WO2016173959A1

WO2016173959A1 - Regorafenib for treating colorectal cancer

Info

Publication number: WO2016173959A1
Application number: PCT/EP2016/059117
Authority: WO
Inventors: Michael Teufel; Henrik Seidel; Susanne Schwenke
Original assignee: Bayer Pharma Aktiengesellschaft
Priority date: 2015-04-28
Filing date: 2016-04-25
Publication date: 2016-11-03
Also published as: WO2020193458A1

Abstract

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.

Description

Regorafenib for Treating Colorectal Cancer

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. Worldwide nearly 1.25 million patients are diagnosed with colorectal cancer and more than 600 000 patients die therefrom each year. At least 50% of patients develop metastases and most of these patients have unresectable tumours (Ann Oncol, 21 (suppl 2) (2010), pp. v93-v97). 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). In patients with KRAS wild-type tumours, 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. EGFR, VEGF receptor, platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR)) and downstream signalling cascades (RAS-RAF-MEK-ERK and PI3K-PTEN-AKT-mTOR), (Clin Colorectal Cancer, 11 (2012), pp. 1-13). Standard treatment regimens for metastatic colorectal cancer (CRC) 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). The availability of these agents has contributed to incremental benefits in overall survival (OS), progression-free survival (PFS), and response rates in CRC (Joulain, F. et al. Br. J. Cancer. 109, 1735-1743 (2013)). Marisa et al. ((2013) 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). Unsupervised consensus hierarchical clustering applied to gene expression data from a discovery subset of 443 CC samples identified six molecular subtypes (CI (n = 95, 21%), C2 (n = 83, 19%), C3 (n =56, 13%), C4 (n= 46, 10%), C5 (n = 118, 27%), and C6 (n = 45, 10%) (Figure 1 ; Table S2)). These subtypes are associated with distinct clinicopathological characteristics, molecular alterations, specific enrichments of supervised gene expression signatures (stem cell phenotype-like, normal-like, serrated CRC phenotype-like), and deregulated signaling pathways. Based on their main biological characteristics, 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. the CORRECT trial (patients with metastatic colorectal cancer treated with regorafenib or placebo after failure of standard therapy) assessed efficacy and safety of regorafenib in patients with metastatic colorectal cancer, progressing after all approved standard therapies (The Lancet, Volume 381, Issue 9863, 26 January-1 February 2013, Pages 303-312).

Regorafenib which is 4 {4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}- pyridine-2-carboxylic acid methylamide, a compound of formula (I)

is described in WO 2005/009961. Furthermore salts of the compound of formula (I) such as its hydrochloride, mesylate and phenylsulfonate are mentioned in WO 2005/009961. The monohydrate of the compound of formula (I) is mentioned in WO 2008/043446. An improved process for the manufacturing of regorafenib in high purity is described in WO 201 1/128261. Due to the limited solubility of regorafenib monohydrate an applicable pharmaceutical composition containing regorafenib is in form of a solid dispersion as described in WO 2006/026500 and WO 2014/039677.

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. Surprisingly 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.

Furthermore 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.

Patient Stratification:

Humans suffering colorectal cancer can be classified into six sub-groups CI to C6 (Marisa et al. ((2013) PLoS Med 10(5): el001453, including the supplementary methods Text SI). Gene expression data normalization

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))

(2) to have a variance significantly different from the median variance of all probe sets (i.e. variance test p-value<0-01)

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.

(3) to have a high robust coefficient of variation (rCV > 0- 186). 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

The subtypes were determined using the consensus clustering approach described in Monti et al ((2003) Machine learning 52:91-118) and implemented in the R package ConsensusClusterPlus (Matt Wilkerson (2011). ConsensusClusterPlus: ConsensusClusterPlus. R package version 1.6.0). In brief, a clustering analysis is performed n times on subsets of the probe sets and of the samples selected randomly. Then all derived partitions for a given number of clusters k are summarized by clustering the (samples x samples) co-classification matrix*. The whole data were first gene median centered and the parameters used were set as follows:

- Clustering algorithm: hierarchical clustering - Clustering metrics: (1 -Pearson correlation) distance and Ward linkage

- n resamplings: 1000

- Proportion of samples and probe sets used in each resampling: 90%,

- k tested: from 2 to 8.

As described in Monti et al, ((2003) Machine learning 52:91-118) 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.

Molecular subtype prediction

To assign a subtype to each sample from the validation series, 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 |log2 fold change|>0-5) were retained

- Then 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.

- To avoid the selection of highly correlated probe sets (redundancy) probe sets are clustered using hierarchical clustering (distance=l -Pearson, linkage method=Ward), cut the tree to isolate uncorrelated clusters (tree cut-off (1 -correlation) = 0.9) and kept one probe set per cluster, the one having the best AUC and a gene symbol annotation.

- To select the 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.

Using those probe sets, 6 centroids are computed on the gene-median centered discovery dataset and for each validation dataset (RMA normalized and gene-median centered), the distance to the 6 centroids of each sample is computed and samples are assigned to the closest centroid subtype. The decision rule is based on the diagonal quadratic discriminant analysis method (DQDA) and is defined as follows:

DQD .X -

where N is the number of genes (here N=57), x the expression normalized values, μ) ,ί and vj,i the mean and the variance of the gene i across samples of the subtype j from the discovery data set (i.e. the centroid). 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). More specifically, 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.

Table 1 :

CIT Probe Set Gene Chromosomal Entrez

CCMST ID Symbol Location Gene

CI 224376_ s at C20orf24 chr20ql l .23 55969

CI 202924_ s at PLAGL2 chr20ql l .21 5326

CI 229215_. at ASCL2 chrl lpl5.5 430

CI 210052_ s at TPX2 chr20ql l .2 22974

CI 204044_ at QPRT chrl6pl l .2 23475

CI 227276_ at PLXDC2 chrl Op 12.31 84898

CI 202478_ at TRIB2 chr2p24.3 28951

CI 225636_ at STAT2 chrl2ql3.3 6773

C1.C2 226459 at PIK3AP1 chrl0q24.1 118788

CI 226545_ at CD 109 chr6ql3 135228

C2 219403 s at HPSE chr4q21.3 10855

C2 218802_ at CCDC109B chr4q25 55013

C2 200629_ at WARS chrl4q32.31 7453

C2 219211 at USP18 chr22ql l .21 11274

C2 220936_ s at H2AFJ chrl2pl2 55766

C2 212062 at ATP9A chr20ql3.2 10079

C2 209108_ at TSPAN6 chrXq22 7105

C2 213169_ at SEMA5A chr5pl5.2 9037

C2 222244_ s at TUG1 chr22ql2.2 55000

C3,C5 203240_ at FCGBP chrl 9ql 3.1 8857

C3 222764_ at ASRGL1 chrl lql 2.3 80150

C3 214106 s at GMDS chr6p25 2762

C3 223970_ at RETNLB chr3ql3.1 84666

C3 220929_ at GALNT8 chrl2pl3.3 26290

C3 201147 s at TIMP3 chr22ql2.1- 7078

ql3.2|22ql2.3

C3 203748_ x at RBMS1 chr2q24.2 5937

C3 224791_ at ASAP1 chr8q24.1- 50807

q24.2

C3 211959_ at IGFBP5 chr2q33-q36 3488

C3,C5 217853_ at TNS3 chr7pl2.3 64759

C4 226069_ at PRICKLE 1 chrl2ql2 144165

C4 202291 s at MGP chrl 2p 12.3 4256 C4 225464_at FRMD6 chrl4q22.1 122786

C4 221019_s_at COLEC12 chrl 8pter- l l .3 81035

C4 210517_s_at AKAP12 chr6q24-q25 9590

C4 218687_s_at MUC13 chr3q21.2 56667

C4 204130_at HSD11B2 chrl6q22 3291

C4 235350_at C4orfl9 chr4pl4 55286

C4 222904_s_at TMC5 chrl6pl2.3 79838

C4 211715_s_at BDH1 chr3q29 622

C5 212406_s_at PCMTD2 chr20ql3.33 55251

C5 213090_s_at TAF4 chr20ql3.33 6874

C5 218641_at Cl lorf95 chrl lql3 65998

C5 223253_at EPDR1 chr7pl4.1 54749

C5 223447_at REG4 chrlpl3.1-pl2 83998

C5 209114_at TSPAN1 chrlp34.1 10103

C5 228232_s_at VSIG2 chrl lq24 23584

C5 213059_at CREB3L1 chrl lpl l .2 90993

C6 214142_at ZG16 chrl6pl l .2 653808

C6 205950_s_at CA1 chr8q21.2 759

C6 207432_at BEST2 chrl9pl3.2 54831

C6 204697_s_at CHGA chrl4q32 1113

C6 209301 at CA2 chr8q22 760

C6 1553956_at ALS2CR4 — 65062

C6 226661 at CDCA2 chr8p21.2 157313

C6 227801_at TRIM59 chr3q25.33 286827

C6 228774_at CEP78 chr9q21.2 84131

C6 209527_at EXOSC2 chr9q34 23404

Regorafenib is the compound of the formula (I)

The term "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). The term "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. In addition, pharmaceutically acceptable salts include salts of inorganic bases, such as 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). Preference is given to the hydrochloride, mesylate or phenylsulfonate salt of regorafenib.

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 monohydrate of regorafenib as a compound of the present invention.

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.

Preference is given to an amount of the compound of the invention in the pharmaceutical composition from 4 to 400 mg, preferably from 10 to 200 mg, more preferably from 10 to 100 mg.

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.

Nevertheless, it may in some cases be advantageous to deviate from the amounts specified, depending on body weight, individual behavior toward the active ingredient, type of preparation and time or interval over which the administration is affected. For instance, less than the aforementioned minimum amounts may be sufficient in some cases, while the upper limit specified has to be exceeded in other cases. In the case of administration of relatively large amounts, it may be advisable to divide these into several individual doses over the day. This pharmaceutical composition will be utilized to achieve the desired pharmacological effect by preferably oral administration to a patient in need thereof, and will have advantageous properties in terms of drug release, bioavailability, and/or compliance in mammals. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease.

Preference is given to a pharmaceutical composition which is a an immediate release tablet.

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.

Pharmaceutical 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.

Of particular interest is a pharmaceutical composition in the form of a solid dispersion or a pharmaceutical composition comprising a solid dispersion. 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.

The term "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.

Of particular interest is a pharmaceutical 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. 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. In a preferred embodiment 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.

Furthermore 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, β-cyclodextrin, hydroxypropyl-B-cyclodextrin or sulfobutyl ether cyclodextrin or a mixture thereof.

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.

Additional suitable excipients that are useful in the formation of the matrix of the solid dispersion include, but are not limited to alcohols, organic acids, organic bases, amino acids, phospholipids, waxes, salts, fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and urea.

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.

Another aspect of the invention of particular interest are 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. Preferably the solid dispersion comprises microcrystalline cellulose and/or croscarmellose sodium.

In another preferred embodiment, 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.

Furthermore 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. Alternatively ready-to-use mixtures can be used which include but are not limited to for example Opadry™ II 85G35294 pink, Opadry™ II 85G25457 red, Opadry™ II 85G23665 orange (provided by Colorcon), Kollicoat™ IR white (provided by BASF), Sepifilm™ IR (provided by SEPPIC). Preference is given to Opadry™ II 85G35294 pink, Opadry™ II 85G25457 red, Opadry™ II 85G23665 orange.

Combination with other pharmaceutical agents:

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. For example, 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 ^Λ 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, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use with the 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. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2', 2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.

Other 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.

Generally, 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,

(2) provide for the administration of lesser amounts of the administered chemotherapeutic agents,

(3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies,

(4) provide for treating a broader spectrum of different cancer types in mammals, especially humans,

(5) provide for a higher response rate among treated patients, (6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments,

(7) provide a longer time for tumor progression, and/or

(8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects. "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.

All publications, applications and patents cited above and below are incorporated herein by reference.

The weight data are, unless stated otherwise, percentages by weight and parts are parts by weight.

Examples:

Example 1 : Coated tablet comprising regorafenib a) Solid dispersion

A solution of 0.415 kg of regorafenib monohydrate (corresponding to 0.40 kg regorafenib) and 1.60 kg of polyvinyl pyrrolidone (PVP 25) in a mixture of 4.80 kg acetone and 1.20 kg ethanol was prepared. Using a fluidized bed vacuum granulator this solution was sprayed onto a powder bed of 1.00 kg croscarmellose sodium and 1.00 kg microcrystalline cellulose at a temperature of 60 - 70°C. b) Tableting The granulate of step a) was roller compacted and screened 3.15 mm and 1.0 mm. Subsequently the compacted granulate was blended with 0.54 kg croscarmellose sodium, 0.0240 kg colloidal anhydrous silica and 0.0360 kg magnesium stearate. This ready-to-press blend was compressed on a rotary tablet press into tablets containing 20 mg and 40 mg of regorafenib. c) Film coating For coating of the 20 mg tablets 0.160 kg of Opadry™ II 85G35294 pink was homogeneously dispersed in 0.640 kg water. For coating of the 40 mg tablets 0.120 kg of Opadry™ II 85G35294 pink was homogeneously dispersed in 0.480 kg water. These coating suspensions were sprayed onto the 20 mg respectively 40 mg tablets of step b) in a perforated drum coater at an outlet air temperature of 35°C. The coating process resulted in evenly coated tablets with a smooth surface. Coating defects could not be observed.

Commercially available Opadry™ 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

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:

In the CORRECT Ph3 trial, 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. Initial biomarker subgroup analyses presented by Jeffers et al. (2013) J Clin Oncol 31, 2013 (suppl 4; abstr 381) suggested that regorafenib was associated with clinical benefit (vs. placebo) in all mutational subgroups.

Methods: Archival tissue collected from 281 patients enrolled in CORRECT were subjected to gene expression analysis using Affymetrix Gene ST1.0 array. For a hypothesis-free analysis of the various data types, Cox proportional hazards models were used to identify potentially prognostic or predictive biomarkers and to build signatures for the prediction of OS and PFS. Gene expression data were subjected to hierarchical molecular tumor classification gene signatures using the tools provided by Marisa (2014) - in particular the algorithm and the underlying software - aiming to identify molecular CRC subgroups that correlate with clinical response. Cox proportional hazard models for both survival endpoints were built for each of the two subtype definitions suggested by Marisa et al. (2013): the six originally discovered subtypes, and the two- class signature combining subtypes 'C4' ('CSC') and 'C6' ('CINnormL') in one class and the other subtypes in a second class.

Results: Hypothesis-free analysis of gene expression data did not reveal distinct effects with respect to OS or PFS. The data were subsequently subjected to published CRC gene signatures describing different molecular subtypes. Table 3 exemplifies the distribution of samples in the six different subtypes as originally given in Marisa et al. (2013) as well as for all 281 samples from CORRECT and moreover for those 271 samples from CORRECT classified into the core set.

Table 3: Frequency of subtypes in dataset by Marisa et al. (2013) and in CORRECT (frequency (n)).

Weak evidence was found for an interaction effect between treatment and subtype for PFS (p=0.0831). Whereas within the placebo-treated patients, there was no evidence for a difference between the two subtypes (p=0.7813, HR=0.902, CI=[0.461 ; 2.035]), evidence of an improved survival for the subgroup 'C4&C6' as compared to 'CI, C2, C3 & C5' (p=0.0301, HR=1.986, CI=[1.120; 3.917]) was found within the regorafenib treated group. It has to be noted, though, that the combined group 'C4&C6' contained only 26 patients, thus a confirmation of this result has to be sought on an independent data set.

Claims

What is claimed is:

1. 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.

2. 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 sub-group C4 or C6.

3. A pharmaceutical composition containing 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.

4. 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 a pharmaceutical composition containing 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 sub-group C4 or C6.