WO2014058785A1

WO2014058785A1 - Combination therapy

Info

Publication number: WO2014058785A1
Application number: PCT/US2013/063696
Authority: WO
Inventors: Michael NIEDBALA; Michael Shi; Paul CORN
Original assignee: Novartis Ag; Board Of Regents, The University Of Texas System
Priority date: 2012-10-10
Filing date: 2013-10-07
Publication date: 2014-04-17
Also published as: AR092935A1; TW201420102A

Abstract

A pharmaceutical combination comprising (a) a RTK inhibitor selected from the group consisting of compounds of Formula I or a tautomer thereof, compounds of Formula II or a tautomer thereof, compounds of Formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof; and (b) one or more CYP17 inhibitors such as abiraterone; and methods of treating a subject suffering from a proliferative disease comprising administering a therapeutically effective amount of such combination.

Description

COMBINATION THERAPY

FIELD OF THE INVENTION

A pharmaceutical combination comprising: (a) at least one receptor tyrosine kinase (RT ) inhibitor compounds targeting/decreasing a protein or lipid kinase activity, selected front the group consisting of compounds of Formula I or a tautomer thereof, compounds of Formula II or a tautomer thereof! compounds of Formula ΙΠ or a tautomer thereof, a pharmaceutical ly acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof; and (b) one or more CYP17 inhibitors, or a pharmaceutically acceptable salt thereof; such as (3β)- 1 7-(pyridin-3-y!)androsta-5J6-dien-3-ol (abiraterone), abiraterone acetate, l -(2- cbloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-tmidazolidin-2-one, ketoconazole or VN/ 124-1 (TQK-OG I ); the uses of such combination in the treatment or prevention of proliferative diseases such as prostate cancer; and methods of treating a subject suffering from a proliferative disease comprising administering a therapeutically effective amount of such combination.

BACKGROUND OF THE INVENTION

Standard front-line androgen deprivation therapy (ADT) with medical castration (e.g. with LHRH agonists) initially induces a remission in 80% to 90% of patients with advanced prostate cancer. After progression on medical castration, patients can typically be "re-induced" into remission with conventional second-line hormonal ablative therapies including non-steroidal anti-androgens (e.g. bicalutamide), ketoconaozole, and DES. The successful application of serial andogen-ablative therapies results in a median progression-free survival of 12 to 33 months, at which time a castrate-resistant phenotype dominates. Prostate cancer preferentially metastasizes to the skeleton, where it elicits an osteoblastic reaction that can produce significant pain, constitutional symptoms, anemia, and death. Until recently, after exhaustion of standard androgen-ablative therapies, patients with metastatic castrate-resistant prostate cancer (mCRPC) had few options besides cytotoxic chemotherapy. Unfortunately, however, chemotherapy results in only a modest survival benefit and is associated with significant toxicities. Efforts to advance therapy options beyond chemotherapy have met with littie success until recently, when insights about basic prostate cancer biology encouraged rational integration of novel ''targeted" agents that inhibit critical growth-promoting pathways involved in the development of castrate-resistant disease. Three principal insights have emerged from transiationai research:

1 ) During the evolution of castrate-resistant disease, there is a shift in androgen biosynthesis from endocrine (testes and adrenal glands) to paracrine/autocrine sources within the tumor-bone microenvironment. Intratumoral production of androgens (in addition to endocrine) is potently inhibited by novel CYPI 7 inhibitors such as Abiraterone.

2) Androgen receptor (AR)-independent, "stromal-epithelial" growth signaling pathways involved in norma! prostate gland development frequently become dysreguiated during the evolution of castrate-resistant disease. Examples of such pathways include c- et, NOTCH, and FGF signaling. These pathways have presented novel targets for small molecule

therapeutics.

3) The relatively modest effectiveness of agents that block stromal-epithelial interacting pathways suggests that persistent intratumoral androgen signaling is the dominant survival pathway driving castrate-resistant growth in bone. This line of reasoning has led to the hypothesis that efficient inhibition of ntratumoral androgen signaling will be a critical aspect of rational combinatorial strategies with small molecule therapeutics that target stromal-epithelial interacting pathways.

Abiraterone was recently FDA-approved for the treatment of patients with mCRPC who have previously received docetaxel after it was shown to prolong overall survival in a randomized phase 111 study. After a median follow-up of 12.8 months, overall survival was longer in the abiraterone-prednisone group than in the placebo-prednisone group (14.8 months vs. .10.9 months; hazard ratio, 0.65; 95% confidence interval 0.54 to 0.77; PO.00.1 ). Despite these encouraging results, up to one third of patients do not appear to respond to abiraterone and the remaining 70% who do will eventually progress. Molecular-pathologic analysis of tumor-

9 infiltrated bone marrow biopsies revealed that homogeneous, intense nuclear expression of AR, combined with >10% CYP 1 7 tumor expression, was correlated with iongertime to treatment discontinuation (>4 months). Taken together, these findings suggest that androgen receptor (AR)-independent growth pathways promote castrate-resistant growth following Abiraterone.

The compounds of Formula 1, Formula II and Formula il l inhibit various protein kinases, such as receptor tyrosine kinases (RTKs). Receptor tyrosine kinases (RTKs) are transmembrane polypeptides that regulate developmental cell growth and differentiation, remodeling and regeneration of adult tissues. Polypeptide ligands known as growth factors or cytokines, are known to activate RTKs. Signalling RTKs involves ligand binding and a shift in conformation in the external domain of the receptor resulting in its dimertzation. Binding of the ligand to the RTK results in receptor irans-phosphor lation at specific tyrosine residues and subsequent activation of the catalytic domains for the phosphorylation of cytoplasmic substrates.

Two subfamilies of RTKs are specific to the vascular endothelium. These include the vascular endothelial growth factor (VEGF) subfamily and the Tie receptor subfamily. Class ill RTKs include vascular endothelial growth factor receptor 1 (VEGFR-1). vascular endothelial growth factor receptor 2 (VEGFR-2), and vascular endothelial growth factor receptor 3

(VEGFR-3).

Inhibited tyrosine kinases include Cdc2 kinase (cell division cycle 2 kinase), Fyn (FY oncogene kinase related to SRC, PGR, YES), Lck (lymphocyte-specific protein tyrosine kinase), c- it (stem cell factor receptor or mast cell growth factor receptor). p60src (tyrosine kinase originally identified as the v-src oncogene of the rous sarcoma virus), c-ABL (tyrosine kinase that stands for an oncogene product originally isolated from the Adelson leukemia virus), VEGFR3. PDGFRa (platelet derived growth factor receptor a), PDGFRp (platelet derived growth factor receptor β), FGFR3 (fibroblast growth factor receptor 3), FLT-3 (fms-like tyrosine kinase-3). or Tie-2 (tyrosine kinase with lg and EGF homology domains).

it has been discovered that a pharmaceutical combination comprising: (a) at least one receptor tyrosine kinase (RTK) inhibitor compounds targeting/decreasing a protein or lipid kinase activity, selected from the group consisting of compounds of Formula ! or a tautomer thereof, compounds of Formula Π or a tautomer thereof, compounds of Formula ill. or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceuticaliy acceptable salt of the tautomer, or a mixture thereof; and (b) one or more CY.P17 inhibitors, or a

pharmaceutically acceptable salt thereof improves the anti-tumoral activity of a CYP 17 inhibitor such as Abiraterone by inhibiting FGF, an A R- independent signaling pathway that contributes to Abiraterone resistance.

SUMMA R Y OF THE INVEN TION

The present invention relates to a pharmaceutical combination comprising: (a) at least one RTK inhibitor compound, selected from the group consisting of compounds of Formula 1 or a tautomer thereof, compounds of Formula i ! or a tautomer thereof, compounds of Formula I II or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof; and (b) one or more CYP 17 inhibitors, or a pharmaceutically acceptable salt thereof; such as (3p)-17-(pyridin-3-yl)androsta-5, 16-dten-3-ol (abiraterone), abiraterone acetate, I -(2-chIoro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)- imidazolidin-2-one, ketoconazole or VN/ 124-1 (TOK-G01); for simultaneous, separate or sequential administration, in particular for treating or preventing a proliferative disease.

The present invention also pertains to a combination such as a combined preparation of a pharmaceutical combination comprising: (a) at least one RTK inhibitor compound selected from the group consisting of compounds of Formula 1 or a tautomer thereof, compounds of Formula 11 or a tautomer thereof, compounds of Formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable sale of the tautomer, or a mixture thereof; and (b) one or more CY P17 inhibitors, or a pharmaceutically acceptable salt thereof; such as as (3p)-17-(pyridin-3-y!)androsta-5, 16-dien-3-ol (abiraterone), abiraterone acetate, l-(2- chloro-pyridm-4-yi)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one, ketoconazole or VN/ 124- 1 (TOK-001).

The present invention particularly pertains to a COMBINATION OF THE INVENTION useful for treating or preventing a proliferative disease in a subject in need thereof. The present invention aiso pertains to a COMBINATION OF THE INVENTION for use in the preparation of a pharmaceutical composition or medicament for the treatment or prevention of a proliferative disease in a subject in need thereof.

DE TAILED DESCRIPTION OF THE .INVENTION

The general terms used herein are defined with the following meanings, unless explicitly stated otherwise:

The terms "comprising" and "including" are used herein in their open-ended and nonlimittng sense unless otherwise noted.

The terms "a" and "an" and "the" and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.

The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oi l, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's

Pharmaceutical Sciences^" by E. W. Martin.

The term "combination" or "pharmaceutical combination", as used herein, defines either a fixed combination in one dosage unit form, or non-fixed combination (or a kit of parts) for the combined administration where a compound of the Formula 1, Formula 11 or Formula i l l and a combination partner (e.g. a CYP 17 inhibitor drug as explained below, also referred to as "therapeutic agent^" or "co-agent^") may be administered independently at the same time or separateiv within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect. The term "combined administration" or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "fixed combination^" means that the active ingredients, e.g. a compound of Formula ( 1), Formula 11 or Formula ill and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The terms "non-fixed combination" or "kit of parts^" mean that the active ingredients, e.g. a compound of Formula I, Formula 11 or Formula i l l and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

The term "CYP 17 inhibitor", as used herein, relates to a compound which inhibits cytochrome P450, 17-a-I-lydroxylase, 17-20 lyase (CYP 17), a mufti functional enzyme that plays a key role in the biosynthesis of steroid hormones. The term includes, but is not limited to, (3β)- 1 7-(pyridin-3-yi)androsta-5,16-dien-3-o! (abiraterone), abiraterone acetate, (Abiraterone has been discussed in patents such as WO 200900132, WO 2008024485, WO 2006021776, WO 09509178, WO 09320097), 1 -(2-chloro-pyridin-4-> )-3-(4-methyl-pyridin-3-yl)-irnidazolidin-2- one, ketoconazo!e and VN/124- 1 (TOK-001).

Kfto-iwiajcok'. i Abiri»uw»<?, 2 VN/J 2- i^'K> -9t)l), 5

The term " T inhibitors" as used herein, includes, but is not limited to, protein tyrosine kinase and'or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, for example: i) compounds targeting, decreasing or inhibiting the activity of the vascular

endothelial growth factor-receptors (VEGF), such as compounds which target, decrease or inhibit the activity of VEGF, especially compounds which inhibit the VEGF receptor, such as, but not limited to. 7H-pyrrolo[2,3-d]pyrimidine derivatives (AEE788); BAY 43-9006: isochoiine compounds disclosed in WO 00/09495 such as (4-t^·sr but !- h yl)-94- >τ^din-4- lmethyi soqum iin-ί -yi)- amine (AAL88 ! }; and

ii) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, e.g., a A-phenyl-2-pyrimidine-amine derivative, e.g., imatmib, SU 101 , SU0668 and GFB- n i ;

iii) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR);

iv) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family;

v) compounds targeting, decreasing or inhibiting the activity of the FLT3 receptor tyrosine kinase family; and

vi) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases (part of the PDGFR. family), such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, e.g., imatinib; and vii) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase, such as imatinib mesylate (GLEEVEC); tyrphostin or

pyrymidylaminobenzamide and derivatives thereof (TASIGNA). A tyrphostin is preferably a low molecular weight (M_r <1500) compound, or a pharmaceuticai iy acceptable salt thereof, especially a compound selected from the benzylidenemalonitrile class or the S-arylbenzenemalonirile or bisubstrate quinoline class of compounds, more especially any compound selected from the group consisting of Tyrphostin A23/RG-508.10, AG 99, Tyrphostin AG 213, Tyrphostin AG 1748, Tyrphostin AG 490, Tyrphostin B44, Tyrphostin B44 (+) enantiomer, Tyrphostin AG 555, AG 494, Tyrphostin AG 556; AG957 and adaphostin (4-{[(2.5-dihydroxyphenyl)methyi]amino}-benzotc acid adamantyl ester, NSC 680410, adaphostin).

The term "pharmaceuticai composition" is defined herein to refer to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human, in order to prevent or treat a particular disease or condition affecting the mammal.

The term "pharmaceutically acceptable" is defined herein to refer to those compounds, materials, compositions and for dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues a subject, e.g., a mammal or human, without excessive toxicity, irritation allergic response and other problem complications commensurate with a reasonable benefit / risk ratio.

The term "co-administration" or "combined administration" as used herein is defined to encompass the administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

The term "treating" or "treatment" as used herein comprises a treatment relieving, reducing or alleviating at least one symptom in a subject or eff ecting a delay of progression of a disease. For example, treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer. Within the meaning of the present invention, the term "treat" also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease. The term "protect" is used herein to mean prevent delay or treat, or all, as appropriate, development or continuance or aggravation of a disease in a subject.

The term "prevent", "preventing" or "prevention" as used herein comprises the prevention of at least, one symptom associated with or caused by the state, disease or disorder being prevented.

The term "jointly therapeutically active" or "joint therapeutic effect" means that the therapeutic agents may be given separately (in a chronologically staggered manner, especially a sequence-specific manner) in such time intervals that they prefer, in the warm-blooded animal, especially human, to be treated, still show a (preferably synergistic) interaction (joint therapeutic effect). Whether this is the case can, inter alia, be determined by following the blood levels, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals.

The term "pharmaceutically effective amount" or "clinically effective amount" of a combination of therapeutic agents is an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the disorder treated with the combination.

The term "subject" or "patient" as used herein includes animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits rats and transgenic non-human animals, in the preferred embodiment, the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancers. The term about" or "approximately" shall have the meaning of within 10%, more preferably within 5%, of a given value or range.

Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that e lement. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium.

The phrase "iinsubstituted alkyl" refers to alkyl groups that do not contain heteroatoms. Thus the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyi, hept l, oetyl, nonyi, decyi, undecyi. dodecyl and the like. The phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: -CH(CH₃)₂, -CH(CH₃)(CH₂CH₃), -CH(CH₂CH₃)₂, -C(CH₃)₃, -C(CH₂CH₃)₃, -CH₂CH(CH₃)2_f -CH₂CH(CH₃)(CH₂CH3), -CH₂CH(CH₂CH₃)2, -C¾C(CH₃)₃, -CH₂C(CH₂CHJ)₃, -CH(CH₃)CH(CHJ)(CH₂CH₃), -CH₂CH₂CH(CH₃)_2J

-CH₂CH₂CH(CH₃)(CH₂CH₃), ~CH₂C¾CH(CH₂CH₃)₂, -CH₂CH₂C{CH₃)₃,

-CH₂CH2C(CH2CH3)3, -CH(CH₃)CH₂CH(CH₃)2₅ -CH(CH3)CH(CH3)CH(CH3)2»

-CH(CH₂CH₃)CH(CH₃)CI-I(CH3)(CH₂CH3), and others. The phrase also includes cyclic alkyl groups such as cycloalkyl groups such as cyc!opropyl, cyclobutyl, cyclopenlyl, cyciohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as defined above. The phrase also includes polycyclic alky! groups such as, but not limited to, adamantyl norbornyl, and bicyclo[2.2.2]octyl and such rings substituted with straight and branched chain alkyl groups as defined above. Thus, the phrase iinsubstituted alkyl groups includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Unsubstituted alkyl groups may be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound. Preferred unsubstituted alkyl groups include straight and branched chain alky! groups and cyclic alkyl groups having 1 to 20 carbon atoms. More preferred such unsubstituted alkyl groups have from 1 to 10 carbon atoms while even more preferred such groups have from 1 to 5 carbon atoms. Most preferred unsubstituted alkyl groups include straight and branched chain alkyl groups having from 1 to 4 or from 1 to 3 carbon atoms and include methyl, ethyl, propyl, and -CH(CH₃)₂. The phrase "substituted alky J'^* refers to an unsubstituted alky I group as defined above in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atoms such as, but not limited to, a halogen atom in halides such as F, CI, Br, and I; an oxyge atom in groups such as hydroxy! groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, a!kylamines, dialkylamines. arylamines, alkylarylarnines, diaryiamines, N-oxides, imides, and enamines; a silicon atom in groups such as in triaikylsily! groups, dialkylarylsilyl groups, alkyldiarylsiiyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. Substituted alkyl groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a bond to a heteroatom such as oxygen in carbonyl, carboxyi, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles. Preferred substituted alky! groups include, among others, alkyl groups in which one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluorine atoms. One example of a substituted alkyl group is the trifluoromethyl group and other alkyl groups that contain the trifluoromethyl group. Other alkyl groups include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxy I, alkoxy, aryloxy group, or heterocyciyloxy group. Still other alkyl groups include alk l groups that have an amine, alkylamine, dialkyiamine. arylamine,

(alkyl)(ary!)amine, diary (amine, eterocyclylamine. (alkyl)(heterocyclyl)amine,

(aryl)(heterocyclyi)amine, or diheterocyclylamine group.

The phrase "unsubstituted aryl" refers to aryl groups that do not contain heteroatoms. Thus, by way of example, the phrase includes, but is not limited to, groups such as phenyl, bipheny!, anthracenyl, and naphthyl. Although the phrase "unsubstituted aryl" includes groups containing condensed rings such as naphthalene, it does not include aryi groups that have other groups such as alkyl or halo groups bonded to one of the ring members, as aryl groups such as t.olyl are considered herein to be substituted aryl groups as described below. A preferred unsubstituted aryi group is phenyl. In some embodiments, unsubstituted aryl groups have from 6 to 14 carbon atoms. Unsubstituted aryl groups may be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s). and/or sulfur atom(s) in the parent compound. The phrase "substituted aryi group'^" has the same meaning with respect to unsubstituted aryl groups that substituted alky] groups had with respect to unsubstituted a!kyl groups.

However, a substituted aryl group also includes aryl groups in which one of the aromatic carbons is bonded to one of the non-carbon or non-hydrogen atoms described above and also includes aryi groups in which one or more aromatic carbons of the aryi group is bonded to a substituted or unsubstituted alkyl, alkenyl, or alkynyi group as defined herein. This includes bonding arrangements in which two carbon atoms of an aryl group are bonded to two atoms of an alkyl, alkenyl, or alkynyi group to define a fused ring system (e.g. di.hydronapb.thyl or

ietrahydronaphthyl). Thus, the phrase "substituted aryl" includes, but is not limited to groups such as tolyl, and hydroxyphenyl among others.

The phrase "unsubstituted alkenyl" refers to straight and branched chain and cyclic groups such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Examples include, but are not limited to vinyl, -CH=C(H)(CH₃), -CH=C(C¾)₂, -C(CH₃)-C{H)₂, - C(CH₃)=C(H)(CH₃), -C(Cl¾Cl h)=CH₂, cyclohexenyl, cyclopentenyl, cyelohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. In some embodiments, unsubstituted alkenyl groups have from 2 to 8 carbon atoms.

The phrase "substituted alkenyl" has the same meaning with respect to unsubstituted alkenyl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups. A substituted alkenyl group includes alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon double bonded to another carbon and those in which one of the non-carbon or non-hydrogen atoms is bonded to a carbon not involved in a double bond to another carbon.

The phrase "unsubstituted alkynyi" refers to straight and branched chain groups such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Examples include, but are not limited to -C≡C(H), -CsC(CH₃). -OC(CH₂CH₃), -C(H₂)OC(H), -C(H)₂C≡C(CH₃), and -C(H)₂Cs (CH₂CH₃) among others, in some embodiments, unsubstituted alkynyl groups have from 2 to 8 carbon atoms.

The phrase "substituted alkynyl" has the same meaning with respect to unsubstituted alkyn l groups that substituted alky! groups had with respect to unsubstituted a!kyl groups. A substituted alkynyl group includes alkynyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon triple bonded to another carbon and those in which a non-carbon or non- hydrogen atom is bonded to a carbon not involved in a triple bond to another carbon.

The phrase ''unsubstituted beterocyclyF' refers to both aromatic and nonaromatk ring compounds including monocyclic, bicyciic, and polycyclic ring compounds such as, but not limited to, quinuclidyl, containing 3 or more ring members of which one or more is a heteroatom such as, but not limited to, N, O, and S. Although the phrase "unsubstituted heterocyclyl^" includes condensed heterocyclic rings such as benzimidazolyl, it does not include heterocyclyl groups that have other groups such as alkyl or halo groups bonded to one of the ring members as compounds such as 2-methylbenzimidazolyl are substituted heterocyclyl groups. Examples of heterocyclyl groups include, but are not limited to: unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyi, imidazo!yl, pyrazo!yL pyridinyl. dihydropvridinyl, pyrimidy^'L pyrazinyl, pyridazinyi, triazolyi (e.g. 4H-l ,2,4-triazolyi, l i !-L2,3-triazolyl, 2H- 1 ,2.3 -triazolyi etc.), tetrazolyl, {e.g. lH-tetrazolyl, 2H tetrazoiyi. etc.); saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyi; condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms such as, but not limited to, indolyl, isomdolyl, indolinyl, indoiizinyl. benzimidazolyl, quinolyl. isoquinoiyl. indazolyl, benzotriazolyl; unsaturated 3 to 8 membered rings containing I to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxazolyl, isoxazoiyl, oxadiazolyi (e.g. 1 ,2.4-oxadiazolyi, 1 ,3,4-oxadiazolyl, 1 ,2,5- oxadiazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, morpholinyl; unsaturated condensed heterocyclic groups containing i to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazoly!, benzoxadiazolyl, benzoxaztnyl (e.g. 2H- 1 ,4-benzoxaziny 1 etc.); unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and I to 3 nitrogen atoms such as, but not limited to. thiazolyl. isothiazolyl, thiadiazoiyl (e.g. 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,3,4-thiadiazolyI, i ,2,5 hiadiazoiyl, etc.); saturated 3 to 8 membered rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolodinyi; saturated and unsaturated 3 to 8 membered rings containing I to 2 sulfur atoms such as, but not limited to. thienyL

dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene, tetrahydrothiopyran; unsaturated condensed heterocyclic rings containing ^"1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, benzothiazofyl, benzothiadiazo!yl, benzothiazinyl (e.g. 2H- 1.4-benzothiazinyi, etc.), dihydrobenzothiazinyl (e.g. 2H-3,4~dihydrobenzothiazmyi. etc.), unsaturated 3 to 8 membered rings containing oxygen atoms such as, but not limited to fury 1; unsaturated condensed heterocyclic rings containing i to 2 oxygen atoms such as benzodioxo!yl (e.g. 1 ,3- benzodioxoyl. etc.); unsaturated 3 to 8 membered rings containing an oxygen atom and 1 to 2 sulfur atoms such as, but not limited to, dihydrooxathiinyl; saturated 3 to 8 membered rings containing I to 2 oxygen atoms and 1 to 2 sulfur atoms such as 1 ,4-oxathiane; unsaturated condensed rings containing 1 to 2 sulfur atoms such as benzothienyl, benzodithiinyl; and unsaturated condensed heterocyclic rings containing an oxygen atom and 1 to 2 oxygen atoms such as benzoxathiinyl. Heterocyclyl group also include those described above in which one or more S atoms in the ring is double-bonded to one or two oxygen atoms (sulfoxides and sulfones). For example, heterocyclyl groups include tetrahydrothiophene oxide, and tetrahydrothiophene 1 ,1 -dioxide. Preferred heterocyclyl groups contain 5 or 6 ring members. More preferred heterocyclyl groups include morpholine, piperazine, pipendine, pyrrolidine, imidazole, pyrazole, 1 ,2,3-triazole, 1 ,2,4-trtazole, tetrazole, thiophene, thiomorpholine, thiomorpholine in which the S atom of the thiomorpholine is bonded to one or more O atoms, pyrrole, homopiperazine, oxazolidin-2-one, pyrrol idin-2-one, oxazole, quinuclidine, thiazole, isoxazole, furan. and tetrahydrofuran.

The phrase "substituted heterocyclyl" refers to an unsubstituted heterocyclyl group as defined above in which one or more of the ring members is bonded to a non-hydrogen atom such as described above with respect to substituted a Ik l groups and substituted aryl groups.

Examples, include, but are not limited to, 2-methylbenzimidazolyl, 5-metbylbenzimidazolyl, 5- chlorobenzthiazolyh N-aJkyl piperazinyl groups such as 1 -methyl piperazinyl, piperazine-N- oxide, N-alkyl piperazine N-oxides, 2-phenoxy-thiophene, and 2-chloropyridinyl among others. In addition, substituted heterocyclyl groups also include heterocyclyl groups in which the bond to the non-hydrogen atom is a bond to a carbon atom that is part of a substituted and

unsubstituted ary!, substituted and unsubstituted aralk i, or unsubstituted heterocyclyl group. Examples include but are not limited to 1-benzyipiperidinyl 3-phenythiomorphoiinyl, 3- (pyrrolidin-1 -yl)-pyrrolidinyl. and 4-{ pi per i d in- Ϊ -y 1 )-pi per id ί ny I . Groups such as N-alkyl substituted piperazine groups such as N-methyl piperazine, substituted morphoHne groups, and piperazine -oxide groups such as piperazine N-oxide and N-alkyl piperazine N-oxides are examples of some substituted heterocyclyl groups. Groups such as substituted piperazine groups such as N-alkyl substituted piperazine groups such as -meth l piperazine and the like, substituted morpholine groups, piperazine N-oxide groups, and N-alkyl piperazine N-oxide groups are examples of some substituted heterocyclyl groups that are especially suited as R⁶ or R ' groups.

The phrase "unsubstituted heterocyclylalkyP^" refers to unsubstituted alkyl groups as defined above in which a hydrogen or carbon bond of the unsubstituted alkyl group is replaced with a bond to a heterocyclyl group as defined above. For example, methyl (-Cf h) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a heterocyclyl group, such as if the carbon of the methyl were bonded to carbon 2 of pyridine (one of the carbons bonded to the N of the pyridine) or carbons 3 or 4 of the pyridine, then the compound is an unsubstituted heterocyclyl alk l group.

The phrase "substituted heteroeyc!ylalkyr has the same meaning with respect to unsubstituted heterocycly!alky! groups that substituted aralkyi groups had with respect to unsubstituted aralkyi groups. However, a substituted heterocyc!ylalkyl group also includes groups in which a non-hy drogen atom is bonded to a heteroatom in the heterocyclyl group of the heterocyclylalkyl group such as, but not limited to, a nitrogen atom in the piperidine ring of a piperidinylaikyl group. In addition, a substituted heterocyclylalkyl group also includes groups in which a carbon bond or a hydrogen bond of the alkyl part of the group is replaced by a bond to a substituted and unsubstituted aryl or substituted and unsubstituted aralkyi group. Examples include but are not limited to pbenyi-(piperidin- l -y1)-methyl and phenyi~(morpholin-4-yl)- methyl. The phrase "substituted heterocyclyloxy" refers to a hydroxy! group (-OH) in which the bond to the hydrogen atom is replaced by a bond to a ring atom of an otherwise substituted heterocyciyi group as defined above.

The phrase "unsubstituted aryioxyaikyl^" refers to an unsubstituted aikyl group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to an unsubstituted and group as defined above.

The phrase "substituted aryioxyaikyl" refers to an unsubstituted aryioxyaikyl group as defined above in which a bond to a carbon or hydrogen group of the alkyi group of the aryioxyaikyl group is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted alkyi groups or in which the aryl group of the aryioxyaikyl group is a substituted aryl group as defined above.

The phrase "^'"unsubstituted heterocyclyloxyalkyi'^" refers to an unsubstituted alkyi group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to an unsubstituted heterocyciyi group as defined above.

The phrase "substituted heterocyclyloxyalkyi" refers to an unsubstituted

heterocyclyloxyalkyi group as defined above in which a bond to a carbon or hydrogen group of the alkyi group of the heterocyclyloxyalkyi group is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted alkyi groups or in which the heterocyciyi group of the heterocyclyloxyalkyi group is a substituted heterocyciyi group as defined above.

The phrase "unsubstituted heterocyclylalkoxy" refers to an unsubstituted aikyl group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to the parent compound, and in which another carbon or hydrogen bond of the unsubstituted aikyl group is bonded to an unsubstituted heterocyciyi group as defined above. The phrase ''substituted heterocyclylalkoxy'^" refers to an unsubstituted

heterocyclylalkoxy group as defined above in which a bond to a carbon or hydrogen group of the aikyl group of the heterocyclylaikoxy group is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted alkyi groups or in which the heterocyclyi group of the heterocyclylalkoxy group is a substituted heterocyclyi group as defined above. Further, a substituted heterocyclylalkoxy group also includes groups in which a carbon bond or a hydrogen bond to the alkyi moiety of the group may be substituted with one or more additional substituted and unsubstituted heterocycles. Examples include but are not limited to pyrid-2-ylmorpholin-4- ylmethyl and 2-pyrid-3-yl-2-morpholin-4-ylethyl.

The phrase ''unsubstituted alkoxyalkyl" refers to an unsubstituted aikyl group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to an unsubstituted aikyl group as defined above.

The phrase "substituted alkoxyalkyl" refers to an unsubstituted alkoxyalkyl group as defined above in which a bond to a carbon or hydrogen group of the alky! group and/or the alkoxy group of the alkoxyalkyl group is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted aikyl groups.

The term "'protected" with respect to hydroxy! groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art such as those set forth in Protective Groups in Organic Synthesis, Greene, T.W.: Wuts, P. G. M.. John Wiley & Sons, New York, NY, (3rd Edition, 1999) which can be added or removed using the procedures set forth therein. Examples of protected hydroxy 1 groups include, but are not limited to, siiyl ethers such as those obtained by reaction of a hydroxy I group with a reagent such as, but not limited to, i-butyldimethyl- chlorosiiane, trimethylchlorosilane, triisopropvichlorosiiane. triethyichlorosilane; substituted methyl and ethyl ethers such, as, but not limited to methoxymetbyl ether, methythiomethyl ether. benzyJoxymethyl ether, -butoxymethyl ether. 2-methoxyethoxymethyt ether, tetrahydropyranyl ethers, 1 -ethoxyethyi ether, ally! ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trich!oroacetate. and trifluoracetate. Examples of protected amine groups include, but are not limited to, amides such as, formannde, acetamkie,

trtfluoroaeetamide, and benzamide; tmides, such as phthaiimide. and dithiosuccin imide; and others. Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S -benzyl thioether, and S-4-picolyi thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.

Pharmaceutical combinations of the present invention include (a) at least one RTK inhibi tor compound selected from the group consisting of compounds of Formula Ϊ or a tautomer thereof, compounds of Formula fi or a tautomer thereof, compounds of Formula ! ! I or a tautomer thereof a pharmaceutically acceptable salt of the compound, a pharmaceutical ly acceptable salt of the tautomer, or a mixture thereof.

The RTK inhibitor compound may be selected from a compound of formula 1, a tautomer of the compound, a salt of the compound, a salt of the tautomer, or a mixture thereof, wherein the compound of formula I has the following formula:

wherein:

R^! , R~, R\ and R⁴ may be the same or different and are independently selected from Ci. Br. F, 1, -OR^{! ,J} groups, - Rⁿ R^!2 groups, substituted or unsubstituted primary, secondary tertiary aiky! groups, substituted or unsubstituted ar l groups, substituted or unsubstituted alken l groups, substituted or unsubstitiited alkynyl groups, substituted or imsubstituted heterocyciyl groups, or substituted or imsubstituted

heterocy c ly 1 a Iky 1 gro ups ;

R\ R^b, R⁷, and may be the same or different and are independently selected from H, CI, Br, F, I, -OR^{) 3} groups, ~NR ^l4R ¹ groups, -SR^{! 1} groups, substituted or unsubstituted primary, secondary, or tertiary alky I groups, substituted or unsubstituted aryl groups, substituted or unsubstitirted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyciyl groups, substituted or unsubstituted heterocyciylalkyl groups, substituted or unsubstituted aikoxyalkyl groups,

substituted or unsubstituted aryloxyaikyl groups, or substituted or unsubstituted

heterocy cly loxyaiky 1 groups:

R^t0 and R may be the same or different and are independently selected from substituted or unsubstituted aikyl groups, substituted or unsubstituted aryl groups, substituted or

unsubstituted heterocyciyl groups, substituted or unsubstituted heterocyciylalkyl groups, substituted or unsubstituted aikoxyalkyl groups, substituted or unsubstituted aryloxyaikyl groups, or substituted or unsubstituted beterocyciyloxyalkyi groups;

R^{1 !} and R¹⁴ may be the same or different and are independently selected from substituted or unsubstituted alky ί groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyciyl groups;

R'² and R^!" may be the same or different and are independently selected from substituted or unsubstituted alky I groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyciyl groups; and

R¹⁶ is selected from substituted or unsubstituted aikyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyciyl groups.

The RT inhibitor compound may also be selected from a compound of Formula I I or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof, wherein the

compound of formula 11 has the following formula:

wherein:

R' is a substituted or unsubstituted heterocyclyl group, in some embodiments, R⁷ is a substituted or unsubstituted heterocyclyl group selected from a substituted or unsubstituted piperidin i group, piperazinyl group, or morpholinyl group, in other embodiments, R' is a substituted or unsubstituted N-alkyl piperazinyl group, in further embodiments, R' is a substituted or unsubstituted N-aikyl piperazinyl group and the alkyi group of the N-aikyl piperaziny l comprises from 1 to 4 carbon atoms.

The RTK inhibitor compound may also be selected from a compound of Formula H i or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof, wherein the compound of formula I I! has the following formula:

m Compounds of Formula 11! include 4-amino-5-fluoro-3- 5-(4-methylpiperazin-.l - I)~l H- benzimidazol~2~yl]quinolin-2( l H)~one (Compound A) and (4~ammo-5-fluoro~3-[6~(4- methylpiperazm- 1 -yl)- 1 H-benzimidazol~2~yl]quinolin-2( 1 Fi)-one) (Compound B).

In a preferred embodiment, the pharmaceutical combination of the present invention includes at least one compound of Formula 1 or a tautomer thereof, compound of Formula Π or a tautomer thereof, compound of Formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof that is Compound A.

In another preferred embodiment, the pharmaceutical combination of the present invention includes at least one compound of Formula I or a tautomer thereof, compound of Formula 11 or a tautomer thereof, compound of Formula 01 or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof that is Compound B.

The RTK inhibitor compounds of Formula 1 or a tautomer thereof, compounds of Formula Π or a tautomer thereof, compounds of Formula 111 or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof: formulations of same, and methods for preparing same are described in, for example, WO2002/222598, WO2003/0870 5, WO2005/046589, WO2006/127926, WO2006/124413, WO2007/064719. WO2009/1 1 5562 and WO2012/001074 which are hereby incorporated by reference in entirety.

The compound of the invention may be administered in free form or in pharmaceutically acceptable salt form.

A "pharmaceutically acceptable salt", as used herein, unless otherwise indicated, includes a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid. As salts of inorganic bases, the invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and ammonia. As salts of organic bases, the invention includes, for example, trimethylamine, triethyiamine, pyridine, picoline, ethanoiamine, diethanolamine, and triethanolamine. As salts of inorganic acids, the instant invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid. As salts of organic acids, the instant invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, lactic acid, citric acid, succinic acid, malic acid, methanesuifonic acid, benzenesulfonic acid, and p-toluenesuifonic acid. As salts of basic amino acids, the instant invention includes, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid.

The monolactate salt of the compound of Formula 1 exists in a variety of polymorphs, including, e.g., the monohydrate form and the anhydrous form. Polymorphs occur where the same composition of matter (including its hydrates and solvates) crystallizes in a different lattice arrangement resulting in different thermodynamic and physical properties specific to the particular crystalline form.

Additional pharmaceutically acceptable salts of Compound A and Compound B suitable for the present invention include the salts disclosed in WO2005/04658.

Unless otherwise specified, or clearly indicated by the text, reference to therapeutic agents useful in the pharmaceutical combination of the present invention includes both the free base of the compounds, and all pharmaceutically acceptable salts of the compounds.

The structure of the compounds identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g., Patents international (I MS World Publications). The corresponding content thereof is hereby incorporated by reference.

In each case where citations of patent applications are given herein, the subject matter relating to the compounds is hereby incorporated into the present application by reference. The compounds used as therapeutic agents in the pharmaceutical combinations of the present invention can be prepared and administered as described in the cited documents, respectively. Comprised are likewise the pharmaceutically acceptable salts thereof, the corresponding racemates, diastereoisomers, enantiomers, tautomers, as well as the corresponding crystal modifications of above disclosed compounds where present, e.g. solvates, hydrates and polymorphs, which are disclosed therein. Also withi the scope of this invention is the combination of two separate therapeutic agents as set forth above, i.e., a pharmaceutical combination within the scope of this invention could inc lude three therapeutic agents or more.

According to the present invention, the preferred combination partners are (a) a RTK inhibitor compound selected from the group consisting of 4-amino-5-fluoro-3-[5-(4- methylpiperazin-l -yl)-l H-benzimidazoi-2-yl]quinolin-2(l H)-one (Compound A) and (4-amino- 5-fiuoro-3-[6-(4-metbylpiperazm-i -yl)-l H-benzimidazol-2-yi]quinolin-2(l H)-one) (Compound B) or a pharmaceutically acceptable salt thereof, and (b) (3P)- 1.7-(pyridin-3-yl)androsta-5, 16- dien-3-ol or a pharmaceutically acceptable salt thereof. Preferably, these compounds are administered at therapeutically effective dosages which, when combined, provide a beneficial effect. The administration may be simultaneous or sequential.

In one embodiment, the proliferative disease is cancer. The term "cancer" is used herein to mean a broad spectrum of tumors, including all solid tumors and hematological malignancies. Examples of such tumors include but are not limited to benign or malignant tumors of the brain and central nervous system, lung (in particular small-cell lung cancer and non-small cell lung cancer), bladder, prostrate, gastric, pancreatic, breast, head and neck, renal, kidney, ureter, ovarian, prostate, colorectal, esophageal, testicular, gynecological (e.g., ovarian, uterine sarcomas, carcinoma of the fallopian tubes, endometrial, cervix, vagina or vulva), thyroid, pancreatic, bone, skin, melanoma, rectal, anal, colon, testicular, Hodgkin's disease, small intestine, endocrine system (e.g., thyroid, parathyroid, or adrenal glands), soft tissue and bone sarcoma, urethra, penis, leukemia, lymphomas, multiple myeloma, biliary, liver,

neurofibromatosis, acute myelogenous leukemia (AML), myelodysplastic syndromes ( .DS), and Kaposi's sarcoma. According to a further aspect, the present invention provides a synergistic combination for administration to humans comprising (a) a RTK inhibitor compound selected from the group consisting of 4~amino-5-ffuoro-3-[5-(4-metby^

2( ! 1- !)-one (Compound A) and (4-amino-5-fluoro-3-[6-(4-methy ipiperazin- 1 ~yi)~ 1- benzimidazol-2-yl]quinolin-2( i H)-one) (Compound B) or a pharmaceutically acceptable salt, thereof, and (b) (3β)-1 7-(pyridin-3-yi)androst.a-5, J.6~dien-3-ol or a pharmaceutically acceptable salt thereof, where the dose range of each component corresponds to the synergistic ranges observed in a suitable tumor model, e.g., the tumor models described in the Examples belosv, primarily used to identify a synergistic interaction.

It is one objective of this invention to provide a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against a proliferative disease comprising the COMBINATION OF THE INVENTION. In this composition, the combination partners (a) and (b) can be either administered in a single formulation or unit dosage form, administered concurrently but separately, or administered sequentially by any suitable route. The unit dosage form may also be a fixed combination.

The pharmaceutical compositions for separate administra tion of both combination partners, or for the administration in a fixed combination, i.e.. a single galenical composition comprising the COMBINATION OF THE INVENTION, may be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including humans, comprising a therapeutically effective amount of at least one pharmacologically active combination partner alone, e.g. as indicated above, or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application.

The novel pharmaceutical composition contains may contain, from about 0.1 % to about 99.9%, preferably from about 1 % to about 60 %, of the therapeutic agent(s).

Suitable pharmaceutical compositions for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulating, sugar-coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those ski lled in the art. it will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units,

A unit dosage form containing the combination of agents or individual agents of the combination of agents may be in the form of micro-tablets enclosed inside a capsule, e.g. a gelatin capsule. For this, a gelatin capsule as is employed in pharmaceutical formulations can be used, such as the hard gelatin capsule known as CAPSUGEL, available from Pfizer. The unit dosage forms of the present invention may optionally further comprise additional conventional carriers or excipients, used for pharmaceuticals. Examples of such carriers include, but are not limited to, disintegrants, binders, lubricants, glidants, stabilizers, and fillers, diluents, colorants, flavours and preservatives. One of ordinary skill in the art may select one or more of the aforementioned carriers with respect to the particular desired properties of the

dosage form by routine experimentation and without any undue burden. The amount of each carriers used may vary within ranges conventional in the art. The following references which are all hereby incorporated by reference disclose techniques and excipients used to formulate oral dosage forms. See The Handbook of Pharmaceutical Excipients, 4^th edition, owe et al., Eds.. American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 2oth edition, Gennaro, Ed., Lippincott Williams & Wilkins (2003).

These optional additional conventional carriers may be incorporated into the oral dosage form either by incorporating the one or more conventional carriers into the initial mixture before or during granulation or by combining the one or more conventional carriers with granules comprising the combination of agents or individual agents of the combination of agents in the oral dosage form. In the latter embodiment, the combined mixture may be further blended, e.g., through a V-biender, and subsequently compressed or molded into a tablet, for example a monolithic tablet, encapsulated by a capsule, or filled into a sachet. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates: gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone; cross-linked sodium carboxymethylceliulose or croscarmellose sodium, e.g., ACDI- SOL from PMC; and cross-linked calcium carboxymethylceliulose; soy polysaccharides; and guar gum. The disintegrant may be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the disintegrant is present in an amount from about 0.1 % to about 5% by weight of composition.

Examples of pharmaceutically acceptable binders include, but are not limited to, starches; celluloses and derivatives thereof, for example, microcrystalline cellulose, e.g., AVICEL PIT from FMC (Philadelphia, PA), hydroxypropyl cellulose hydroxy lethyl cellulose and

hydroxylpropylmethyl cellulose METHOCEL from Dow Chemical Corp. (Midland, MI);

sucrose; dextrose; corn syrup; polysaccharides; and gelatin. The binder may be present in an amount from about 0% to about 50%, e.g., 2-20% by weight of the composition.

Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisiiicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol powdered cellulose and microcrystalline cellulose. The lubricant may be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the lubricant may be present in an amount from about 0.1 % to about 1.5% by weight of composition. The glidant may be present in an amount from about 0.1 % to about 10% by weight.

Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates. dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc. The filler and/or diluent, e.g., may be present in an amount from about 0% to about 80% by weight, of the composition. in one embodiment, the present invention also pertains to a COMBINATION OF THE INVENTION for use in the preparation of a pharmaceutical composition or medicament for the treatment or prevention of a proliferative disease in a subject in need thereof.

In a further embodiment, the present invention pertains to the use of a RTK inhibitor compound selected from the group consisting of 4-amtno-5-^"fliioro-3-i 5-(4-methylpipera .in- l - yl)-II-|-benziraidazoi-2-yl]qumoHn-2(.l H)-one (Compound A) and (4-amino-5-f!uoro-3-[6-(4- methylpiperazin- l -yi)-] H-benzimidazoi-2~yl]qumolin-2{ lH)-one) (Compound B) or a pharmaceutically acceptable salt thereof, in combination with at least one anti-estrogen, particularly fulvestrant. or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition or medicament for the treatment or prevention of a proliferative disease in a subject in need thereof. in accordance with the present invention, a therapeutically effective amount of each of the combination partner of the COMBINATION OF THE INVENTION may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination. For example, the method of treating a proliferative disease according to the invention may comprise (i) administration of the first agent (a) in free or pharmaceutically acceptable salt form and (u) administration of an agent (b) in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily or intermittently dosages corresponding to the amounts described herein. The individual combination partners of the COMBINATION OF THE INVENTION may be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. Furthermore, the term "administering" also encompasses the use of a prodrug of a combination partner that convert in vivo to the combination partner as such. The instant invention is therefore to be understood as embracing ail such regimens of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

The effective dosage of each of the combination partners employed in the COMBINATION OF THE INVEN TION may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, and the severity of the condition being treated. Thus, the dosage regimen of the

COMBINATION OF THE INVENTION is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient. A clinician or physician of ordinary skill can readily determine and prescribe the effective amount of the single therapeutic agents required to alleviate, counter or arrest the progress of the condition.

The optimum ratios, individual and combined dosages, and concentrations of the combination partners (a) and (b) of the COMBINATION OF THE INVENTION that yield efficacy without toxicity are based on the kinetics of the therapeutic agents' availability to target sites, and are determined using methods known to those of skil l in the art.

The optimal dosage of each combination partner for treatment of a proliferative disease can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal dosages may be established using routine testing and procedures that are well known in the art.

The amount of each combination partner that may be combined with the carrier materials to produce a single dosage form will vary depending upon the individual treated and the particular mode of administration. In some embodiments the unit dosage forms containing the combination of agents as described herein will contain the amounts of each agent of the combination dial are typically administered when the agents are administered alone.

Frequency of dosage may vary depending on the compound used and the particular condition to be treated or prevented. In general, the use of the minimum dosage that is sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be fami liar to those of ordinary skill in the art. The present invention further provides a commercial package comprising as therapeutic agents COMBINATION OF THE INVENTION, together with instructions for simultaneous, separate or sequential administration thereof for use in the delay of progression or treatment of a proliferative disease in a subject in need thereof.

The following Examples illustrate the invention described above; they are not, however, intended to limit the scope of the invention in any way. The beneficial effects of the

pharmaceutical combination of the present invention can also be determined by other test models known as such to the person skilled in the pertinent art.

EXAMPLE 1

Pre-clinical studies using human prostate cancer xenografts supported the hypothesis that FGF signaling contributes to evolution of AR-independent castrate-resistant disease. MDA PCa 1 1 8b is a prostate cancer xenograft derived from a bone metastases in a man with advanced castrate- resistant disease. Molecular-pathologic analysis revealed that MDA PCa 1 1 8b cells do not express AR but do overexpress high FGF9 levels. MDA PCa 1 18 be cells induced the proliferation of cocultured osteoblasts in vitro and induced a strong osteoblastic reaction in the bone of imn modeficient mice in an FGF9-depependent manner. MR! analysis of MDA PCa 1 18b orthotopic bone tumors five weeks after cell injection demonstrated that mice treated with FGF9 neutralizing antibody developed significant smaller tumors than controls. These compelling clinical data prompted testing FGF inhibition in human patients with inCRPC utilizing TKI258.

An ongoing clinical study of TKI258 included patients with castrate-resistant prostate cancer and skeletal metastases (mCPRC) with the goal to evaluate markers of bFGF signaling in bone marrow biopsy specimens. Patients are receiving 500 mg PO q Day for 5 days, followed by a 2 day rest period. Each cycle is 28 days and response is assessed every 56 days (8 weeks). Patients are continued on TKI258 until disease progression, unacceptable toxicity, or withdrawal of consent. Seventeen of 40 patients have been enrolled thus far. Median age is 68, all patients have skeletal metastases, 41 % of patients also have lymph node and/or viscera! metastases, and 82% of patients have previously received at least one regimen of cytotoxic chemotherapy.

Median follow up is 63 days and median PFS has not yet. been reached. Most common therapy- associated toxicities have been grade 1/2 including fatigue (37%), nausea (50%), and diarrhea (50%). Grade 3 toxicities have been rare including fatigue ( 12%) and dyspnea (12%). There have been no grade 4 toxicities thus far. At the 8 week time point, 9/17 (52%) of patients

demonstrated stable disease, 2/17 (1 0%) demonstrated a PR in lymph nodes, 2/17 ( 10%) came off study for radiographic progression, 3/17 ( 18%) of patients came off study for clinical progression, and 1/17 (6%) withdrew. To date, four of 17 patients (25%) have experienced durable responses of > 4 months and 3 are actively receiving therapy. Preliminary molecular- pathologic analyses of tumor- infiltrated bone marrow biopsies reveal T I258-induced downregulation of FGFR 1 and its downstream target phospho-MAPK.

Based on these promising preliminary results, the clinical hypothesis was explored that TI258 will improve the anti-tumoral activity of Abiraterone by inhibiting FGF, an AR-independent signaling pathway that contributes to Abiraterone resistance.

Primary Objectives/End poin ts

In this study, safety and clinical efficacy of T I258 combined with Abiraterone in men metastatic castration-resistant prostate cancer will be determined. The primary end points are:

1) To assess the tolerance and safety of T 1258 in combination with Abiraterone in this patient group.

2) Progression Free Survival (PFS) is the primary eodpoint. PFS will be a composite endpoint defined as the time from study entry to first occurrence of any of the following:

• Progression of measurable disease by RECIST criteria. To be considered measurable, baseline lymph nodes, visceral metastases, and soft tissue metastases must be >2 cm in longest dimension. Equivocal RECIST progression must be confirmed by a follow up scan > 6 weeks later.

• Two or more new areas by bone scan attributable to prostate cancer (rather than flare) OR new/increasing size of lytic lesions by CT scan or MRI. Equivocal progression on bone scan must be confirmed by other imaging modalities (eg, CT or MRI) and/or performing a confirmatory bone scan > 6 weeks later.

• Need for palliative radiation involving more than one site

« Surgery or kyphoplasty to any neoplastic bone lesion

• Cancer-associated clinical deterioration as determined by the treating physician. PSA progression alone w ll not be used to define progression.

3) To collect and bank blood and tissue specimens for future hypothesis-generating studies. Secondary Objectives / Endpoints

1 ) Overall Survival

2) Radiologic responses

3) Biomarker modulation (for example PSA, CTC, serum cytokine profiles, bone specific alkaline phosphatase, urine n-teiopeptides)

4) Tumor pharmacodynamic measures (molecular-pathologic analysis of FGF and

Androgen-Receptor (A ) signaling pathways using metastatic tissue samples).

Study Design:

Prior to initiating the phase Π portion of the study, a dose escalation phase I schema will be utilized to acquire safety data and select the optimal starling close of T 1258 in combination with Abiraterone.

As shown below, cohorts of 3 to 6 patients will be treated with TK1258 and Abiraterone using a 28 day cycle. The starting dose (level 0) for TKI258 will be 200 mg PO q Day 5 days on, 2 days off and the dose for Abiraterone will be 1000 mg PO q Day. Prednisone will be administered at Smg PO BlD.

Table 1 . Dose Escalation Schedule

The dose escalation criteria as described in Table 1 must be met at each dose level during cycle 1 in order to enroll and treat patients at the next dosing level.

Applying the 3+3 design, the first cohort of 3 patients will be treated at dose level 0. The algorithm is as follows: (1) If 0 out of 3 patients experiences DLT, the next cohort of 3 patients will be treated at the next higher dose level. (2) if 1 out of 3 patients develops a DLT. an additional 3 patients will be treated at the same dose level. If no more DLT develops at the dose, i.e. I out of a total of 6 patients develops DLT, the dose escalation continues for the next cohort of 3 patients. (3) At any given dose, if greater than 1 out 3 patients or 1 out of 6 patients experience DLT, the dose level exceeds the MTD and 3 more patients will be treated at the next lower dose if there are less than 6 patients already treated at that dose. The MTD is the highest dose studied in which one or fewer of 6 patients has DLT.

At each given dose level, there will be a one-week gap to evaluate toxicity between the inclusion of the first patient and the next 2 patients.

Dose-Limiting Toxicities (DLT) and Maximum Tolerated Dose (MTD):

To qualify for DLT, the clinical adverse event (AE) or laboratory abnormality should be drug related as assessed by the treating physician, principal investigator, or sponsor. The DLTs will be defined (according to NCi-CTCAE v 4 grading scale) during the first treatment cycle. Any drug- related grade 3 or 4 toxicity {excluding nausea, vomiting, or diarrhea controlled by standard therapies) that occurred in the first cycle— except the anticipated toxicities that related to a syndrome of secondary mineralocorticoid excess, including hypertension, hypokalemia, and fluid overload— was considered a dose limiting toxicity (DLT). Toxicity related to elevated mineralocorticoid levels will be managed with a mineralocorticoid receptor antagonist

(eplerenone 50 to 200 mg/d). Treatment with dexamethasone 0.5 mg daily to suppress ACTH was only utilized if mineralocorticoid antagonism did not reverse these toxicities.

After selection of the optimal starting dose of TKI2S8 with Abiraterone, the phase ! l portion of the study will begin. Approximately 40 patients wi ll receive treatment on study until any of the following criteria are met:

• Disease progression

• Unacceptable toxicity

• Patient decision to withdraw

• Palliative radiation involving more than one site

• In the judgment of the investigator, further treatment would not be in the best interest of the patient.

Number of Patients «& Centers

Total number of patients: 60

Number of patients by treatment group: N A

Number of Centers; DACC

Population:

inclusion Criteria

1 ) Patient or his legally authorized representative must provide written informed consent.

2) Age 18

3) ECGG performance status <2

4) Histologic evidence of prostate adenocarcinoma

5) Metastatic castration-resistant prostate cancer

6) Patients must have surgical or ongoing chemical castration (with LHRH agonists or LHRH antagonists), with a baseline testosterone level < 50ng/dL.

7) Patients must have documented evidence of progressive disease as defined by any of the following:

• PSA progression: minimum of 2 rising values (3 measurements) obtained a

minimum of 7 days apart with the last result being at least > 2.0 ng/mL

• New or increasing non-bone disease (RECIST)

• Positive bone scan with 2 or more new lesions (PCWG2). Patients must have

ev idence for metastatic prostate cancer by bone scan and/or CT/MRl (i.e., soft tissue, visceral, lymph node). If lymph node, viscera! and/or soft-tissue metastases are the only evidence of metastasis, at least one lesion must be > 2 cm in diameter.

8) The following pretreatment laboratory data within 14 days before registration:

Absolute neutrophil count (ANC) > 1 ,500/m!

Platelets > 100,000/ml

Total bilirubin < Upper Limit of Normal with the exception of isolated

hyperbilirubinemia due to Gilbert's syndrome SGPT, (ALT^') AND/OR SCOT (AST) < 1.5 x the ULN. (if patient has liver metastases, < 2.5 x ULN)

9) Patient has creatinine clearance >30 ml/min. using the Cockroft-Gault equation.

1.0) Men whose partner is a woman of chiidbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter.

1 1 ) Patients may have received prior treatment with androgen ablative therapies (such as bieafutamide, ketoconazole, DES) and/or "targeted^" therapies (such as tyrosine kinase inhibitors) but these therapies must be discontinued > 5x the half life of the prior treating drug before initiation of study treatment.

12) Patients may have received up to 2 prior cytotoxic chemotherapy regimens for the treatment of metastatic castration-resistant disease. At least one of the regimens must have contained docetaxei.

Exclusion Criteria

.1) Patients with histologic evidence of small ceil carcinoma of the prostate

2) Prior therapy with Τ .Ϊ258 or Abiraterone

3) Radiation therapy (including palliative radiotherapy to a metastatic lesion) within 14 lays or major surgery (e.g., open abdominal, pelvic, thoracic, orthopedic or neurosurgery) within 28 days of the date of the first dose of study drugs.

4) Samarium- 1 53 within 28 days of registration, or Strontium-89 w ithin 12 weeks (336 days) of registration. Patients who have received 2 or more doses of bone- see king radioisotopes are not eligible.

5 ) Current treatment on another therapeutic clinical trial

6) impending complication from bone metastases (fracture and/or cord compression).

Properly treated or stabilized fractures and/or cord compression is allowed.

7) Presence of ongoing urinary obstruction (e.g., urinary retention, hydronephrosis)

requiring medical intervention. Properly treated urinary obstruction is allowed.

8) Patient has an uncontrolled intercurrent illness (e.g., uncontrolled diabetes, uncontrolled hypertension).

9) Patient has another serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the patient's abiiity to provide informed consent or w ith the completion of treatment according to this protocol.

10) Patients with an active second malignancy that could, in the investigator's opinion,

potentially interfere with the patient's ability to participate and/or complete this trial.

Minimum /Ma x i in u in Age:

1 years of age

Study Duration:

Patients will receive treatment on study until any of the following criteria are met;

• Disease progression

• Unacceptable toxicity

• Patient decision to withdraw • Palliative radiation involving more than one site

• In the judgment of the investigator, further treatment would not be in the best interest of the patient- Based on our prior experience with patients

Study Milestone Dates

Month and Year must be entered

FPFV, LPFV, and CSR dates required for CC study code allocation

Study start (FPFV): August.2012

Recruitment end (LPFV): September 20 i 4

Study end (LPLV): March 201 5

Completion of Clinical Study Report (CSR): Preliminary data for abstract to be presented January 201

Publication date: December 2015 Basis for Sample Size:

This is a phase 1/11 exploratory trial assessing the safety and efficacy of TKI258 in combination with Abiraterone for the treatment of patients with metastatic castrate resistant prostate cancer. The primary outcome is progression- free survival (PFS). Based on historical mean PFS of 4 months, a mean survival time on average > 6 months would be considered promising evidence of anti-disease activity. The planned sample size is ~ 60 patients (to complete the phase 1 and phase II portions of the trial), with an anticipated accrual rate o 3 patients per month. Based on historical experience using carefully selected candidates with evidence for iliac involvement on bone scan, we anticipate that -60% of patients will have positive biopsies. No early stopping rule in terms of the probability of PSA response will be employed because it is not known whether combined inhibition of stromal-epilhelial interactive pathways will lead to reductions in PSA (conversely, targeting principally the epithelial compartment with Abiraterone would result in predictable PSA reductions). Consequently, it may be the case that PSA does not drop but PFS is prolonged. Given the short PFS of these patients and anticipated accrual rate of 3 patients per month, it also will not be feasible to implement an early stopping rule in terms of observed PFS times. Based on an historical rate of 20% grade 3 or 4 toxicity with standard therapies, the method of I^'liall and Sung (1 98) will be used to monitor toxicity. Unadjusted PFS times will be estimated using the method of Kaplan and Meier (1958) and the effects of the following four potential prognostic covariates: inhibition of FGF and AR signaling by bone marrow biopsy at 4 w eeks, modulation of the bone markers (a) urinary NTX and (b) bone specific alkaline phosphatase, and baseline signature of FGF and AR signaling in terms of FGF R- l , FGF R-3, FGF 9. AR, and CYP 17 using logistic regression.

Based on a historical rate of 20% grade 3 or 4 toxicity with standard therapies, it wili be assumed that p = Prob (grade 3 or 4) follows a beta prior with parameters (.20, .80). Using the method of Thai! and Suung, based on the observed toxicity data, accrual to the trial will be stopped early based on the observed toxicity data if Pr(p > .20 j data) > .95, with this rule applied after successive cohorts f size 5. This rule says to stop the trial if [# patients with a grade 3 or 4 toxicity }/[# patients evaluated^"} is greater than or equal to 3/5. 5/ 10, 7 15, 8/20. 9/25. 1 1 /30. 12/35.^" Safety Criteria:

Ail study patients who have received any dose of TKI258 will be evaluabie for safety.

Adverse events including laboratory adverse events deemed clinically significant by the investigator will be graded and summarized according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). version 4.

Claims

CLAIMS:

I . A pharmaceutical combination comprising:

(a) a R K inhibitor compound comprising a compound of Formula II or a tautomer thereof, a pharmaceuticaily acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof, wherein the compound of formula II has the following formula and R' is a substituted or unsubstituted heterocyciyl group:

Π

; and

(b) at least one CYP17 inhibitor or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential administration.

2. A pharmaceutical combination comprising:

(a) a compound of Formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof, wherein the compound of formula 10 has the follow ing formula:

; and

(b) at ieast one CYP ! 7 inhibitor or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential administration.

3. The pharmaceutical combination according to claim 2, wherein the T inhibitor is selected from 4-amino-5-fluoro-3-[5-(4-methylpiperazm^

2( l H)-one or a pharmaceutically acceptable salt thereof and (4-amino-5-fluoro-3-[6-(4- methylpiperazin- ! -y i)- l H~benzimidazoi-2-yl]quinolin-2(l H)-one) or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical combination according to claim 3, wherein the least one CYP17 inhibitor is selected from (3p)-17-(pyridin-3-yl)androsta-5, 16-dien-3-ol (abiraterone), l -(2- chloro-pyrjdin-4-yl)-3-(4-methyl-pyridtn-3-yl)-tmidazolidin-2-one, ketoconazole, VN/124- 1 (TOK-001 ) and pharmaceuticall acceptable salts thereof.

5. A pharmaceutical combination comprising: 4-amino-5-fluoro-3-[5-(4-methy!piperazin- l - yl)- l l-l-benzimidazoi-2-yl]quinolin-2(l H)-one or a pharmaceutically acceptable salt thereof and (3p)- 17-(pyrid.in-3-yl)androsta-5,16-dien-3-o.l (abiraterone) or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical combination according to claim 5 for use in the preparation of a medicament for the treatment of prostate cancer.

7. A method for treating prostate cancer comprising the simultaneous, separate or sequential administration of a therapeutically effective amount of a RTK inhibitor selected from 4-amino~5- fluoro-3-[5-(4-methylpiperazin-l -yl)- 1 H-benzimidazol-2- l]quinol in-2( 1 H)-one and (4-am^'mo-5- fluoro-3-[6-(4-raethylpiperazin-l -yl)-l H-benzimidazol-2-yl]quinolin-2( 1 H)-onc) or a pharmaceutically acceptable salt thereof, in combination with at least one CYP17 inhibitor or a pharmaceutically acceptable salt thereof, to a patient having a proliferative disease.

8. A method according to claim 7, wherein the least one CYP17 inhibitor is selected from (3β)- 17-(pyridin-3-yl)androsta-5, 16-dien-3-oi (abiraterone), 1 -(2-chioro-pyridin-4-yl)-3-(4- methyt-pyridm-3-y{)-imidazoiidin-2-one, ketoconazole and VN/124- 1 (TO -00 i ) a

pharmaceutically acceptable salt thereof.