer is a homopolymer or copolymer of N-vinyl pyrrolidone. In one embodiment, the polymer is a homopolymer of polyvinylpyrrolidone (PVP or povidone) or a copolymer (e.g., those comprising monomers of N-vinyl pyrrolidone and vinyl acetate (copovidone) or N-vinyl pyrrolidone and vinyl propionate). Suitable povidones include, without limitation, those having a K-value (a measure of viscosity of an aqueous solution of the povidone) of about 12, about 15, about 17, about 25, about 30 or about 90, and mixtures thereof. In one embodiment, the polymer is polyvinylpyrrolidone K30. In one embodiment, the polymer is poly(l-vinylpyrrolidone-co- vinyl acetate).

[0114] In one embodiment, the polymer is a vinyl acetate polymer (e.g., copolymers of vinyl acetate and crotonic acid, polyvinyl acetate, polyvinyl alcohol, or partially hydrolyzed polyvinyl acetate). In one aspect, the polymer is a copolymer of vinyl acetate and vinylpyrrolidone, in particular polyvinylpyrrolidone vinyl acetate 6:4 co-polymer (Copovidone, Kollidon PVP / VA64).

[0115] In one embodiment, the polymer is a polyacrylamide.

[0116] In one embodiment, the polymer is a graft copolymer of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g., SOLUPLUS™ of BASF or equivalent product). In one embodiment, the polymer is an oligo- or polysaccharide (e.g., carrageenans, galactomannans, or xanthan gum).

[0117] In one embodiment, the polymer is a polyalkylene oxide. In one embodiment, the polymer is a high molecular weight polyalkylene oxide. In one embodiment, the polymer is polyethylene oxide (PEG or PEG) or copolymers of ethylene oxide and propylene oxide (poloxamers). Suitable PEGs include, without limitation, PEG 400, PEG 600, PEG 1450, PEG 3350, PEG 4000, PEG 6000, PEG 8000, PEG 20000 and mixtures thereof. Suitable poloxamers include, without limitation, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407 and mixtures thereof. In one embodiment, the polymer is polyethylene glycol) methyl. In one embodiment, the polymer is polyethylene glycol 6000 (PEG 6000).

[0118] In one embodiment, the polymer is selected from methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, cellulose acetate phthalate (CAP), hypromellose (HPMC), hydroxypropyl cellulose, hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), polyethylene glycol) methyl, poly-ethylene glycol vinyl acetate vinylcaprolactam (e.g., SOLUPLUS™), polyethylene glycol 6000 (PEG 6000), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVP-VA), Poly (ethyl aery late-co-m ethyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1 :2:0.1 (Eudragit RS 100), methyacrylic acid copolymer type B (Eudragit S 100), Sureteric, Pluronic F-68 and polyoxyethylene (20) sorbitan monooleate (Tween 80). In one embodiment, the polymer is selected from HPMC, HPMCAS-L, HPMCAS- M, HPMCAS-H, PVP-VA, Eudragit L100 or Soluplus.

[0119] In one embodiment, the polymer is selected from HPMCAS grade L (HPMCAS-L), HPMCAS grade M (HPMCAS-M) and HPMCAS grade H (HPMCAS-H). In one embodiment, the polymer is HPMCAS-L.

[0120] An amorphous solid dispersion disclosed herein may be characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), modulated differential scanning calorimetry (mDSC), scanning electron microscopy (SEM), Karl Fischer water titration (KF), residual solvent, particle size, bulk density, tapped density, chiral high pressure liquid chromatography (HPLC) and achiral HPLC.

[0121] In one embodiment, an amorphous solid dispersion disclosed herein was characterized by PXRD.

[0122] In one embodiment, the amorphous solid dispersion comprises less than 5% of impurities by weight, such as less than 2% impurities by weight, such as less than 1.5% impurities by weight, such as less than 1.0% impurities by weight, such as less than 0.5% impurities by weight of the amorphous solid dispersion. In some embodiment, the amorphous solid dispersion comprises between about 0.20% and 1.1 % impurities by weight of the amorphous solid dispersion. In one embodiment, the solid dispersion comprises less than 2% of impurities by weight of the amorphous solid dispersion after 13 weeks of storage at 25°C / 60% relative humidity. In one embodiment.

[0123] In one embodiment, amorphous solid dispersions provided in tablet formulation herein are appropriate for use in a solid formulation for oral administration.

[0124] In one embodiment, the formulation containing the amorphous solid dispersion is obtained by spray drying. In one embodiment, the solid dispersion is obtained by melting, solvent evaporation, spray drying, fusion, kneading, co-grinding, lyophilization, holt melt extrusion, melt agglomeration, or supercritical fluid technology. The amorphous solid dispersions of the invention may be formulated by any process known to those skilled in the art as described in Sonal V. Bhujbal et al., Acta Pharmaceutica Sinica B, Volume 11 , Issue 8, August 2021 , Pages 2505-2536 "Pharmaceutical amorphous sold dispersions: a review of manufacturing strategies”.

[0125] In one embodiment, the invention provides a process for preparing an amorphous solid dispersion described herein, comprising: (a) providing a solution of encorafenib, surfactant and the polymer in a solvent; and (b) removing the solvent to provide the solid dispersion. In one embodiment, the solvent comprises a mixture of acetone and water. In one embodiment, the solvent comprises acetone. In one embodiment, the solvent comprises up to 10% water. In one embodiment, the solvent is removed by freeze evaporation or spray drying. In one embodiment, the solvent is removed by spray drying. The process may further comprise drying the solid dispersion in a tray dryer, thereby removing residual solvent. In one embodiment, the solution of encorafenib is prepared using anhydrous crystalline form of encorafenib. In one embodiment, the solution of encorafenib is prepared using hydrate crystalline form of encorafenib.

[0126] In one embodiment, step (a) comprises adding encorafenib to the solvent, for example a mixture of acetone and water (e.g., 9 / 1 acetone / water) and mixing the resultant mixture until encorafenib is fully dissolved, or until a clear solution is obtained. Step (a) may further comprise adding a suitable polymer (e.g., HPMCAS-L, HPMCAS-M, HPMC E3, or PVP-PA) to the solution of encorafenib in an acetone / water mixture, followed by mixing. In one embodiment, the removing of solvent in step (b) comprises spray drying the solution of encorafenib, the surfactant and the polymer in the solvent. Spray drying can be completed in any suitable dryer. In one embodiment, the inlet temperature is elevated, such as between 90 to 160 °C. The outlet temperature may also be elevated, such as between 30 to 70 °C. In one embodiment, the drying gas flow rate is about 500 g / min.

[0127] Secondary drying is optionally used to remove residual solvent remaining after spray drying. Secondary drying may comprise tray drying. In one embodiment, the solid dispersion is loaded into the trays of the tray dryer to a depth of approximately 1 inch. The temperature of the dryer is typically elevated, such as from 30 to 50 °C, for example 40 °C. In one embodiment, secondary drying has a duration of 1 to 24 hours, such as 6 to 18 hours, or about 15 hours.

[0128] In one embodiment, the present disclosure provides a process for preparing a solid dispersion disclosed herein, comprising (a) providing a solution of encorafenib, one or more surfactants or one or more polymers in a solvent; and (b) removing the solvent to provide the solid dispersion. The polymer can be selected from any suitable polymer described herein, such as HPMCAS, for example HPMCAS-L. The solvent can be selected from any suitable solvent. In one embodiment, the solvent is a mixture of acetone and water. In one embodiment, the solvent is removed by spray drying. Pharmaceutical Formulations

[0129] In one embodiment, provided herein are high drug loading pharmaceutical formulations in tablet form for delivery of encorafenib.

[0130] In one embodiment, a high drug loading pharmaceutical formulation comprises an amorphous solid dispersion of encorafenib, including one or more surfactants and polymers, further comprising optional pharmaceutically acceptable excipients. In one embodiment, the pharmaceutical formulation is formulated for oral delivery.

[0131] A high drug loading pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., encorafenib), one or more surfactants and polymers, and one or more pharmaceutically acceptable excipients and / or carriers, including but not limited to, inert solid diluents and fillers, binders, diluents, disintegrants, lubricants, glidants, coatings. A solid dispersion of the present disclosure may be formulated in any suitable pharmaceutical formulation. In some embodiments, the one or more pharmaceutically acceptable excipients are selected from microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.

[0132] Pharmaceutical formulations may be provided in any suitable form, which may depend on the route of administration. In one embodiment, the high drug loading pharmaceutical formulation disclosed herein can be formulated in a dosage form for administration to a subject. In one embodiment, the dosage form is formulated for oral administration. For example, the high drug loading pharmaceutical formulation can be formulated in the form of a pill, a tablet, a capsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or a powder. In one embodiment, the high drug loading pharmaceutical formulation is formulated in the form of a pill, a tablet, or a capsule.

[0133] In some embodiments, a high drug loading pharmaceutical formulation of the invention is formulated as a capsule or a tablet. In one embodiment, the pharmaceutical formulation is a tablet.

[0134] In one embodiment, the one or more pharmaceutically acceptable excipients comprise a binder, a filler, a disintegrant, a glidant and a lubricant. In one embodiment, the one or more pharmaceutically acceptable excipients further comprise a coating. In one embodiment, the one or more pharmaceutically acceptable excipients comprise a filler, a disintegrant, a lubricant, a glidant and a coating. In one aspect, the invention provides a pharmaceutical composition comprising an amorphous solid dispersion according to the invention, a filler, a disintegrant, a glidant, and a lubricant. In another aspect, said pharmaceutical composition further comprises a coating.

[0135] In one aspect of the present invention, an inner phase is prepared. The inner phase is am amorphous solid dispersion comprising encorafenib in an amount of about 25% to about 45% w / w, which is composed, for example, of one or more polymers, one or more low molecular weight surfactants (including and not limited to SLS) and optional additional excipients, which are known in the art, followed by milling to reduce particle size.

[0136] Prior to tableting or encapsulation, the inner phase is preferably combined with additional excipients, which are collectively referred to herein as the external phase. One or more of an acidifier, filler, a disintegrant, a flow enhancer and a lubricant can be typically included in the external phase. In another aspect of the invention, the formulation omits one or more of an acidifier or flow aid..

[0137] In one embodiment, a pharmaceutical formulation of the invention further comprises a filler in an amount from about 14% up to about 50% by weight of the pharmaceutical composition. Suitable fillers include microcrystalline cellulose, pregelatinized starch, sugars (lactose monohydrate, maltodextrin), sugar alcohols (mannitol, sorbitol), maltodextrin, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose and sucrose esters. In one embodiment, the filler is microcrystalline cellulose or lactose monohydrate or combinations thereof. In one embodiment, the filler is lactose monohydrate. In one aspect, said pharmaceutical formulation of the invention comprises an external phase which comprises the filler.

[0138] The pharmaceutical formulation of the invention may comprise a binder but in preferred embodiments, the formulation does not comprise a binder.

[0139] In one embodiment, a pharmaceutical formulation of the invention comprises a disintegrant. In one aspect of the embodiment, the formulation comprises an external phase which comprises the disintegrant.

[0140] In one embodiment, a pharmaceutical formulation comprises a disintegrant in an amount from about 1.0% to about 10.0% by weight of the solid dosage form. Suitable disintegrants include croscarmellose sodium, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. In one embodiment, the disintegrant is croscarmellose sodium. In one aspect, said pharmaceutical formulation of the invention comprises an external phase which comprises the disintegrant.

[0141] In one embodiment, a pharmaceutical formulation of the invention comprises a glidant. In one embodiment, a pharmaceutical formulation of the invention further comprises a glidant in an amount from about 0.1 % to about 1.25% by weight of the pharmaceutical formulation. Suitable glidants include colloidal silicon dioxide, tricalcium phosphate, and talc. In one embodiment, the glidant is colloidal silicon dioxide. In another aspect of the embodiment, the formulation of the invention comprises an external phase which comprises the glidant.

[0142] In one embodiment, the pharmaceutical formulation comprises a lubricant. In one embodiment, the pharmaceutical formulation of the invention comprises a lubricant in an amount from 0.25% to about 1.25% by weight of the pharmaceutical composition. Suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. In one embodiment, the lubricant is magnesium stearate. In another aspect of the embodiment, the formulation comprises an external phase which comprises the lubricant.

[0143] In one embodiment, a pharmaceutical formulation of the invention comprises a coating. In one embodiment, the coating is HPMC or polyvinyl alcohol (PVA)-based, such as Opadry White, Opadry II, Opadry QX or Opadry TF. The pharmaceutical formulation may comprise a coating in an amount from 1 % to 7% by weight of the pharmaceutical formulation, such as about 3% to about 4% by weight. In one embodiment, the pharmaceutical formulation comprises a coating in an amount of about 4% by weight of the pharmaceutical composition.

[0144] In one embodiment, a pharmaceutical formulation comprising an amorphous solid dispersion comprising encorafenib is selected from tablet formulations comprising the components shown in Tables 1 to 3 below.

[0145] Table 1 : Tablet formulation comprising 75 mg of encorafenib

[0146] Table 2: Tablet formulation comprising 75 mg of Encorafenib

[0147] Table 3: Comparative table of inner phase HMEs (amorphous solid dispersions) with Encorafenib A, B, and C. Tablet formulations of the invention are able to maintain dissolution performance as drug loadings are increased in surfactant (SLS, with PVP VA64)-based amorphous solid dispersions (ASDs) of encorafenib. The addition of a ternary surfactant component, in this case, sodium lauryl sulphate (SLS) to the inner phase was studied over a range (w / w %) of 4.76 to 9.1 % to identify compositions for tablet formulation. Alternate surfactant formulations comprising SLS include SLS at 1 , 2.5 and 4% SLS w / w.

[0148] Table 4 Inner Phase HMEs (amorphous solid dispersion) with Lower SLS% w / w.

[0149] Prior to identifying SLS as a useful ternary formulation component in the inner phase, an alternative surfactant (Poloxamer 188) was trialed with addition of succinic acid as a microenvironmental acidifier as an intra-hot melt extrudate (HME) component. Dissolution performance was mainted as the drug loading of encorafenib was increased to higher levels (such as 43.5% w / w DL for Poloxamer containing prototypes and 37.5% w / w DL for succinic acid containing protoypes). It was found that a composition containing high load of encorafenib in a range of 25-45%(w / w), more particularly 38.1 % (w / w) encorafenib could be achieved by the inclusion of SLS at about 1 -10 % (w / w), particularly 4.76% (w / w) level with about 50-65% (w / w) of polymer such as copolymer of vinyl acetate and vinylpyrrolidone, more particularly 57.14% (w / w) polyvinylpyrollidone vinyl acetate 6:4 co-polymer (commercial grade Kollidon VA 64). This inner phase composition could be processed by hot-melt extrusion, with adequate chemical and physical stability and was shown to maintain dissolution performance when tested using compendial USP 2 equipment (in pH 1.2, 4.5 and 6.8 media) and in TIM-1 gastrointestinal simulator under simulated fasted, fed and PPI clinical administration conditions, as further described below. Processing of this inner phase composition using alternative techniques such as spray-drying or co-precipitation is possible. The proposed inner phase composition represents a significant improvement on the API load achieved in the first generation product ASD of 23% (w / w) by enabling API drug load to exceed 25% and provides an option to create a smaller, more patient-centric dosage form for encorafenib. By enabling an increased API drug load exceeding 25% w / w, the formulations of the invention enable much smaller formulation compositions; for example 75 mg dosage form in size 00 (22 mm) capsules can be reduced to 13 mm oval tablet size), a decrease in about 41 % size, thereby allowing for much enhanced patient experience.

[0150] In one embodiment of any of said high drug loading pharmaceutical formulations of amorphous solid dispersion of encorafenib, the pharmaceutical formulation further comprises a coating.

[0151] In one embodiment of any of said high drug loading pharmaceutical formulations of amorphous solid dispersion of encorafenib, the pharmaceutical formulation is formulated as a tablet.

[0152] Methods of treatment

[0153] The invention further provides a method of treating a proliferative disease such as cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a solid form of encorafenib or a pharmaceutical formulation thereof.

[0154] In one embodiment, the methods described herein are useful for the treatment of BRAF -associated cancers. The BRAF-associated cancer can be a primary tumor or a metastatic tumor.

[0155] The term “cancer” as used herein refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. In one embodiment the BRAF - associated cancer expresses a BRAF V600 mutation, including BRAF V600E and BRAF V600K mutations. In another embodiment of the invention, the method further comprises administration of a MEK inhibitor. In another embodiment of the invention, the method further comprises administration of binimetinib. Nonclinical data have demonstrated the enhanced activity of combining BRAF and MEK inhibition in BRAFV600-driven tumors (Stuart et al, 2012; Flaherty et al, 2012; Joshi et al, 2015; Khunger et al, 2018). This combination has been validated clinically by the efficacy observed for the combination in BRAFV600E-mutant NSCLC (Planchard et al, 2017), and also in the treatment of BRAR^^-mutant melanoma where the combination of BRAF and MEK inhibition is an established standard-of-care based on 4 pivotal trials of various BRAF / MEK inhibitor combinations (Long et al, 2014; Ascierto et al, 2016; Robert et al, 2016; Dummer et al, 2018a).

[0156] Encorafenib is a potent and selective BRAF inhibitor and binimetinib is a potent and selective MEK inhibitor. In a Phase 3 study of encorafenib with or without binimetinib compared to vemurafenib (a standard-of-care BRAF inhibitor comparator) in patients with advanced BRAFV600E / K-mutant melanoma (Study CMEK162B2301 ; COLUMBUS trial), the combination was shown to improve PFS, OS and ORR compared to vemurafenib treatment (Dummer et al, 2018a; Dummer et al, 2018b). Median PFS, median OS and confirmed ORR for the combination of encorafenib plus binimetinib were 14.9 months (95% Cl 11.0, 18.5), 33.6 months (95% Cl 24.4, 39.2) and 63.0% (by central review; 95% Cl 55.8, 69.9) / 75.0% (by local review; 95% Cl 68.3, 81.0), respectively. These results compared favorably to the PFS, OS and ORR of 7.3 months (95% Cl 5.6, 8.2), 16.9 months (95% Cl 14.0, 24.5) and 40.3% (by central review; 95% Cl 33.3, 47.6) / 49.0% (by local review; 95% Cl 41.9, 56.5), respectively, for vemurafenib, which performed almost identically on all endpoints compared to its performance in other pivotal trials in BRAFV600-mutant melanoma where it was used as a control (Larkin et al, 2014; Robert et al, 2015). These data compare favorably with results from trials of dabrafenib plus trametinib in a similar melanoma setting, with median PFS of 11.4 months, median OS of 25.6 months (95% Cl 23.1 , 34.3) and ORR of 64% by local review (95% Cl 59, 69) for the combination of dabrafenib plus trametinib and median PFS of 7.3 months, median OS of 18 months (95% Cl 15.6, 20.7) and ORR of 51 % by local review (95% Cl 46, 97) for vemurafenib (Robert et al, 2015; Robert et al, 2016).

[0157] Importantly, the combination of encorafenib plus binimetinib has a different safety and tolerability profile (Flaherty et al, 2017) from dabrafenib plus trametinib. Pyrexia, manifesting as a distinctive recurrent febrile syndrome refractory to NSAIDs and associated in a minority of patients with chills, dehydration and renal failure, is a significant toxicity associated with dabrafenib and trametinib, and is seen in over 50% of patients (Long et al, 2014). Treatment with encorafenib and binimetinib was associated with a lower incidence of pyrexia (18% of patients) in the COLUMBUS trial and these events were generally low grade, nonrecurrent and not associated with other manifestations (Dummer et al, 2018a; Dummer et al, 2018b); 64% of patients with previously untreated BRAF-mutant metastatic NSCLC, and 46% of patients with previously treated BRAF-mutant advanced NSCLC who received dabrafenib plus trametinib reported pyrexia (Planchard et al, 2016a Planchard et al, 2017).

[0158] Encorafenib plus binimetinib may represent an alternative BRAF / MEK inhibitor combination regimen for the treatment of BRAFV600E-mutant NSCLC, and potentially for other V600 Class 1 BRAF mutations (e.g. K or D), though very rare. Encorafenib plus binimetinib has a differentiated safety profile and may have enhanced efficacy based on results observed in the treatment of BRAFV600-mutant melanoma.

[0159] The study described in Example 4 below seeks to generate data to explore the bioavailability of this formulation for use in cancers including non-small cell lung cancer.

[0160] EXAMPLE 1 : Comparative Dissolution Studies of SLS versus Poloxamer 188 in High Loading Encorafenib Formulations

[0161] Binary Hot Melt Extrudates (HMEs) containing various proportions of encorafenib and PVPVA64 were prepared (encorafenib drug loading: 25% w / w - 50% w / w). Intrinsic dissolution was studied using HME compacts in FIG 6 clearly shows that the rate of intrinsic dissolution reduced significantly when HME drug loading was increased from 23% w / w (equivalent to the drug loading in the hot-melt extrudate used in the commercial capsule) to 30% w / w. Drug release above 35% w / w drug loading was negligible.

[0162] Poloxamer 188 used in the commercial capsule formulation is a surfactant in addition to a process aid. Inclusion of 7.72% w / w poloxamer 188 (8% w / w in commercial capsule) in the HMEs with increasing encorafenib loading was not necessary to enhance intrinsic dissolution (FIG 6).

[0163] Several intra-HME additives were evaluated to assess the ability to enhance drug release from high drug loaded encorafenib: PVPVA64 HMEs, Sodium Lauryl Sulphate (SLS) (a small - medium chain surfactant contrary to the large chain poloxamer P188) and succinic acid (SA) were found effective (FIG. 8) relative to poloxamer 188.

[0164] If HME tablets solely relied upon erosion, the rate and the extent of drug release would reduce as the drug loading is increased, see FIG 6. However, HME tablets can be formulated with common tablet excipients (such as diluents and disintegrants) to allow disintegration into small particles, prior to dissolution. These particles allow faster drug release than eroding tablets due to significantly greater surface area and a greater impact of hydrodynamics on the physical removal of a stagnant hydrated polymer layer.

[0165] Suitable particle size of the encorafenib: PVPVA64 HME was identified initially as having diameter size (50%) as Dso of 100 - 200 pm and diameter size 90%, D90, of 200 - 350 pm.

[0166] Kinetic Solubility Studies:

[0167] Kinetic solubility of HME particles was studied using the following protocol.

[0168] A quantity of HME adjusted according to drug loading was weighed and added to glass vials containing 25 mL of pre-heated (37 °C) dissolution buffer. Vials were maintained at 37 °C throughout the experiment and samples were withdrawn at appropriate intervals (e.g. 5, 10, 15, 20, 30, 45, 60, 75, 190 and 120 minutes). Samples were appropriately diluted with a mobile phase and assayed using the HPLC technique. Encorafenib has a basic pKa of 4.5 and an acidic pKa of 7.2. It has high solubility in acidic media and can supersaturate as a weak base on transfer to intestinal pH conditions. Solubility is lowest around the pKa of 4.5 and dissolution performance at this pH was used as a sensitive test to screen formulations.

[0169] TIM-1 System

[0170] As an alternative to compendial dissolution methodology, the comparative performance of encorafenib 75 mg capsules and tablets was assessed using the TIM-1 gastrointestinal simulator (The Tim Company, Delft, The Netherlands). The TIM-1 system is a multi-compartmental and computer-controlled advanced dissolution model that simulates the gastric and small intestinal regions of the gastrointestinal tract. The TIM-1 system uses hollow fiber membrane filters situated in the small intestinal jejunal and ileal compartments to continuously remove dissolved drug from the intestinal lumen. This system is used to determine the bio-accessibility, or the amount made available for absorption from oral drug products. This is defined as the sum of filtrated drug obtained from the jejunal and ileal compartments in relation to dose tested.

[0171] FIG 8 and FIG 9 show that addition of SLS alone, rather than SLS combined with acidifier succinic acid, increased the kinetic solubility of high drug loaded encorafenib: PVPVA64 milled extrudates (particles). Overall, the HMEs had a far superior solubility than encorafenib drug substance (API) alone. Succinic acid enhances solubility of the API by providing an acidic microenvironment, while SLS enhances solubility by the combined surfactant action and prevention of amorphous: amorphous phase separation. This novel combined action distinguishes low molecular weight (<2 kDa) surface active agents in achieving high drug loaded encorafenib amorphous solid dispersions than the high molecular weight poloxamer 188, which was not as effective as SLS despite the surfactant property. Encorafenib: PVPVA64 HMEs described here were further formulated into tablets (Tables 1 and 2) and evaluated using USPII dissolution testing (FIG 11 and FIG 12). This data further confirms a superior ASD dissolution performance conferred by SLS over succinic acid and poloxamer.

[0172] EXAMPLE 2: Manufacturing of High Drug Loading HME Encorafenib Formulations.

[0173] The manufacturing process of the tablet formulations of the current invention is performed similar to previous capsule formulation, wherein the inner phase is comprised of encorafenib, polymer (including but not limited to PVP-VA) and surfactants (including but not limited to SLS) as described above. The outer phase comprises the compression aid, either ductile and / or brittle filler (including but not limited to microcrystalline cellulose, mannitol, lactose monohydrate or dibasic calcium phosphate), a flow aid (colloidal silicon dioxide or talc), disintegrant (crospovidone, croscarmellose sodium, low-sub hydroxypropyl cellulose, starch 1500 or Sodium starch glycolate) and a lubricant (including but not limited to glyceryl behenate, magnesium stearate or sodium stearyl fumarate).

[0174] The manufacturing process is performed by hot-melt extrusion using either a 10 mm or 18 mm twin-screw extruder, followed by milling the extrudates, blending with the external phase and screening. Following blending, the blend is compressed into tablets (8 mm round or 13 mm or 18 mm oval) for drug doses of 50 mg, 75 mg or 150 mg respectively. Enhanced dissolution performance of an ASD can be partly attributed to the higher solubility of the amorphous form of the drug compared to the crystalline form. Additionally, intermolecular interactions with a soluble polymer help to maintain a supersaturated state in the physiological medium and prevent nucleation. Generally, this is enabled by the presence of a monophasic amorphous matrix and congruent drug and polymer release rates. High drug loading (>25%) increases the risk of amorphous - amorphous phase separation, which can produce heterogenous drug rich and polymer rich regions. Differential solubility of such regions is believed to disrupt the congruent drug - polymer release and subsequently result in poor supersaturation and / or nucleation.

[0175] The schematic as shown in FIG. 12 summarizes the unit operations involved in the manufacture of development batches 221 A- 227A and 231A- 233A.

[0176] In brief, a physical mixture of encorafenib with PVP VA 64 and additional components such as surfactant / plasticizers or acidifier was prepared by blending in a PK lab blender. Hot melt extrudates were generated by extruding the physical mixture through a 10 mm Rondol extruder, or 18 mm Leistritz extruder for commercial scale batches. The 10 mm extruder is equipped with co-rotating twin screws and heated barrels with 7 zones. The extruder was heated to desired temperature with thermostatic control at the front and rear end of barrel to maintain a desired barrel temperature. The system was allowed to heat soak for ~30 min. The twin screws were rotated to a desired speed and the powder blend was added with steady feed rate with the help of K-tron MT12 feeder or vibratory feeder. The screw profile consisted of three kneading zones. All the material exiting the extruder through a 0.5-mm round die opening were collected onto an aluminum foil and allowed to cool to room temperature and then milled in a grinder. The milled material then passed through mesh #35 and the resultant material was utilized for further evaluation. For tableting, HME milled extrudate was mixed with extra granular material and compressed on the Globe Pharma carver press.

[0177] Table 5: Tablet Formulations 221A - 227A Containing Encorafenib: PVPVA64 HMEs with Variable Drug Loading and Intra-HME Additives Used for Comparative USP II Dissolution Assessment.

[0178] Table 6: Tablet Formulations 231 A - 233A Containing Encorafenib: PVPVA64

[0179] HMEs with Variable Drug Loading and Intra-HME Additives Used for Comparative USP II Dissolution Assessment.

[0180] Table 7: Composition of Laboratory Scale HME Batches Containing Varied SLS levels and Drug Loading (AQ-21 -0042 / 43 / 44 / 50).

[0181] Table 8: Example Tablet Formulations Made using Laboratory Scale HME Batches Containing Varied SLS levels and Drug Loading (AQ-21 -0042 / 43 / 44 / 50).

[0182] Further HME batches (Table 7) were made using 18mm Leistritz extruder and compressed into several tablet formulations using the process flow and equipment train described in Figure 12. Further formulations with external phase excipients from these trials are given in Table 8.

[0183] Since encorafenib shows lowest solubility at pH 4.5 (basic pka), this pH was selected for screening formulations prepared during development. Due to higher relative solubility at the gastric and intestinal pH relative to pH 4.5, the magnitude of differences observed at pH 4.5 aren’t expected at gastric and intestinal pHs (i.e. in vivo). FIG 14 and 15 show USP II dissolution profiles for tablets made using the high drug loaded (36.4% - 38.1 %) encorafenib amorphous solid dispersions (HMEs). It is clear that an immediate release profile is observed for all formulations containing SLS, and the ability to achieve the desired profile by adjusting the level of SLS and type / level of extra granular components is demonstrated. AQ-21 -0050A and AQ-21 -0050D contained HMEs with 50% drug loading (DL) but no SLS showed relatively poor release. Increasing the 50% DL, no SLS HME load in the tablet formulation also decreased the drug release considerably. The non-polymeric surfactant evaluated here allows drug dissolution from a high drug loaded encorafenib ASD by the combined surfactant action and preventing the amorphous-amorphous phase separation. Since tablet disintegration is considered important for such systems (FIG 8), rate of dissolution can be further adjusted by varying the extra-ASD (extra-HME) components.

[0184] Further example is presented in FIG 16, where encorafenib: PVPVA64 HME containing 38.1 % drug loading and 1 % w / w, 2.5% w / w and 4% w / w SLS were manufactured. These HMEs were milled into a larger PSD (Dso ~2OO pm, D90 ~400 pm), but sieve cuts were taken to separate <210pm and >210pm particles, which were further compressed into tablet formulation with the following composition (45.8% w / w Extrudates, 44% Microcrystalline Cellulose (MCC), 10% crospovidone, 0.2% sodium steryl fumarate).

[0185] USPII dissolution results presented in FIG 16 demonstrate ability to manipulate the drug release by varying the SLS level (as discussed previously) along with HME PSD, which alters the drug release profile by offering a control over disintegration time, dissolution hydrodynamics and kinetics of amorphous : amorphous phase separation as described in FIG 8.

[0186] Amorphous Solid Dispersions (ASDs) generated by the hot melt extrusion process, listed in Tables 6 and 7 showed complete amorphous conversion of encorafenib and acceptable assay, impurities and stability profiles over periods of 7, 14, and 21 days as shown in accelerated conditions described in Tables 9 and 10.

[0187] EXAMPLE 3: ASAP and Long Term Chemical StabilityThe high drug loading formulations of the invention (Table 8 (AQ-21-0042 / 43 / 44 / 50). showed excellent chemical stability upon storage at accelerated stability conditions (ASAP conditions 50°C over 21 days) at with little evidence of any degradation products for encorafenib. Long Term Chemical Stabiity Results for Table 8 formulations are shown in Table 9 below. Table 9:

[0188] Table 10 gives composition for HME and tablet batches studied in a clinical setting against commercial capsules. The manufacturing process flow for these batches is described in FIG 12. In vitro USPII dissolution performance of these batches was studied in multiple media and compared to that of commercial capsule formulation with a significantly lower HME drug loading (38.1 % w / w Vs 23% w / w). A comparable in vitro dissolution performance was demonstrated as shown in FIG 16. Fasted State Pharmacokinetic parameters observed for the new (high drug loaded) formulations against the commercial capsule (Low HME drug loading) are given in Table 12. The high drug loaded formulations produce comparable AUCinf and Cmax as the commercial capsules indicating reasonable agreement in the relative bioavailability of these formulations. These studies further demonstrate the ability to achieve desired drug release (and in vivo pharmacokinetic) performance with high drug loaded encorafenib amorphous solid dispersions, by inclusion of small molecule (<8kDa) surfactants that prevent amorphous-amorphous phase separation. Further control on drug release is offered by carefully controlling the level of surfactant within the claimed window and the particle size distribution (PSD) of ASD (or HME). Tables 12 and 13 confirm chemical stability of these formulations.

[0189] Table 10: Composition of Drug Products Used in the Relative Bioavailability Clinical Study

[0190] Table 11 : Fasted State Pharmacokinetic (PK) Comparison of New Formulations Containing High Drug Loaded Encorafenib: PVPVA64 HME with SLS and Commercial Capsules Containing Low Drug Loaded HME.

[0191] Table 12: Chemical Stability of High Drug Loaded Encorafenib: PVPVA64 ASD Formulation DP-004294 Used in the Relative Bioavailability Study

[0192] Chemical stability studies of high drug loaded encorafenib PVPVA64 ASD in the relative bioavailability study reflected no significant changes after 9M (long term) or 6M (accelerated stability) in assay or degradation products. XRPD data indicate physical stability of the amorphous solid dispersion formulation (no indication of conversion to the crystalline drug substance) upon storage at accelerated stability conditions of 40 °CZ 75 % RH for 6 months.

[0193] Table 13: Chemical Stability of High Drug Loaded Encorafenib: PVPVA64 ASD

[0194] Formulation DP-004294 Used in the Relative Bioavailability Study

[0195] • No significant changes after 9M (long term) or 6M (accelerated stability) in assay or degradation products.

[0196] • 40°C / 75%RH samples failed specification for PXRD at 6M due to water uptake caused by incorrectly sealed packaging (bottles).

[0197] Inner Phase HME particle size distribution (PSD) for example batches of encorafenib amorphous solid dispersion / HME is presented in Table 14 below. Batches AQ-21- 0010 through 0012 are being studied further to further understand the control offered by the HME PSD in combination with the surfactant level on drug release from high drug loaded encorafenib ASDs / HMEs. Additional low molecular weight surfactants, namely Tween 20, Tween 80, sorbitan monolaurate, sorbitan trioleate, , D-a-Tocopherol polyethylene glycol 1000 succinate, Gelucire, Span 85, or CTAB at 1 .0% w / w - 5.0% w / w levels may demonstrate advantage to surfactant SLS in the formulation design space for high drug loaded amorphous solid dispersion containing drugs such as encorafenib. Table 14: Particle Size Distribution for Encorafenib: PVPVA64 HME batches made with various SLS levels and during various stages of development.

[0198] Feed rates for HME manufacture for these studies were targeted to be 2.5 kg / hr to 3.5 kg / hr and the HME screw speed of 300rpm - 400 rpm. A suitable screw configuration was identified.

[0199] Post-Extrusion Milling Post extrusion milling was performed using a hammer mill in a single step Mill setting process parameters included 3000 rpm milling speed with 0.5 mm - 1.0 mm screen.

[0200] EXAMPLE 4: Bioavailability Study

[0201] An open-label, randomized, study was conducted to study encorafenib immediate- release (IR) tablet formulations: IR tablet formulated with MCC (eMCC) and another with MCC and lactose (eMCCL) as described in Table 12 above Study Table 4A:

[0202] For binary or categorical variables, number of participants, numbers and percentages of participants A total of 5 treatment options (Treatments A to E) were planned. Eighteen participants were to be randomized into 1 of 6 treatment sequences to receive 4 of study treatments, 1 each in 4 periods as described in Table 4B.

[0203] STUDY DESIGN

[0204] Study Table 4B: a. between successive encorafenib doses

[0205] Treatment A: a single dose of encorafenib 75 mg as eMCC under fasted condition;

[0206] Treatment B: a single dose of encorafenib 75 mg as eMCCL under fasted condition;

[0207] Treatment C: a single dose of encorafenib 75 mg as CAP under fasted condition;

[0208] Treatment D: a single dose of encorafenib 75 mg eMCC (fasted) following 5 days of rabeprazole 20 mg daily;

[0209] Treatment E: a single dose of encorafenib 75 mg eMCCL (fasted) following 5 days of rabeprazole 20 mg daily.

[0210] Periods 1 through 3 were intended to estimate the relative BA of the 2 new encorafenib IR tablet formulations (eMCC and eMCCL) compared to the commercially available CAP formulation using a 75 mg encorafenib single dose all administered under fasted conditions. Period 4 was intended to explore the potential effect of a PPI (rabeprazole) on the PK of eMCC and eMCCL formulations with participants receiving one of the formulations with rabeprazole.

[0211] Eighteen participants were to be enrolled according to the study design.

[0212] During the study, 18 participants were enrolled as planned. All participants with evaluable PK parameters for encorafenib were included in the PK analysis. One participant did not have evaluable PK for Treatments C and D as the participant was discontinued from the study due to an AE following the treatment 75 mg encorafenib eMCCL in period 2. All the 18 participants were evaluable for the safety analysis. Enrolled in the study were healthy adult participants (male / female; BMI of 17.5 to 30.5 kg / m^; body weight >50 kg [110 lb]) who had no critical medical history or any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy). Study interventions administered in this study were encorafenib and rabeprazole.

[0213] Encorafenib 75 mg IR tablets (eMCC and eMCCL) and capsules (CAP) were supplied to the PCRU in bulk along with individual dosing containers for unit dosing. Delayed release 20 mg rabeprazole were supplied. The batch numbers and formulation components for encorafenib dispensed in this study are provided in Tables 10 and 11 above.

[0214] The total duration of the study was to be approximately 90 days from screening to the final follow-up. 13 out of 18 participants were male. The mean age was 46.5 years. The mean weight and BMI were 79.479 kg and 25.67 kg / m^ respectively.

[0215] 18 (100%) participants received a single dose of encorafenib eMCC 75 mg; 18 (100%) participants received a single dose of encorafenib eMCCL 75 mg; 17 (94.4%) participants received a single dose of encorafenib CAP 75 mg; 8 (88.9%) participants received a single dose of encorafenib eMCC 75 mg + rabeprazole 20 mg; and 9 (100%) participants received a single dose of encorafenib eMCCL 75 mg + rabeprazole 20 mg.A

[0216] No death, serious adverse event (SAE) or severe adverse event (AE) was reported during the study. All but 1 treatment-emergent AEs (TEAEs) were mild in seventy. One participant permanently discontinued from the study associated with a moderate AE of dermatitis allergic following the administration of a single dose of encorafenib 75 mg as eMCCL in Period 2.

[0217] Study Table 4C presents the study design elements.

[0218] Study Table 4C. Study Design Elements Study Table 4C. Study Design Elements Study Table 4C. Study Design Elements

Claims

We claim:1 . A pharmaceutical formulation of the invention comprising an inner phase of(a) an amorphous solid dispersion comprising about 25 mg, 50 mg, 75 mg, 100 mg or 150 mg of encorafenib:(b) one or more surfactants,(c) one or more polymers; and optionally an external phase comprising (d) one or more pharmaceutically acceptable excipients; wherein the encorafenib is present in an amount of about 25% to about 45% w / w, and the surfactant is selected from the group consisting of sodium lauryl sulfate, Tween 80, sorbitan monolaurate, sorbitan trioleate, docusate sodium, D-alpha-tocopheryl polyethyleneglycol succinate, and cetyl trimethyl ammonium bromide.

2. The formulation of claim 1 , wherein encorafenib is present in an amount of about 30% to about 45% w / w.

3. The formulation of claim 2, wherein encorafenib is present in an amount of about 33% to about 39% w / w.

4. The formulation of claim 3, wherein the surfactant is sodium lauryl sulfate.

5. The formulation of claim 4, wherein the formulation is present in a unit dose which is less than about 20 mm in length.

6. The formulation of claim 5, wherein the formulation is present in a unit dose which is less than about 15 mm in length.

7. The formulation of claim 5, wherein the surfactant is present in an amount of about 2% to about 7% w / w.

8. The formulation of claim 7, wherein the polymer is present in an amount of about 50% to about 65% w / w.

9. The formulation of claim 8, wherein the polymer is present in an amount of about 55% to about 60% w / w.

10. The formulation of claim 9, wherein the polymer is selected from the group consisting of vinyl acetate polymers, graft polymers of polyethylene glycol, polyvinyl caprolactam, polyvinyl acetate, high molecular weight polyalkylene oxides, cellulose polymers or HPMCAS polymers.11 . The formulation of claim 10, wherein the polymer is polyvinylpyrrolidone vinyl acetate 6:4 co-polymer.

12. The formulation of claim 1 , wherein the pharmaceutically acceptable excipient is selected from a binder, filler, disintegrant, glidant or lubricant.

13. The formulation of claim 12, pharmaceutically acceptable excipients include one or more of microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide or magnesium stearate.

14. The formulation of claim 1 , wherein the formulation does not include an acidifier.

15. The formulation of claim 14, wherein the formulation does not include a flow aid.

16. A pharmaceutical formulation of the invention comprising an inner phase of(a) an amorphous solid dispersion comprising about 25 mg, 50 mg, 75 mg, 100 mg or(b) one or more surfactants,(c) one or more polymers; and optionally an external phase comprising (d) one or more pharmaceutically acceptable excipients; wherein the encorafenib is present in an amount of about 25% to about 45% w / w, and the surfactant is selected from the group consisting of sodium lauryl sulfate, Tween 80, sorbitan monolaurate, sorbitan trioleate, docusate sodium, D-alpha-tocopheryl polyethyleneglycol succinate, and cetyl trimethyl ammonium bromide, and wherein the pharmaceutically acceptable excipients are present in the amounts of(a) 14% to 50% of microcrystalline cellulose;(b) 14% to 50% of lactose monohydrate;(c) 1 % to 6% of croscarmellose sodium;(d) 0.1 % to 1.25% of colloidal silicon dioxide; and(e) 0.25% to 1 .25% of magnesium stearate.

17. The formulation of claim 16, wherein the formulation is a tablet.

18. The formulation of claim 17, wherein the amorphous solid dispersion comprises about 50 mg, 75 mg, or 150 mg of encorafenib.

19. The formulation of claim 18, wherein the amorphous solid dispersion comprises about 75 mg of encorafenib.

20. The formulation of claim 18, wherein the amorphous solid dispersion comprises about 150 mg of encorafenib.

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