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WO2016173959A1 - Régorafénib pour le traitement du cancer colorectal - Google Patents

Régorafénib pour le traitement du cancer colorectal Download PDF

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Publication number
WO2016173959A1
WO2016173959A1 PCT/EP2016/059117 EP2016059117W WO2016173959A1 WO 2016173959 A1 WO2016173959 A1 WO 2016173959A1 EP 2016059117 W EP2016059117 W EP 2016059117W WO 2016173959 A1 WO2016173959 A1 WO 2016173959A1
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Prior art keywords
regorafenib
colorectal cancer
human
acid
pharmaceutically acceptable
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PCT/EP2016/059117
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English (en)
Inventor
Michael Teufel
Henrik Seidel
Susanne Schwenke
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Bayer Pharma AG
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Bayer Pharma AG
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01M—CATCHING, TRAPPING OR SCARING OF ANIMALS; APPARATUS FOR THE DESTRUCTION OF NOXIOUS ANIMALS OR NOXIOUS PLANTS
    • A01M1/00—Stationary means for catching or killing insects
    • A01M1/02—Stationary means for catching or killing insects with devices or substances, e.g. food, pheronones attracting the insects
    • A01M1/026—Stationary means for catching or killing insects with devices or substances, e.g. food, pheronones attracting the insects combined with devices for monitoring insect presence, e.g. termites
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01M—CATCHING, TRAPPING OR SCARING OF ANIMALS; APPARATUS FOR THE DESTRUCTION OF NOXIOUS ANIMALS OR NOXIOUS PLANTS
    • A01M7/00—Special adaptations or arrangements of liquid-spraying apparatus for purposes covered by this subclass
    • A01M7/005—Special arrangements or adaptations of the spraying or distributing parts, e.g. adaptations or mounting of the spray booms, mounting of the nozzles, protection shields
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01M—CATCHING, TRAPPING OR SCARING OF ANIMALS; APPARATUS FOR THE DESTRUCTION OF NOXIOUS ANIMALS OR NOXIOUS PLANTS
    • A01M7/00—Special adaptations or arrangements of liquid-spraying apparatus for purposes covered by this subclass
    • A01M7/0089—Regulating or controlling systems

Definitions

  • the present invention relates to the use of regorafenib, a hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof or a polymorph thereof for treating colorectal cancer in humans responding favorably to regorafenib.
  • regorafenib a hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof or a polymorph thereof for treating colorectal cancer in humans responding favorably to regorafenib.
  • Standard treatment for these patients involves chemotherapy based on fluoropyrimidines, oxaliplatin, and irinotecan (used in combination and sequentially); and monoclonal antibodies targeting vascular endothelial growth factor (VEGF; bevacizumab).
  • VEGF vascular endothelial growth factor
  • monoclonal antibodies targeting epidermal growth factor receptor (EGFR; cetuximab and panitumumab) are also used. Additional options are needed for patients who have disease progression despite all currently available standard therapies, because many patients maintain good performance status and might be candidates for further therapy.
  • Various signalling pathways have been implicated in the development and progression of colorectal cancer, involving receptor tyrosine kinases (e.g.
  • Standard treatment regimens for metastatic colorectal cancer include agents that target the molecular drivers of colorectal cancer pathogenesis, such as vascular endothelial growth factor (VEGF; e.g. bevacizumab and ziv-aflibercept) and epidermal growth factor receptor (EGFR; e.g. cetuximab and panitumumab).
  • VEGF vascular endothelial growth factor
  • EGFR epidermal growth factor receptor
  • PLoS Med 10(5): el001453 describes the investigation of gene expression profiles (GEP) in CRC primary tumor samples from a large multicenter cohort of 750 patients with stage I to IV CRC who underwent surgery between 1987 and 2007 in seven centers were characterized for common DNA alterations, including BRAF, KRAS, and TP53 mutations, CpG island methylator phenotype, mismatch repair status, and chromosomal instability status, and were screened with whole genome and transcriptome arrays (Marisa et al., (2013) PLoS Med 10(5): el001453).
  • GEP gene expression profiles
  • a deficient mismatch repair subtype a KRAS mutant subtype, a cancer stem cell subtype, and three chromosomal instability subtypes, including one associated with down-regulated immune pathways, one with up-regulation of the Wnt pathway, and one displaying a normal-like gene expression profile were distinguished.
  • the subtypes C4 and C6, but not the subtypes CI , C2, C3, and C5, were independently associated with shorter relapse-free survival, even after adjusting for age, sex, stage, and the emerging prognostic classifier Oncotype DX Colon Cancer Assay recurrence score (hazard ratio 1.5, 95% CI 1.1-2.1, p 0.0097). According to Marisa et al. patients having CRC can be stratified into six sub-groups (CI to C6) on the basis of GEP determined in patients' primary CRC tumor samples.
  • Regorafenib is a novel oral multikinase inhibitor that blocks the activity of several protein kinases, including kinases involved in the regulation of tumour angiogenesis (VEGFR1 [also known as FLT1], VEGFR2 [KDR], VEGFR3 [FLT4], TIE2 [TEK]), oncogenesis (KIT, RET, RAF1 , BRAF, and BRAFV600E), and the tumour microenvironment (PDGFR and FGFR), (Int J Cancer, 129 (2011), pp. 245-255). In preclinical studies, regorafenib has shown antitumour activity, including in colorectal cancer models. E.g.
  • Regorafenib which is 4 ⁇ 4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy ⁇ - pyridine-2-carboxylic acid methylamide, a compound of formula (I)
  • the problem to be solved by the present invention is to provide a method for the identification of a patient disposed to respond favorably to regorafenib for treating colorectal cancer.
  • regorafenib shows an improved activity in patients classified under C4 and C6 according to Marisa et al., ((2013) PLoS Med 10(5): el 001453).
  • the present invention pertains to regorafenib, a hydrate, solvate, metabolite or pharmaceutically acceptable salt of regorafenib, or a polymorph thereof for use in treating colorectal cancer in a human which suffers colorectal cancer and which was stratified into sub-group C4 or C6 by determining in vitro the gene expression profile in the tumor cells of said human.
  • the present invention pertains to a method of stratification of a human which suffers colorectal cancer into one of sub-groups CI to C6 in a first step by determining in vitro the gene expression profile in the tumor cells of said human and in a second step the use of regorafenib, a hydrate, solvate, metabolite or pharmaceutically acceptable salt of regorafenib, or a polymorph thereof for treating colorectal cancer in a human which was stratified in the first step into subgroup C4 or C6.
  • the 288 CEL files of the CORRECT trial cohort were normalized and transformed to a gene expression matrix using a pre-processing workflow implemented in Genedata Expressionist ® Refiner Array (v8.0).
  • the workflow comprises a background correction using anti-genomic background probes, quantile normalization of probe intensities, and the summarization of probe intensities to probe set intensities using median polish. Further analyses are based on log2 -transformed intensities for probe sets of the "main" category as defined by the vendor's annotation (Affymetrix NetAffx array annotation, version 33.2). Molecular subtype determination according to Marisa et al. Reference is made to Marisa et al. which is cited in the following: Unsupervised Probe set selection:
  • the probe sets used for subtype determination fulfill the three following criteria: (1) to be expressed in at least 5% of the samples (i.e. 5th decile of normalized intensities across samples > log2(15))
  • Variance test For each probe set (P) is tested whether its variance across samples is different from the median of the variances of selected probe sets in (1).
  • the statistic used is ((n-l)xVar(P) / Vanned), where n refers to the number of samples. This statistic is compared to a percentile of the Chi-squared distribution with (n-1) degrees of freedom (this criteria is used in the BRB ArrayTools filtering tool, described in the User's Manual (Simon R, and Peng Lam A. (2003) BRB-ArrayTools software v3.1 User's Manual linus.nci.nih.gov/BRB-ArrayTools.html) and yields a p-value for each probe set.
  • rCV rCV for each probe set is calculated by dividing the standard deviation by the mean, eliminating the highest and lowest expression value across the samples for each probe set.
  • rCV threshold determination the cut-off point is defined using Gaussian mixture model clustering approach (R package mclust (Chris Fraley and Adrian E. Raftery (2006) MCLUST Version 3 for R: Normal Mixture Modeling and Model-based Clustering. Technical Report No. 504, Department of Statistics, University of Washington (revised 2009)) which defined 4 groups of rCV. Consensus Unsupervised class discovery approach
  • Clustering algorithm hierarchical clustering - Clustering metrics: (1 -Pearson correlation) distance and Ward linkage
  • the choice of the number of clusters can be based on the delta area plot and should correspond to the number of clusters k where the Cumulative distribution (CDF) levels off and the corresponding relative increase in the CDF area gets closes to zero.
  • CDF Cumulative distribution
  • a centroid-based predictor using the most discriminating probe sets (over and under expressed) of each subtype is used.
  • the selection of the probe sets used in the centroids is performed among the probe sets selected in the 2 first steps of the subtype determination approach and having an Affymetrix grade A annotation (NetAffx (Liu et al. (2003) Nucleic Acids Res;31(l):82-6). Annotations version na31 are used) and then as follows for each subtype: - Probe sets significantly differentially expressed in samples of the given subtype compared to samples of other subtypes according to the Limma moderated t-test (Smyth, G.K. (2004) Stat Appl Genet Mol Biol 3, Article3) or the Welch t-test (adjusted p-value ⁇ le-5 and
  • the selected probe sets are ordered according to their AUC score (computed using the R package PresenceAbsence (Freeman, Elizabeth (2007) PresenceAbsence: An R Package for Presence-Absence Model Evaluation. USDA Forest Service, Rocky Mountain Research Station, 507 25 th street, Ogden, UT, USA) and only those with a score superior to 0.7 are kept.
  • PresenceAbsence Freeman, Elizabeth (2007) PresenceAbsence: An R Package for Presence-Absence Model Evaluation. USDA Forest Service, Rocky Mountain Research Station, 507 25 th street, Ogden, UT, USA
  • probe sets to use in the centroid use a 10-fold crossvalidation approach.
  • the discovery dataset is split into 10 subsets.
  • the top up/down regulated pairs of probe sets were used to build centroids on 9 of the 10 subsets and the assignment (see below) was then computed on the remaining subset. This procedure was repeated for each subset and for each number of probe set pairs tested. The lowest global misclassification was obtained for 5 top up/down pairs. This procedure yields 57 probe sets (corresponding to 57 unique genes, see Table 1), 3 probe sets being specific to several subtypes but with inverted regulation.
  • DQDA diagonal quadratic discriminant analysis method
  • the confidence of the prediction is evaluated by identifying outliers (too distant samples) and mixed assignment samples (when a sample is close to several centroids).
  • a sample is said to be an outlier if its distance to the closest centroid is superior to n times the median absolute deviation (mad) of the distances of the samples used to compute the centroid; n is defined as the maximum (distances to centroid-mediandistances to centroid)/maddistances to centroid).
  • a sample has a mixed assignment if the difference of its distance to centroid is inferior to the 1st decile of the difference between centroids on data used to compute centroids.
  • Regorafenib is the compound of the formula (I)
  • the compound of formula (I) or “regorafenib” refer to 4- ⁇ 4-[( ⁇ [4 (trifluoromethyl)phenyl] amino ⁇ carbonyl)amino] -3 -fluorophenoxy ⁇ -N-methylpyridine-2- carboxamide as depicted in formula (I).
  • compound of the invention or “active agent” or “active ingredient” refer to regorafenib, a hydrate, solvate, metabolite or pharmaceutically acceptable salt of regorafenib, or a polymorph thereof.
  • Solvates for the purposes of the invention are those forms of the compounds or their salts where solvent molecules form a stoichiometric complex in the solid state and include, but are not limited to for example water, ethanol and methanol.
  • Hydrates are a specific form of solvates, where the solvent molecule is water. Hydrates of the compounds of the invention or their salts are stoichiometric compositions of the compounds or salts with water, such as, for example, hemi-, mono- or dihydrates. Preference is given to the monohydrate of regorafenib.
  • Salts for the purposes of the present invention are preferably pharmaceutically acceptable salts of the compounds according to the invention.
  • Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, / toluenesulfonic acid (tosylate salt), 1- naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid.
  • salts of inorganic bases include salts containing alkaline cations (e.g., Li + Na + or K + ), alkaline earth cations (e.g., Mg +2 , Ca +2 or Ba +2 ), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonation or peralkylation of triethylamine, NN- diethylamine, NN-dicyclohexylamine, lysine, pyridine, NN-dimethylaminopyridine (DMAP), 1,4- diazabiclo[2.2.2]octane (DAB CO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU).
  • alkaline cations e.
  • Metabolites of regorafenib for the purpose of the present invention include 4-[4-( ⁇ [4-chloro-3- (trifluoromethyl)phenyl]carbamoyl ⁇ amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide 1 - oxide, 4-[4-( ⁇ [4-chloro-3-(trifluoromethyl)phenyl]carbamoyl ⁇ amino)-3-fluorophenoxy]-N- (hydroxymethyl)pyridine-2-carboxamide, 4-[4-( ⁇ [4-chloro-3-(trifluoromethyl)phenyl]carbamoyl ⁇ - amino)-3-fluorophenoxy]pyridine-2-carboxamide and 4-[4-( ⁇ [4-chloro-3-(trifluoromethyl)phenyl]- carbamoyl ⁇ amino)-3-fluorophenoxy]pyridine-2-carboxamide 1 -oxide. Preferred are regorafenib and
  • the total amount of the active ingredient (compound of the invention) to be administered preferably via the oral route using the pharmaceutical composition of the present invention will generally range from about 0.1 mg/kg to about 50 mg/kg body weight per day. Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper - proliferative disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the pharmaceutical compositions of this invention can readily be determined by those skilled in the art.
  • the amount of the administered active ingredient can vary widely according to such considerations as the particular compound and dosage unit employed, the mode and time of administration, the period of treatment, the age, sex, and general condition of the patient treated, the nature and extent of the condition treated, the rate of drug metabolism and excretion, the potential drug combinations and drug-drug interactions, and the like.
  • a pharmaceutical composition can comprise regorafenib in an amount of 4 to 400 mg, preferably from 10 to 200 mg, more preferably from 10 to 100 mg.
  • the daily dose of the compound of the present invention, in particular regorafenib is from 10 to 1000 mg, preferably 40 to 500 mg, more preferably 80 to 320 mg, e.g. 160 mg.
  • the pharmaceutical composition can be administered one or more, preferably up to three, more preferably up to two times per day. Preference is given to an administration via the oral route.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease.
  • the pharmaceutical composition according to the invention is preferably a solid pharmaceutical compositions and is administered orally or rectally, preferably orally.
  • the pharmaceutical composition of the present invention includes any solid formulation which is applicable to be coated.
  • compositions according to the invention include but are not limited to granules, pellets, tablets, dragees, pills, melts or solid dispersions and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. Preference is given to tablets, solid dispersions, pellets and granules. Most preferably the pharmaceutically compositions according to the invention is a tablet.
  • the solid dispersion may be a solid solution, glass solution, glass suspension, amorphous precipitation in a crystalline carrier, eutectic or monotectic, compound or complex formation or combinations thereof.
  • a solid dispersion comprises at least a compound of the invention and a pharmaceutically acceptable matrix.
  • matrix or “matrix agents” as used herein refers to both polymeric excipients, non- polymeric excipients and combinations thereof, capable of dissolving or dispersing the compound of the invention.
  • composition comprising a solid dispersion, wherein the matrix comprises a pharmaceutically acceptable polymer, such as polyvinylpyrrolidone, vinylpyrrolidone/vinylacetate copolymer, polyalkylene glycol (i.e. polyethylene glycol), hydroxyalkyl cellulose (i.e. hydroxypropyl cellulose), hydroxyalkyl methyl cellulose (i.e.
  • a pharmaceutically acceptable polymer such as polyvinylpyrrolidone, vinylpyrrolidone/vinylacetate copolymer, polyalkylene glycol (i.e. polyethylene glycol), hydroxyalkyl cellulose (i.e. hydroxypropyl cellulose), hydroxyalkyl methyl cellulose (i.e.
  • hydroxypropyl methyl cellulose carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polymethacrylates, polyvinyl alcohol, polyvinyl acetate, vinyl alcohol/vinyl acetate copolymer, polyglycolized glycerides, xanthan gum, carrageenan, chitosan, chitin, polydextrin, dextrin, starch, proteins or a mixture thereof.
  • at least one from the group of polyvinylpyrrolidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol and polyethylene oxide is used as matrix agent in the solid dispersion. More preferably polyvinylpyrrolidone and/or hydroxypropyl cellulose are used as matrix agents. Most preferably polyvinylpyrrolidone is used as matrix agent.
  • the pharmaceutical composition can comprise a solid dispersion, wherein the matrix comprises a sugar and/or sugar alcohol and/or cyclodextrin, for example sucrose, lactose, fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol, erythritol, inositol, trehalose, isomalt, inulin, maltodextrin, ⁇ -cyclodextrin, hydroxypropyl-B-cyclodextrin or sulfobutyl ether cyclodextrin or a mixture thereof.
  • a sugar and/or sugar alcohol and/or cyclodextrin for example sucrose, lactose, fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol, erythritol, inosi
  • the solid dispersion comprises the compound of the invention (calculated as solvent-free regorafenib base which is the compound of formula (I)) and the matrix agent in a weight ratio of 1 :0.5 to 1 :20, preferably 1 :1 to 1 : 10, most preferably 1 :1 to 1 :5.
  • the solid dispersion may contain certain additional pharmaceutical acceptable ingredients, such as surfactants, fillers, disintegrants, recrystallization inhibitors, plasticizers, defoamers, antioxidants, detackifier, pH-modifiers, glidants and lubricants.
  • additional pharmaceutical acceptable ingredients such as surfactants, fillers, disintegrants, recrystallization inhibitors, plasticizers, defoamers, antioxidants, detackifier, pH-modifiers, glidants and lubricants.
  • solid dispersions containing croscarmellose sodium, sodium starch glycolate, crospovidone, low substituted hydroxypropyl cellulose (L-HPC), starch, microcrystalline cellulose or a combination thereof as carrier or disintegrant.
  • the solid dispersion comprises microcrystalline cellulose and/or croscarmellose sodium.
  • the solid dispersion comprises polyvinylpyrrolidone, croscarmellose sodium and optionally microcrystalline cellulose.
  • the solid dispersion can comprise the compound of the invention (calculated as solvent-free regorafenib base which is the compound of formula (I)) and the sum of carrier and disintegrant in a weight ratio of 1 :0.5 to 1 :20, preferably 1 : 1 to 1 :10, most preferably 1 : 1 to 1 :6.
  • the solid dispersion can be prepared according to methods known to the art for the manufacture of solid dispersions, such as fusion/melt technology, hot melt extrusion, solvent evaporation (i.e. freeze drying, spray drying or layering of powders of granules), coprecipitation, supercritical fluid technology and electrostatic spinning method which are for example described in WO 2006/026500 or in WO 2014/039677.
  • the pharmaceutical composition which is a solid dispersion the compound of the invention is preferably substantially amorphous.
  • the pharmaceutical composition can be coated by a polyvinyl alcohol based polymer as film-forming agent.
  • the polyvinyl alcohol based polymer according to the present invention includes but is not limited to fully hydrolysed polyvinyl alcohol polymer, partially hydrolysed polyvinyl alcohol polymer (contains free alcohol groups and esterified alcohol groups i.e. as acetate) esterified polyvinyl alcohol polymer for example polyvinyl acetate polymer, a co-polymer of the aforementioned with polyethylene glycol for example a polyvinyl alcohol-polyethylene glycol co-polymer or a mixture of the aforementioned. Preference is given to a partially hydrolysed polyvinyl alcohol polymer.
  • the polyvinyl alcohol based polymer in the coating is present in an amount of 30 to 70%, preferably 35 to 60%, more preferably 35 to 50% by weight of the total coating.
  • the coating of the pharmaceutical composition of the present invention comprises optionally one or more further pharmaceutically acceptable excipients such as plasticizers, colorants, opacifiers, anti-tacking agents, dispersing agents and suspending agents.
  • Plasticizers which may be used in the coating include but are not limited to polyethylene glycol, propylene glycol, sorbitol, glycerol, maltitol, xylitol, mannitol. crythritol. glycerol trioleate, tributyl citrate, tri ethyl citrate acetyl triethyl citrate, glyceryl triacetate, stearic acid, medium chain triglycerides or a mixture thereof. Preference is given to polyethylene glycol, medium chain triglycerides and/or stearic acid.
  • the plasticizer in the coating may be present in an amount of 5 to 30%, preferably 8 to 25%, more preferably 10 to 20% by weight of the total coating.
  • Colorants which may be used in the coating include but are not limited to ferric oxide red, ferric oxide yellow, ferric oxide black, titanium dioxide, indigotine, sunset yellow FCF, tartrazin, erythrosine, quinoline yellow, carbon black, anthocyanin, riboflavin, carmine, curcumin, chlorophyll, carotene or a mixture thereof. Preference is given to ferric oxides and titanium dioxide.
  • the colorants in sum in the coating are present in an amount of 5 to 40%, preferably 8 to 30%, more preferably 10 to 20% by weight of the total coating.
  • Anti-tacking agents which may be used in the coating include but are not limited to talc, magnesium stearate, stearic acid, lecithin, soy lecithin, mineral oil, carnauba wax, acetylated monoglycerides, polysorbate or a mixture thereof. Preference is given to talc, lecithin, soy lecithin, and polysorbate. Anti-tacking agents in sum in the coating are present in an amount of 3 to 30%, preferably 5 to 25%, more preferably 10 to 20%> by weight of the total coating.
  • Opacifiers which may be used in the coating include by are not limited to talc and titanium dioxide. Opacifiers in sum in the coating are present in an amount of 10 to 45%, preferably 15 to 35%, more preferably 15 to 25% by weight of the total coating.
  • the coating material can be prepared from the individual components as mentioned before.
  • ready-to-use mixtures can be used which include but are not limited to for example OpadryTM II 85G35294 pink, OpadryTM II 85G25457 red, OpadryTM II 85G23665 orange (provided by Colorcon), KollicoatTM IR white (provided by BASF), SepifilmTM IR (provided by SEPPIC). Preference is given to OpadryTM II 85G35294 pink, OpadryTM II 85G25457 red, OpadryTM II 85G23665 orange.
  • the compound of the invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the compound of the invention can be combined with known anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • Optional anti-hyper-proliferative agents which can be added to the compositions include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 ⁇ Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednis
  • compositions of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ.
  • anti-hyper-proliferative agents suitable for use with the compositions of the invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.
  • the use of the combinations of the present invention mentioned before will serve to: (1) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone,
  • Combination means for the purposes of the invention not only a dosage form which contains all the components (so-called fixed combinations), and combination packs containing the components separate from one another, but also components which are administered simultaneously or sequentially, as long as they are employed for the prophylaxis or treatment of the same disease. It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein.
  • Example 1 Coated tablet comprising regorafenib a) Solid dispersion
  • OpadryTM II 85G35294 pink contains polyvinyl alcohol (partially hydrolyzed) [44% by weight of the total mixture], polyethylenglycol (PEG 3350) [12.4% by weight of the total mixture], lecithin (soya), ferric oxides, titanium dioxide and talc.
  • Table 2 Composition of tablets containing regorafenib
  • Example 1 The formulation of Example 1 has also been manufactured in different, i.e. larger scales. The ratio of ingredients and the operating principle of the equipment was the same. Clinical Study:
  • regorafenib demonstrated significant improvement in Overall Survival' (OS) and 'Progression -free survival' (PFS) vs. placebo in subjects with metastatic colorectal cancer (mCRC) who had progressed on standard therapies.
  • OS Overall Survival'
  • PFS 'Progression -free survival'
  • mCRC metastatic colorectal cancer
  • Table 3 Frequency of subtypes in dataset by Marisa et al. (2013) and in CORRECT (frequency (n)).

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Abstract

La présente invention concerne l'utilisation du régorafénib, un hydrate, un solvate, un métabolite ou un sel pharmaceutiquement acceptable de celui-ci ou un polymorphe de celui-ci pour le traitement du cancer colorectal chez l'homme répondant favorablement au régorafénib.
PCT/EP2016/059117 2015-04-28 2016-04-25 Régorafénib pour le traitement du cancer colorectal Ceased WO2016173959A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
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WO2018219807A1 (fr) * 2017-06-02 2018-12-06 Bayer Aktiengesellschaft Combinaison de régorafénib et d'inhibiteurs de pd-1/pd-l1(2) pour le traitement du cancer
KR102413226B1 (ko) * 2021-08-26 2022-06-23 충북대학교 산학협력단 레고라페닙을 유효성분으로 포함하는 항노화 조성물

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