WO2018092064A1 - Combinaisons d'inhibiteurs de mdm2 et d'inhibiteurs de bcl-xl - Google Patents

Combinaisons d'inhibiteurs de mdm2 et d'inhibiteurs de bcl-xl Download PDF

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WO2018092064A1
WO2018092064A1 PCT/IB2017/057177 IB2017057177W WO2018092064A1 WO 2018092064 A1 WO2018092064 A1 WO 2018092064A1 IB 2017057177 W IB2017057177 W IB 2017057177W WO 2018092064 A1 WO2018092064 A1 WO 2018092064A1
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inhibitor
pharmaceutical combination
cancer
pharmaceutically acceptable
methyl
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PCT/IB2017/057177
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Emilie Chapeau
Eric Durand
agnieszka GEMBARSKA
Michael Rugaard Jensen
Emeline MANDON
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Novartis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to a pharmaceutical combination comprising (a) an Mdm2 inhibitor and (b) Bcl-xL inhibitor, particularly for use in the treatment of a cancer.
  • This disclosure also relates to uses of such combination for preparation of a medicament for the treatment of a cancer; methods of treating a cancer in a subject in need thereof comprising administering to said subject a jointly therapeutically effective amount of said combination; pharmaceutical compositions comprising such combination and commercial packages thereto.
  • Such inhibitors as Mdm2 inhibitors and Bcl-xL inhibitors demonstrate anti-proliferative (cytostatic) and pro-apoptotic (cytotoxic) activities in vitro and in vivo pre-clinical assays.
  • a pharmaceutical combination comprising
  • an MDM2 inhibitor selected from HDM201 i.e. (6S)-5-(5-Chloro-l-methyl-2- oxo-l,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-l- (propan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one, or a pharmaceutically acceptable salt thereof, and CGM097, i.e.
  • Bcl-xL inhibitor selected from A-l 155463, A-1331852, WEHI-539 or a pharmaceutically acceptable salt thereof,
  • an MDM2 inhibitor selected from (6S)-5-(5-Chloro-l-methyl-2-oxo-l,2- dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-l-(propan- 2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one, or a pharmaceutically acceptable salt thereof, and (S)-l-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4- ⁇ methyl- [4- (4-methyl-3 -oxo-piperazin- 1 -yl)-trans-cyclohexylmethyl] -amino ⁇ -phenyl)- 1 ,4- dihydro-2H-isoquinolin-3-one, or a pharmaceutically acceptable salt thereof; and (b) Bcl-xL inhibitor selected from A-l
  • MEK inhibitors e.g. trametinib, 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5- carboxylic acid (2 -hydroxy ethoxy)-amide, (S)-5-fluoro-2-(2-fluoro-4- (methylthio)phenylamino)-N-(2-hydroxypropoxy)- 1 -methyl-6-oxo- 1 ,6-dihydropyridine- 3-carboxamide, PD0325901, PD-184352, RDEA119, XL518, AS-701255, AS-701173, AS703026, RDEA436, E6201, R04987655, RG7167, and RG7420 or a pharmaceutically acceptable salt thereof) EGFR inhibitors, PI3K inhibitors and BRAF inhibitors.
  • MEK inhibitors e.g. trametinib, 6-(4-bromo-2-fluorophenylamin
  • CDK4/6 inhibitor or standard of care such as paclitaxel can be added to a combination of MDM2 inhibitor ("MDM2i”) and trametinib, which can lead to further synergistic effect or strong induction of apoptosis.
  • MDM2i MDM2 inhibitor
  • trametinib trametinib
  • a combination of the MDM2 inhibitor with a Bcl-xL inibitor can be supplemented by a BRAF inhibitor (e.g. dabrafenib) and CMET inhibitor (e.g. PF-04217903) to form a quadruple combination.
  • BRAF inhibitor e.g. dabrafenib
  • CMET inhibitor e.g. PF-04217903
  • the latter combination was found to be weakly synergistic, but with strongly inducing apoptosis.
  • the present disclosure relates to a pharmaceutical composition comprising the pharmaceutical combination of the disclosure and at least one
  • the present disclosure relates to the pharmaceutical combination or the pharmaceutical composition of the disclosure for use as a medicine.
  • the present disclosure relates to the pharmaceutical combination or the pharmaceutical composition of the disclosure for use in the treatment of cancer.
  • the disclosure provides the use of to the pharmaceutical combination of the disclosure for the preparation of a medicament for the treatment of a cancer.
  • the present disclosure relates to a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination of the present disclosure, or the pharmaceutical composition of the present disclosure.
  • the present disclosure provides the following aspects, advantageous features and specific embodiments, respectively alone or in combination, as listed in the claims below.
  • LOF predicted loss of function
  • Fig2 PiggyBac insertional patterns in BRaf oncogene. Red bars represent insertions in same sense of gene, and blue bars in opposite sense as the gene.
  • the CGM097+ ABT-263 combination showed the 3rd best combination activity (green bar). Only the 25 best combinations are represented; bars are light gray when no statistical significance was found.
  • a hit is defined as a combination with a synergy score above 2 and a maximum growth inhibition above 0.7 in individual cell lines over all assayed cell lines.
  • Cell lines with no TP53 mutation are shown in blue (p53 wt), and cell lines with TP53 modification in green (p53 mt).
  • Boost describes the maximal growth inhibition for any combination versus the highest single agent activity.
  • the curve is representative of two independent experiments of 3-day cell viability assay.
  • the IC50 was of 6 folds higher in average upon Bcl-xL expression.
  • the Western-blot shows expression of Bcl-xL after transient transfection in WM226.4 cells.
  • SNG-M cells (upper panels) or LS-513 cells (lower panels) were treated for 3 days with a 7x7 dose matrix of HDM201 and A-l 155463. Percent inhibition is shown in the left panels, each field representing the average of three replicates. Right panels show the additional (or reduced) effect level in percent relative to drug self-combination based on the Loewe model.
  • B) The average of % body weight change was calculated for each mouse during the course of the treatment. Each dot represents one mouse. Unpaired t test demonstrate a significant difference (P 0.0018) in body weight change between continuous and intermittent regimens.
  • the latter complex locus encodes two tumor suppressor proteins.
  • the INK4a/ARF locus is very frequently disrupted in human tumors, and consequently, these two tumor suppressor genes are disabled, through deletion, mutation or epigenetic silencing either in whole or in part (5). Subsequently, p53 tumor suppressor is degraded by MDM2. Compound specifically inhibiting the interaction between MDM2 and p53, thus preventing p53 degradation, have been discovered. Such agents induce p53 reactivation in tumors where p53 gene is wild-type (6-9). Although pharmacological effect of MDM2 inhibitors anticancer drugs was found beneficial, the tumors commonly relapse most likely because of the selection and growth of drug resistant cells (10, 11). Better understanding of the mechanisms of resistance would be beneficial to patient survival through identification of rational combinations and second line therapies.
  • PB transposon system presents cut-and-paste properties without leaving undesired footprints, and has the ability to integrate randomly throughout the entire genome.
  • mice harboring the active PB transposon would not only acquire mutations that accelerate the rate of tumorigenesis in this Arf-/- sensitized model, but also acquire mutations in the process of progression to HDM201 -resistance.
  • monitoring emerging resistance is technically challenging with spontaneous tumors, we decided to perform the screen after transplanting these tumors in flank of recipient mice and expanding these allografted tumors in larger cohorts of animals, as commonly performed for patient-derived tumor xenograft (PDX) models (10).
  • PDX patient-derived tumor xenograft
  • Transposon-based mutagenesis has been widely used to identify candidate cancer genes in various types of cancers (14-17). However, in only a few studies has this method been used successfully to characterize resistance mechanisms in vitro (18-20) or in mice (21). Our current results shed light on the diversity of resistance mechanisms encountered upon cancer therapy involving disruption of p53/Mdm2 interaction. Our screen also reinforced transposon-based mutagenesis as a powerful tool for the identification of novel resistance genes and mechanisms in genetically modified mouse models, and constitutes the first in vivo resistance screen for p53-Mdm2 inhibition. Our results may lead to better combination strategies in patients with p53 wild-type tumors relapsing while on treatment with Mdm2-p53 inhibitors.
  • the present disclosure relates to a pharmaceutical combination comprising
  • an MDM2 inhibitor selected from (6S)-5-(5-Chloro-l-methyl-2-oxo-l,2- dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-l-(propan- 2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one, or a pharmaceutically acceptable salt thereof, and (S)-l-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4- ⁇ methyl- [4- (4-methyl-3 -oxo-piperazin- 1 -yl)-trans-cyclohexylmethyl] -amino ⁇ -phenyl)- 1 ,4- dihydro-2H-isoquinolin-3-one, or a pharmaceutically acceptable salt thereof; and
  • Bcl-xL inhibitor selected from A-l 155463, A-1331852, WEHI-539, or a pharmaceutically acceptable salt thereof.
  • synergistic effect refers to action of two or three therapeutic agents such as, producing an effect, for example, slowing the progression of a proliferative disease, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol.
  • MDM2 inhibitor refers to any compound inhibiting the HDM2/p53 (Mdm2/p53) interaction association.
  • HDM2 Human homolog of murine double minute 2
  • Mdm2 inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of Mdm2/p53 association is indicated, e.g., in the treatment of tumors and/or cancerous cell growth.
  • Mdm2 inhibitors are useful in the treatment of human cancer, since the progression of these cancers may be at least partially dependent upon overriding the "gatekeeper" function of p53, for example the overexpression of Mdm2.
  • the Mdm2 inhibitor is a compound selected from the group consisting of
  • the MDM2 inhibitor can be (6S)-5-(5-Chloro-l-methyl-2-oxo-l,2- dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-l-(propan-2- yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one, or a pharmaceutically acceptable salt thereof.
  • the Mdm2 inhibitor (6S)-5-(5-Chloro-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)- 6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-l-(propan-2-yl)-5,6- dihydropyrrolo[3,4-d]imidazol-4(lH)-one belongs to a novel class of imidazopyrrolidinone compounds, and shows potent inhibition of the MDM2/p53 interaction (this term including in particular Hdm2/p53 interaction). In particular, this compound acts as an inhibitor of MDM2 interaction with p53 by binding to MDM2.
  • the disclosure encompasses succinic acid co-crystal of the (6S)-5-(5- Chloro-1 -methyl -2 -oxo-1, 2-dihydropyridin-3 -yl)-6-(4-chloropheny l)-2-(2,4- dimethoxypyrimidin-5-yl)-l-(propan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one compound.
  • the compound can be also be in a form of an ethanol solvate.
  • the MDM2 inhibitor can also be (S)-l-(4-Chloro-phenyl)-7-isopropoxy-6- methoxy-2-(4- ⁇ memyl-[4-(4-methyl-3-oxo-piperazin-l-yl)-trans-cyclohexylmethyl]- amino ⁇ -phenyl)- l,4-dihydro-2H-isoquinolin-3 -one, or a pharmaceutically acceptable salt thereof.
  • the Mdm2 inhibitor (S)-l-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4- ⁇ methyl-[4-(4-methyl-3-oxo-piperazin-l-yl)-trans-cyclohexylmethyl]-amino ⁇ -phenyl)- l,4-dihydro-2H-isoquinolin-3-one is a compound of formula II, and described in Example 106 of WO2011/076786, which is hereby incorporated by reference in its entirety:
  • the pharmaceutically acceptable salt of (S)-l-(4-Chloro- phenyl)-7-isopropoxy-6-methoxy-2-(4- ⁇ methyl-[4-(4-methyl-3-oxo-piperazin-l-yl)-trans- cyclohexylmethyl] -amino ⁇ -phenyl)- l,4-dihydro-2H-isoquinolin-3 -one is bisulphate salt.
  • Crystalline form of the bisulfate salt of (S)-l-(4-Chloro-phenyl)-7-isopropoxy-6- methoxy-2-(4- ⁇ memyl-[4-(4-methyl-3-oxo-piperazin-l-yl)-trans-cyclohexylmethyl]- amino ⁇ -phenyl)-l,4-dihydro-2H-isoquinolin-3-one is described in WO2012/066095.
  • Bcl-xL inhibitor or "BCL-XL inhibitor” or “Bcl-X L inhibitor” is defined herein to refer to a compound which targets, decreases or inhibits the protein Bcl- XL of the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family which is composed of proteins such as Bcl-2, Bcl-X L , Bcl-w, Mcl-1, Bfll/A-1, and/or Bcl-B.
  • Bcl-xL inhibitor is preferably used herein to refer to those inhibitors which selectively inhibit Bcl-xL and do not inhibit e.g. Bcl-2.
  • pharmaceutical combination of the present disclosure includes at least one Bcl-xL inhibitor (Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, et al), preferably that one Bcl-xL inhibitor is selected from A-l 155463, A- 1331852, WEHI-539, more preferably the BcL-xL inhibitor is A-l 155463.
  • Bcl-xL inhibitor Te C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, et al
  • the pharmaceutical combination may comprise the MDM2 inhibitor and the Bcl-xL inhibitor.
  • the pharmaceutical combination comprising the MDM2 inhibitor and Bcl-xL inhibitor may further advantageously comprise a further inhibitor, which even further improves antitumor activity of the combination, e.g. a MEK inhibitor.
  • said MEK inhibitor is selected from the group consisting of trametinib, 6-(4-bromo-2-fluorophenylamino)-7- fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide, (S)-5- fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)- 1 -methyl-6-oxo- l,6-dihydropyridine-3-carboxamide, PD0325901, PD-184352, RDEA119, XL518, AS- 701255, AS-701173, AS703026, RDEA436, E6201, R04987655, RG7167, and RG7420 or a pharmaceutically acceptable salt thereof.
  • a MEK inhibitor is defined herein to refer to a compound which targets, decreases or inhibits the kinase activity of MAP kinase, MEK.
  • a target of a MEK inhibitor includes, but is not limited to, ERK.
  • An indirect target of a MEK inhibitor includes, but is not limited to, cyclin D 1.
  • compositions of the present disclosure can include at least one
  • MEK inhibitor compound selected from the group consisting of trametinib, 6-(4-bromo-2- fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2- hydroxyethoxy)-amide, (S)-5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2- hydroxypropoxy)- 1 -methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxamide, PD0325901 , PD- 184352, RDEA119, XL518, AS-701255, AS-701173, AS703026, RDEA436, E6201, R04987655, RG7167, and RG7420, or a pharmaceutically acceptable salt thereof.
  • the MEK inhibitor is trametenib (N-(3- ⁇ 3-cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino] -6, 8-dimethyl-2,4,7-trioxo-3 ,4,6,7-tetrahydropyrido [4,3 -d]pyrimidin- l(2H)-yl ⁇ phenyl)acetamide, also referred to as JPT-74057 or GSK1120212).
  • Trametinib (GSK1120212) is described in PCT Publication No. WO05/121142, which is hereby incorporated by reference in its entirety. The compound has been approved as Mekinist ® .
  • another suitable MEK inhibitor for the combination of the present disclosure is a compound 6-(4-bromo-2-fluorophenylamino)- 7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide of formula (III)
  • MEK inhibitor compound 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H- benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide is described in the PCT Application No. WO 03/077914, and methods for its preparation have been described, for example, in Example 18 therein.
  • MEK inhibitor for the combination of the present disclosure is compound (S)-5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)- l-methyl-6-oxo-l,6-dihydropyridine-3-carboxamide is a compound of formula (IV)
  • MEK inhibitor compound (S)-5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-N- (2-hydroxypropoxy)-l-methyl-6-oxo-l,6-dihydropyridine-3-carboxamide is described in Example 25-BB of PCT Application No. WO2007/044084, and methods for its preparation have been described therein.
  • Additional MEK inhibitors that may be used in the combination of the present disclosure include, but are not limited to, PD0325901 (Pfizer)(See PCT Publication No. WO02/06213), PD-184352 (Pfizer), RDEA119 (Ardea Biosciences), XL518 (Exelexis), AS-701255 (Merck Serono), AS-701173 (Merck Serono), AS703026 (Merck Serono), RDEA436 (Ardea Biosciences, E6201 (Eisai)( See Goto et al, Journal of Pharmacology and Experimental Therapeutics, 3331(2): 485-495 (2009)), R04987655 (Hoffmann-La Roche), RG7167, and/or RG7420.
  • the pharmaceutical combinations of the present disclosure comprising (a) the MDM2 inhibitor and (b)(i) the Bcl-xL inhibitor, and/or (ii) the MEK inhibitor may further advantageously comprise an EGFR inhibitor.
  • an EGFR inhibitor is defined herein to refer to a compound which targets, decreases or inhibits the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) or bind to EGF or EGF related ligands.
  • EGFR epidermal growth factor family of receptor tyrosine kinases
  • the EGFR inhibitor compound used in the combination of the present disclosure is selected from the group consisting of erlotinib, gefitinib, lapatinib, canertinib, pelitinib, neratinib, (R,E)-N-(7-chloro- 1 -( 1 -(4-(dimethylamino)but-2-enoyl)azepan-3 -yl)- 1 H- benzo[d]imidazol-2-yl)-2-methylisonicotinamide, panitumumab, matuzumab, pertuzumab, nimotuzumab, zalutumumab, icotinib, afatinib and cetuximab, and pharmaceutically acceptable salt thereof.
  • the EGFR inhibitor is erlotinib, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination comprises the MDM2 inhibitor selected from (6S)-5-(5-Chloro-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-l-(propan-2-yl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(lH)-one, or a pharmaceutically acceptable salt thereof, and (S)-l-(4-Chloro- phenyl)-7-isopropoxy-6-methoxy-2-(4- ⁇ methyl-[4-(4-methyl-3-oxo-piperazin-l-yl)-trans- cyclohexylmethyl] -amino ⁇ -phenyl)- 1 ,4-dihydro-2H-isoquinolin-3 -one, or a MDM2 inhibitor selected from (6S)-5-(5-Chloro
  • the pharmaceutical combinations of the present disclosure comprising (a) the MDM2 inhibitor and (b)(i) the MEK inhibitor, and/or (ii) the Bcl-xL inhibitor may further advantageously comprise a PI3K inhibitor.
  • a phosphatidylinositol 3-kinase inhibitor or "a PI3K inhibitor” is defined herein to refer to a compound which targets, decreases or inhibits PI3 -kinase.
  • PI3- kinase activity has been shown to increase in response to a number of hormonal and growth factor stimuli, including insulin, platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, colony-stimulating factor, and hepatocyte growth factor, and has been implicated in processes related to cellular growth and transformation.
  • Phosphatidylinositol -3-kinase (PI3K) inhibitors suitable for the present disclosure are selected from the group consisting of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl- 2,3-dihydro-imidazo[4,5-c]quinolin-l-yl)-phenyl]-propionitrile, or a pharmaceutically acceptable salt thereof, 5-(2,6-di-mo ⁇ holin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl- pyridin-2-ylamine, or a pharmaceutically acceptable salt thereof; and (S)-Pyrrolidine-l,2- dicarboxylic acid 2-amide l-( ⁇ 4-methyl-5-[2-(2,2,2-trifluoro-l,l-dimethyl-ethyl)-pyridin- 4-yl] -thiazol-2-yl ⁇ -amide), or a pharmaceutically acceptable salt thereof.
  • WO2006/122806 describes imidazoquinoline derivatives, which have been described to inhibit the activity of PI3K.
  • the compound 2-methyl-2-[4-(3-methyl-2-oxo- 8-quinolin-3 -yl-2,3 -dihydro-imidazo [4,5 -c]quinolin- 1 -yl)-phenyl] -propionitrile has the chemical structure of formula (V)
  • the compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3- dihydro-imidazo[4,5-c]quinolin-l-yl)-phenyl]-propionitrile may be present in the form of the free base or any pharmaceutically acceptable salt thereto.
  • 2-methyl-2-[4- (3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-l-yl)-phenyl]- propionitrile is in the form of its monotosylate salt.
  • WO07/084786 describes specific pyrimidine derivatives which have been found to inhibit the activity of PI3K.
  • the compound 5-(2,6-di-mo holin-4-yl-pyrimidin-4-yl)-4- trifluoromethyl-pyridin-2-ylamine has the chemical structure of formula (VI)
  • the compound, its salts, its utility as a PI3K inhibitor and synthesis of the compound 5-(2,6-di-mo ⁇ holin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine are described in WO 2007/084786, which is hereby incorporated by reference in its entirety hereto, for instance in Example 10.
  • the compound 5-(2,6-di-morpholin-4-yl- pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine may be present in the form of the free base or any pharmaceutically acceptable salt thereto.
  • 5-(2,6-di- mo ⁇ holin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine is in the form of its hydrochloride salt.
  • WO2010/029082 describes specific 2-carboxamide cycloamino urea derivatives which have been found to be highly selective for the alpha isoform of PI3K and can be added to the combinations of the present disclosure.
  • the compound (S)-Pyrrolidine-l,2- dicarboxylic acid 2-amide l-( ⁇ 4-methyl-5-[2-(2,2,2-trifluoro-l,l-dimethyl-ethyl)-pyridin- 4-yl]-thiazol-2-yl ⁇ -amide) has the chemical structure of formula (VII)
  • the compound, its salts, its utility as an alpha-isoform selective PI3K inhibitor and synthesis of the compound (S)-Pyrrolidine-l,2-dicarboxylic acid 2-amide l-( ⁇ 4- methyl-5-[2-(2,2,2-trifluoro-l,l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl ⁇ -amide) are described in WO2010/029082, which is hereby incorporated by reference in its entirety, for instance in Example 15.
  • the compound (S)-Pyrrolidine-l,2-dicarboxylic acid 2-amide l-( ⁇ 4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl ⁇ -amide) may be present in the form of the free base or any pharmaceutically acceptable salt thereto.
  • (S)-Pyrrolidine-l,2-dicarboxylic acid 2-amide l-( ⁇ 4-methyl-5-[2- (2,2,2-trifluoro- 1,1 -dimethyl -ethyl)-pyridin-4-yl]-thiazol-2-yl ⁇ -amide) is in the form of its free base.
  • the PI3K inhibitor compound used in the combination of the present disclosure is (S)-Pyrrolidine-l,2-dicarboxylic acid 2-amide l-( ⁇ 4-methyl-5-[2-(2,2,2- trifluoro-l,l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl ⁇ -amide), or any pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination comprising the MDM2 inhibitor and the Bcl-xL inhibitor may further advantageously comprise the PI3K inhibitor. It has been surprisingly found that this triple combination synergistic inhibition (over the drug pairs in 2/5 cell models tested (Example 4, Table 9) and showed stronger apoptosis compared to the pair wise combinations (Example 4, Figure 14).
  • the pharmaceutical combination comprises the MDM2 inhibitor selected from (6S)-5-(5-Chloro-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-l-(propan-2-yl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(lH)-one, or a pharmaceutically acceptable salt thereof, and (S)-l-(4-Chloro- phenyl)-7-isopropoxy-6-methoxy-2-(4- ⁇ methyl-[4-(4-methyl-3-oxo-piperazin-l-yl)-trans- cyclohexylmethyl] -amino ⁇ -phenyl)- 1 ,4-dihydro-2H-isoquinolin-3 -one, or a MDM2 inhibitor selected from (6S)-5-(5-Chloro
  • the pharmaceutical combinations of the present disclosure comprising (a) the MDM2 inhibitor and (b) (i) the Bcl-xL inhibitor, and/or (ii) the MEK inhibitor may further advantageously comprise a BRAF inhibitor.
  • the pharmaceutical combination of the present disclosure may advantageously comprise (a) the MDM2 inhibitor, (b) the Bcl-xL inhibitor, (c) the MEK inhibitor, and (d) a BRAF inhibitor.
  • a BRAF inhibitor is defined herein to refer to a compound which targets, decreases or inhibits the activity of serine/threonine-protein kinase B-Raf.
  • the BRAF inhibitor is selected from the group consisting of RAF265, dabrafenib (S)-methyl-l-(4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-l-isopropyl-lH- pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, methyl N-[(2S)-l-( ⁇ 4-[3-(5- chloro-2-fluoro-3-methanesulfonamidophenyl)-l-(propan-2-yl)-lH-pyrazol-4- yl]pyrimidin-2-yl ⁇ amino)propan-2-yl]carbamate and vemurafenib, or a pharmaceutically acceptable salt thereof.
  • the BRAF inhibitor is preferably dabrafenib, or a pharmaceutically acceptable salt thereof.
  • the BRAF inhibitor added to the combination is RAF265.
  • the combination of the present disclosure can further comprise a CDK4/6 inhibitor.
  • CDK4/6 inhibitor Cyclin dependent kinase 4/6 (CDK4/6) inhibitor as defined herein refers to a small molecule that interacts with a cyclin-CDK complex to block kinase activity.
  • the Cyclin-dependent kinases (CDK) is a large family of protein kinases that regulate initiation, progression, and completion of the mammalian cell cycle.
  • the CDK4/6 inhibitor is 7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-l-yl)pyridin-2- yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, or pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compound and which typically are not biologically or otherwise undesirable.
  • the compound may be capable of forming acid addition salts by virtue of the presence of an amino group.
  • reference to therapeutic agents useful in the pharmaceutical combination of the present disclosure includes both the free base of the compounds, and all pharmaceutically acceptable salts of the compounds.
  • the term "combination" or “pharmaceutical combination” is defined herein to refer to either a fixed combination in one dosage unit form, a non-fixed combination or a kit of parts for the combined administration where the therapeutic agents may be administered together, independently at the same time or separately within time intervals, which preferably allows that the combination partners show a cooperative, e.g. synergistic effect.
  • the single compounds of the pharmaceutical combination of the present disclosure could be administered simultaneously or sequentially.
  • the pharmaceutical combination of the present disclosure may be in the form of a fixed combination or in the form of a non-fixed combination.
  • the term "fixed combination” means that the therapeutic agents, e.g., the single compounds of the combination, are in the form of a single entity or dosage form.
  • non-fixed combination means that the therapeutic agents, e.g., the single compounds of the combination, are administered to a patient as separate entities or dosage forms either simultaneously or sequentially with no specific time limits, wherein preferably such administration provides therapeutically effective levels of the two therapeutic agents in the body of the subject, e.g., a mammal or human in need thereof.
  • the pharmaceutical combinations can further comprise at least one
  • the present disclosure relates to a
  • composition comprising the pharmaceutical combination of the present disclosure and at least one pharmaceutically acceptable carrier.
  • carrier or “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term "pharmaceutical 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.
  • the present pharmaceutical combinations can be formulated in a suitable pharmaceutical composition 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 skilled in the art.
  • the pharmaceutical composition may contain, from about 0.1 % to about 99.9%, preferably from about 1 % to about 60 %, of the therapeutic agent(s).
  • the amount of each carriers used may vary within ranges conventional in the art. The following references disclose techniques and excipients used to formulate oral dosage forms.
  • 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.
  • the combined mixture may be further blended, e.g., through a V-blender, and subsequently compressed or molded into a tablet, for example a monolithic tablet, encapsulated by a capsule, or filled into a sachet.
  • a tablet for example a monolithic tablet, encapsulated by a capsule, or filled into a sachet.
  • the pharmaceutical combinations of the present disclosure can be used to manufacture a medicine.
  • the present disclosure relates to such pharmaceutical combinations or
  • compositions that are particularly useful as a medicine.
  • combinations or compositions of the present disclosure can be applied in the treatment of cancer.
  • the present disclosure also relates to use of pharmaceutical combinations or pharmaceutical compositions of the present disclosure for the preparation of a medicament for the treatment of a cancer, and to a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination according to the present disclosure, or the
  • treatment comprises a treatment relieving, reducing or alleviating at least one symptom in a subject, increasing progression-free survival, overall survival, extending duration of response or delaying progression of a disease.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer.
  • the term “treatment” 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 in a patient, e.g., a mammal, particularly the patient is a human.
  • treatment as used herein comprises an inhibition of the growth of a tumor incorporating a direct inhibition of a primary tumor growth and / or the systemic inhibition of metastatic cancer cells.
  • a “subject,” “individual” or “patient” is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, mice, simians, humans, farm animals, sport animals, and pets.
  • a therapeutically effective amount of a compound (e.g. chemical entity or biologic agent) of the present disclosure refers to an amount of the compound of the present disclosure that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
  • each combination partner for treatment of a cancer 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.
  • the unit dosage forms containing the combination of agents as described herein will contain the amounts of each agent of the combination that 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 familiar to those of ordinary skill in the art.
  • a therapeutic amount or a dose of (6S)-5-(5-Chloro-l-methyl-2-oxo-l,2- dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-l-(propan-2- yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one may range between 100 and 1500 mg every three weeks, particularly between 100 and 800 mg every three weeks, or between 50 and 600 mg daily, when administered per os.
  • a therapeutic amount or a dose of (6S)- 5 -(5 -Chloro- 1 -methyl -2 -oxo- 1 ,2-dihydropyridin-3 -yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-l-(propan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one can be 400 mg, more preferably is 300 mg for daily administration for the first 21 days of every 28 day cycle.
  • a total therapeutic amount or a total dose of (6S)-5-(5- Chloro-1 -methyl -2 -oxo-1, 2-dihydropyridin-3 -yl)-6-(4-chloropheny l)-2-(2,4- dimethoxypyrimidin-5-yl)-l-(propan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(lH)-one is 560 mg per cycle (40 mg qd 2 wks on / 2 wks off, or 80 mg qd 1 wk on / 3 wks off). Intravenous doses would need to be lowered accordingly.
  • a therapeutic amount or dose of (S)-l-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy- 2-(4- ⁇ methyl-[4-(4-methyl-3 -oxo-piperazin- 1 -yl)-trans-cyclohexylmethyl] -amino ⁇ - phenyl)- l,4-dihydro-2H-isoquinolin-3-one is between 500 and 2000 mg, particularly between 500 and 1200 mg, when administered per os.
  • a therapeutic amount or dose of (S)-l-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4- ⁇ methyl-[4-(4-methyl-3-oxo-piperazin-l-yl)-trans-cyclohexylmethyl]-amino ⁇ -phenyl)- l,4-dihydro-2H-isoquinolin-3-one is 500 mg, more preferably 800 mg. Intravenous doses would need to be lowered accordingly.
  • the Bcl-xL inhibitor A-l 155463 has been dosed 5 ⁇ 10 ⁇ -3 g/kg i.p. s.d. in preclinical studies in mice (PROUS integrity records).
  • the dose escalation study in man will allow to identify the maximum tolerated dose, and will allow to define the recommended clinical dose for pivotal clinical studies.
  • the recommended dose of the MEK inhibitor trametinib is 2 mg daily.
  • the management of adverse reactions may require dose reduction up to 1 mg daily.
  • the MEK inhibitor compound 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3- methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide may be administered to a suitable subject daily in single or divided doses at an effective dosage in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to a preferable dosage range of about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day.
  • the MEK inhibitor compound (S)-5-fluoro-2-(2-fluoro-4- (methylthio)phenylamino)-N-(2-hydroxypropoxy)- 1 -methyl-6-oxo- 1 ,6-dihydropyridine- 3-carboxamide may be administered daily to a suitable subject in single or divided doses at an effective dosage in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 mg/kg/day to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to a preferable dosage range of about 0.07 to 2.45 g/day, preferably about 0.05 to about 1.0 g/day.
  • An effective dose of the Bcl-2 inhibitor navitoclax may range from about 100 mg to about 500 mg daily.
  • the dose may be reduced or a 150 mg 7-day lead-in dose employed. After the lead-in dose a 325 mg dose or up to 425 mg dose can be administered daily.
  • the recommended dose of the EGFR inhibitor erlotinib is 100 mg or 150 mg daily.
  • the PI3K inhibitor compound (S)-pyrrolidine-l,2-dicarboxylic acid 2-amide l-( ⁇ 4- methyl-5-[2-(2,2,2 rifluoro-l,l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl ⁇ -amide) is generally administered orally at a dose in the range from about from 30 mg to 450 mg per day, for example 100 to 400 mg per day in a human adult.
  • the daily dose can be administered on a qd or bid schedule.
  • (S)-pyrrolidine-l,2-dicarboxylic acid 2-amide 1- ( ⁇ 4-methyl-5-[2-(2,2,2-trifluoro- 1 , 1 -dimethyl -ethyl)-pyridin-4-yl]-thiazol-2-yl ⁇ -amide) may administered to a suitable subject daily in single or divided doses at an effective dosage in the range of about 0.05 to about 50 mg per kg body weight per day, preferably about 0.1-25 mg/kg/day, more preferably from about 0.5-10 mg/kg/day , in single or divided doses. For a 70 kg human, this would amount to a preferable dosage range of about 35-700 mg per day. More preferably, the dosage range is of about 35 - 400 mg per day.
  • the PI3K inhibitor compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3- dihydro-imidazo[4,5-c]quinolin-l-yl)-phenyl]-propionitrile is generally administered orally at a dose in the range from about 100 mg to 1200 mg, or about 200 mg to 1000 mg, or about 300 mg to 800 mg, or about 400 mg to 600 mg per day in a human adult.
  • the daily dose can be administered on a qd or bid schedule.
  • the PI3K inhibitor compound 5-(2,6 ⁇ ⁇ 1 ⁇ -4 ⁇ 1 ⁇ -4 ⁇ 1)-4- trifluoromethyl-pyridin-2-ylamine is generally administered orally at a dose in the range from about 30 mg to 300 mg, or about 60 mg to 120 mg, or about 100 mg per day in a human adult.
  • the daily dose can be administered on a qd or bid schedule.
  • the recommended dose of the BRAF inhibitor dabrafenib is 150 mg orally twice daily as a single agent or in combination with trametinib 2 mg orally once daily.
  • each therapeutic agent may be conveniently administered, for example, in one individual dosage unit or divided into multiple dosage units. It is further understood that that each therapeutic agent may be conveniently administered in doses once daily or doses up to four times a day.
  • cancer is used herein to mean a broad spectrum of tumors, in particular solid tumors.
  • tumors include, but are not limited to a benign or malignant tumor of the lung (including small cell lung cancer and non-small-cell lung cancer), bronchus, prostate, breast (including sporadic breast cancers and sufferers of Cowden disease), pancreas, gastrointestinal tract, colon, rectum, colon carcinoma, colorectal cancer, thyroid, liver, biliary tract, intrahepatic bile duct, hepatocellular, adrenal gland, stomach, gastric, glioma, glioblastoma, endometrial, kidney, renal pelvis, bladder, uterus, cervix, vagina, ovary, multiple myeloma, esophagus, neck or head, brain, oral cavity and pharynx, larynx, small intestine, a melanoma, villous colon adenoma, a sarcoma,
  • the cancer is colorectal cancer, melanoma, liposarcoma, glioblastoma, neuroblastoma, lymphoma or leukemia.
  • the cancer is colorectal cancer.
  • colonal cancer refers to cancer in the colon or rectum, also known as colon cancer, rectal cancer or bowel cancer.
  • the present disclosure relates to metastatic colorectal cancer.
  • the combination is expected to achieve superior effects in functional p53 or p53 wild-type cancers.
  • the TP53 gene is one of the most frequently mutated genes in human cancers.
  • tumor suppressor p53 is functionally impaired by mutation or deletion in nearly 50% of human cancers.
  • p53 retains wild-type status but its function is inhibited by its primary cellular inhibitor, the murine double minute 2 (Mdm2, MDM2; HDM2 (human homo log of murine double minute 2)).
  • Mdm2 is a negative regulator of the p53 tumor suppressor.
  • Mdm2 protein functions both as an E3 ubiquitin ligase, that leads to proteasomal degradation of p53, and an inhibitor of p53 transcriptional activation.
  • Mdm2 is found amplified in p53 wild-type tumors. Because the interaction between Mdm2 and p53 is a primary mechanism for inhibition of the p53 function in cancers, which are retaining wild-type p53, the combination of the present disclosure comprising the MDM2 inhibitor is particularly useful for treatment of functional p53 or p53 wild-type cancers.
  • the efficacy of the combination is expected to be increased in cancer, which is characterized by one or more of KRAS mutation and/or BRAF mutation and/or MEK1 mutation and/or PIK3CA mutation and/or PIK3CA overexpression.
  • BRAF mutations include, but not limited to V600E, R46 II, I462S,
  • valine (V) being substituted for by glutamate (E) at codon 600 (now referred to as V600E).
  • MEK1 mutation may be, for example, MEK1 S72G mutation.
  • Examples of PIK3CA mutation and/or PIK3CA overexpression include, but not limited to , amplification of the alpha isoform of PI3K, somatic mutation of PIK3CA, germline mutations or somatic mutations of PTEN, mutations and translocation of p85ot that serve to up-regulate the p85-pl 10 complex, or amplification or overexpression of the beta isoform of PI3K.
  • the pharmaceutical combination of the present disclosure is particularly useful for the treatment of a cancer, particularly colorectal cancer, wherein the cancer is resistant to a treatment with an EGFR inhibitor, or is developing a resistance to a treatment with an EGFR inhibitor, or is under high risk of developing a resistance to a treatment with an EGFR inhibitor, particularly wherein the EGFR inhibitor is selected from the group consisting of erlotinib, gefitinib and afatinib.
  • the pharmaceutical combination of the present disclosure is also suitable for the treatment of poor prognosis patients, especially such poor prognosis patients having a cancer, particularly colorectal cancer, which becomes resistant to treatment employing an EGFR inhibitor, e.g. a cancer of such patients who initially had responded to treatment with an EGFR inhibitor and then relapsed.
  • a cancer particularly colorectal cancer
  • said patient has not received treatment employing a FGFR inhibitor.
  • This cancer may have acquired resistance during prior treatment with one or more EGFR inhibitors.
  • the EGFR targeted therapy may comprise treatment with gefitinib, erlotinib, lapatinib, XL- 647, HKI-272 (Neratinib), BIBW2992 (Afatinib), EKB-569 (Pelitinib), AV-412, canertinib, PF00299804, BMS 690514, HM781-36b, WZ4002, AP-26113, cetuximab, panitumumab, matuzumab, trastuzumab, pertuzumab, or a pharmaceutically acceptable salt thereof.
  • the EGFR targeted therapy may comprise treatment with gefitinib, erlotinib, and afatinib.
  • the mechanisms of acquired resistance include, but are not limited to, developing a second mutation in the EGFR gene itself, e.g. T790M, EGFR amplification; and / or FGFR deregulation, FGFR mutation, FGFR ligand mutation, FGFR amplification, or FGFR ligand amplification.
  • the pharmaceutical combinations as described herein are particularly useful for use in patients which have a resistance to mdm2 inhibitors.
  • the resistance may be caused by regrowth of mdm2 inhibitor resistant cells or by genetic predisposition.
  • the pharmaceutical combinations as described herein may further comprise the use of a TPO receptor agonist to overcome cytopenias, such as thrombocytopenia and/or neutropenia.
  • a preferred TPO receptor agonist is eltrombopag.
  • the present invention provides combinations of drug substances as described herein or any pharmaceutically acceptable salt thereof for use in the treatment of the indications as described herein.
  • the present invention provides methods for the treatment of the indications as described herein in human patients in need of such treatment which comprises administering an effective amount of the combinations of drug substances as described herein or any pharmaceutically acceptable salt thereof.
  • the present invention provides the use of the combinations of the drug substances as described herein or any pharmaceutically acceptable salt thereof for the manufacture/preparation of medicaments for the treatment of the indications as described herein.
  • the present invention provides medicaments for the treatment of the indications as described herein comprising the combinations of drug substances as described herein or any pharmaceutically acceptable salt thereof.
  • mice Before identification of resistance mechanisms to p53-Mdm2 inhibition, we generated a collection of tumors sensitive to such inhibitors.
  • Arf-/- PB tumor models To further utilize these Arf-/- PB tumor models in efficacy experiments, the tumors were serially transplanted as for human patient-derived xenograft. To this end, fragments of spontaneous RosaPB/+;ATP2/+;Arf-/- tumors were implanted
  • Braf was the most frequent transposon insertion found in 90.8% of tumors, indicating it may constitute a major cooperating pathway with Arf loss of function. Indeed, insertions at Braf could not be found in PB tumors with no Arf deletion.
  • the Braf gene was targeted between exons 8 and 12 in a directional manner (Fig2), presumably leading to the expression of a specific constitutively active truncated protein as previously described (23, 27, 28). Similar human BRAF gene truncations or fusions were previously reported in human brain, pancreatic, and prostate tumors (27, 29-34).
  • genomic DNA from resistant and vehicle-treated tumors was subjected to splinkerette PCR and deep sequencing to define genetic landscapes based on gCIS.
  • a differential integration analysis identified PB target genes that were significantly enriched in resistant tumors (Fig5). 87 genes were identified suggesting a diversity and/or heterogeneity of the resistance mechanism.
  • Gene ontology analysis revealed that only the p53 pathway was found significantly enriched.
  • the PB bidirectional pattern predicted a Trp53 loss of function.
  • Bcl211 gene was found as the second major enriched target in HDM201 resistant tumors, with a gain of function insertional pattern that did not allow distinguishing between expressions of Bcl-xL or Bcl-xS transcripts (Fig6).
  • Bcl-xL protein but not Bcl-xS, was expressed in resistant tumors with transposon insertion in the Bcl211 promoter (Fig6).
  • Bcl-xL protein interaction with p53 is known to antagonize the antiapoptotic effect in p53 mitochondrial apoptotic pathway (43, 44), and overexpressing Bcl-xL may therefore allow inhibition of p53 apoptotic pathway.
  • Bcl-xL is a known druggable targets
  • Bcl-xL overexpression was detected in 5 resistant human tumors.
  • Bcl-xL and MDM2 inhibitors act synergistically in p53 wild-type tumor models
  • Bcl-xL can be chemically inhibited by dual Bcl2/Bcl-xL inhibitor like ABT-263 (49) or Bcl-xL selective inhibitor like A-1155463 (50).
  • dual inhibition of Bcl-xL and MDM2 could be beneficial in a broad manner, we evaluated the synergistic effects of 69 compounds with CGM097 in an in vitro viability screen on 485 cancer cell lines(lO).
  • ABT-263 was found the third best combination partner with CGM097 in the 138 of these cell lines that were wild-type for p53 (Fig8).
  • Fig9 no significant synergy in p53 mutant cell lines
  • BCL-XL expression confers resistance to HDM201 treatment specifically with intermittent high dose scheduling
  • HDM201dosing at 40mg/kg instead of lOOmg/kg twice a week which we name intermittent.
  • the continuous treatment was not well tolerated in mice: body weight loss was detrimental and 16 mice out of 60 had to be terminated.
  • the intermittent treatment was well tolerated and only one animal was euthanized due to body weight loss (Fig 1 IB).
  • Bcl211 gene was the second most significant CIS gene enriched in HDM201 resistant tumors, after Trp53. Activating transposon insertions in these resistant samples led to enhanced Bcl-xL protein expression. To our knowledge, no therapy is available to counteract p53 mutations, ⁇ 63 and ⁇ 73. Only MDM4(56) and Bcl-xL (49, 50) can currently be targeted therapeutically. Therefore, upfront combination therapies may provide a more promising therapeutic strategy where complete killing of cancers may be attained.
  • MEK inhibitor as the best combination partner for p53/MDM2 inhibition in p53 wild-type cell lines (FigS9A), consistent with possible cooperation of p53 inhibition through Arf deletion and MAPK pathway activation via BRaf truncation.
  • Such MEK inhibition and p53/MDM2 inhibition combination was also identified as efficacious in long term colony formation assays and enhanced apoptosis induction.
  • Our in vitro assays demonstrated that Bcl-xL inhibition sensitized cells to HDM201 inhibition. Therefore, triple combination of MEK, p53/MDM2, and Bcl-xL inhibition may provide further added benefits to prevent cancer recurrence or prolong partial remission, provided adverse effects can be managed.
  • Tierschutzver Eight animals were allowed to adapt for 7 days and housed in a pathogen-controlled environment (5 mice/Type III cage) with ad libitum access to food and water and were identified with transponders. Mice were housed in a specific pathogen-free facility with a 12-h light/12-h dark cycle. Conditional survival is defined by maximum tumor size estimation at 1.5cm diameter or when mice showed suffering or symptoms of morbidity/moribundity, or more than 15% body weight loss. The following genetic components were combined by crossing mice in order to obtain experimental animals from which derived the tumor fragments : heterozygous for RosaPB et ATP2-S 1, and homozygous for Arf deficient allele.
  • ATP2-S 1 CALB/FVB-TgTn(pb/sb- ATP2)SlBrd mouse line carries 15 transposon copies inserted in chromosome 17.
  • ATP2- S 1 piggyBac transposon contains a unidirectional MSCV promoter and gene traps (splice acceptors and Poly A) acting in both orientations (5).
  • the Arf-/- mouse line was FVB-Cdkn2atmlNesh (6, 7).
  • methylcellulose and 0,1% Tween 80 orally twice a week, with alternation of intervals of 3 days and one of 4 days.
  • Vehicles were generated according to respective formulations.
  • genomic DNA was isolated, sheared to fragment length of 200-600bp on a Covaris sonicator. After end-repair and A- tailing, purified DNA fragments were ligated to a Splinkerette adaptor (obtained after annealing of 5'-gttcccatggtactactcatataatacgactcactataggtgacagcgagcgct-3' and 5'- /5Phos/gcgctcgctgtcacctatagtgagtcgtattataattttttttttcaaaaaa-3').
  • Transposon-containing fragments were enriched with 18 cycles of transposon-specific PCR for both the 5' and 3' transposon ends in separate libraries (5'- gatatacagaccgataaaacacatgcgtca-3' for 3' arm of PB; 5'-gacggattcgcgctatttagaaagagag-3' for 5' arm of PB ; and common Splinkerette primer 5'-gttcccatggtactactcata-3'). Barcoding of individual samples and completion of Illumina adaptor sequences were achieved with an additional 12 cycles of transposon- specific PCR and a custom array of 96 unique bar-coding primers.
  • gCIS strategy In order to identify genes that are commonly integrated, we adapted the gCIS strategy first described for SB (10). Shortly, we defined a gene associated region as the gene transcription unit extended upstream by lOkb of promoter sequence. For each gene associated region, we counted the number of insertions (normalized div counts) and the number of TTAA motifs that fell inside and outside the region. We then performed a Fisher exact test on the resulting 2x2 contingency table. The gCIS method allows identifying genes in aggregates by adding normalized div counts for a pool of samples, but also for a single sample, enabling the analysis of rare/hard to obtain indications. Indeed, thanks to the stringent alignment procedure and the high number of PB integration sites identified in single samples, the gCIS method was verified to recover known cancer genes even in single sample analyses.
  • Proteins were extracted from tumor powder using cold Giordano buffer containing phosphatase inhibitors 100X (Sigma P-0044, and P-5726) and proteases inhibitors 100X (Sigma, P-8340). Protein concentration was determined following Qubit® protein determination kit's protocol. 50ug of protein extract were separated by SDS-PAGE (CriterionTM XT Precast Gel, 4-12% Bis-Tris, BIO-RAD, #345-0124, blotting buffer XT MOPS, BIO-RAD, #161-0788) and transferred onto PVDF membranes (Immobilon-P, MILLIPORE, #IPVH00010) using a wet transfer system (Trans-Blot® Transfer Cell, BIO-RAD, #1703930).
  • SDS-PAGE SeriterionTM XT Precast Gel, 4-12% Bis-Tris, BIO-RAD, #345-0124, blotting buffer XT MOPS, BIO-RAD, #161-0788
  • PVDF membranes Immobilon-P, MILLIPORE,
  • Membranes were probed with antibodies (diluted in 5% skim milk powder in PBS/T20 + 0,05% Sodium Azide) against Vinculin (V91131, Sigma) or Bcl-xL (Cell Signaling, 54H6) overnight. Secondary antibody was HRP -conjugated anti-mouse IgG antibody (7076, cell signaling) or HRP-conjugated anti-rabbit IgG antibody (7074, cell signaling) and blots were revealed with ECL substrate (WesternBright ECL, Advansta #K-12045-D20) on the Fusion FX7 imager.
  • the in vitro combination screen was performed on cancer cell lines and data calculations were previously described (10). Here we focused the data analysis on combinations with CGM097, an MDM2 inhibitor structurally similar to HDM201. In total, 485 cancer cell lines were treated with ranges of concentrations for CGM097 and for 25 other compounds. We integrated the information of p53 mutation status and differentiated cell lines with no p53 mutation from cell lines with p53 alteration. The synergistic effect of combinations of HDM201 and A- 1155463 was assessed using methods previously described (58).
  • NDP- CGM097 A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors. Journal of medicinal chemistry 58(16):6348-6358.
  • medulloblastoma model defines networks that discriminate between human molecular subgroups. Proceedings of the National Academy of Sciences of the United States of America 1 10(46):E4325-4334.

Abstract

La présente invention concerne une combinaison pharmaceutique comprenant (a) un inhibiteur de Mdm2 et (b) un inhibiteur de Bcl-xL, destinée en particulier à être utilisée dans le traitement d'un cancer. Cette invention concerne également des utilisations de cette combinaison pour la préparation d'un médicament destiné au traitement d'un cancer; des méthodes de traitement d'un cancer chez un sujet le nécessitant, comprenant l'administration audit sujet d'une quantité conjointement thérapeutiquement efficace de ladite combinaison; des compositions pharmaceutiques comprenant cette combinaison et des conditionnements commerciaux associés.
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