NZ719050A - Combination therapy combining a cdk4/6 inhibitor and a pi3k inhibitor for use in the treatment of cancer - Google Patents

Abstract

Provided is a combination of a cyclin dependent kinase 4 or cyclin dependent kinase 6 (CDK4/6) inhibitor and a phosphatidylinositol 3-kinase (PI3K) inhibitor useful for the treatment of cancer. A preferred CDK4/6 inhibitor is a compound of Formula A (7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide) (ribociclib). Preferred PI3K inhibitors are the compounds of Formula B1 (5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-(trifluoromethyl)-2-pyrimidinamine) (buparlisib) and Formula B2 ((S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({ 4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl} -amide)) (alpelisib).

Description

PATENTS FORM NO. 5 Our ref: DK0237274NZPR Divisional application out of NZ 618745 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATlON Combination therapy ing a CDK4/6 inhibitor and a Pl3K inhibitor for use in the treatment of cancer We, Novartis AG, of trasse 35, CH-4056 Basel, Switzerland, hereby declare the invention, for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page 1a) COMBINATION THERAPY SING A CDK4/6 INHIBITOR AND A PI3K INHIBITOR FOR USE IN THE TREATMENT OF CANCER FIELD OF THE DISCLOSURE A combination of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor and a Phosphatidylinositol se (PI3Kinase) inhibitor for the treatment of solid tumors and hematological malignancies. This disclosure also relates to the use of the combination thereof, in the management of hyperproliferative es like cancer.

RELATED OUND ART Cyclin dependent kinase 4/6 6) inhibitors are described in, for example, W02007/140222 and WOZOIO/020675 which are hereby incorporated by reference in entirety.

Phosphatidylinositol se (PI3Kinase) inhibitors are described in, for example, W02004/048365, W02007/084786, W02004/O96797, W02010/029082, W02006/122806 which is hereby incmporated by reference in entirety.

BRIEF SUMMARY OF THE DISCLOSURE The disclosure provides a combination comprising a first agent that inhibits the CDK4/6 pathway and a second agent that inhibits PI3Kinase. In another aspect, the disclosure provides combinations including pharmaceutical compositions comprising a therapeutically effective amount of a first agent that inhibits CDK4/6, a second agent that inhibits PI3Kinase, and a pharmaceutically able carrier.

Furthermore, the present disclosure provides for the use of a therapeutically effective amount of a combination comprising a first agent that inhibits the CDK4/6 y and a second agent that inhibits PI3Kinase, or a pharmaceutically able salt or pharmaceutical composition thereof, in the manufacture of a medicament for ng cancer.

The present disclosure has a therapeutic use in the treatment of various proliferative diseases.

The above combinations and compositions can be administered to a system comprising cells or tissues, as well as a human patient or and animal subject. [followed by page 2] The first agent that inhibits the CDK4/6 pathway is Compound A which is 7- Cyclopentyl-Z-(S-piperaziny1-pyridinylamino)-7H-pyrrolo[2,3-d]pyrimidine carboxylic acid dimethylamide or pharmaceutically acceptable salt(s) thereof.

Compound A is described by Formula A: D34“ HN N/ N 0 VI C H Formula A or pharmaceutically acceptable salt(s) thereof.

The second agent that inhibits PI3Kinase is Compound B1 bed by Formula B 1: Formula B1 or pharmaceutically acceptable salt(s) f. nd B1 has been described with several names, such as 4—(trifluoromethyl) (2,6—dimorpholinopyrimidin—4-yl)pyridin—Z—amine; 5—(2,6-di—morpholin~4—yl-pyrimidin— 4-yl)trifluoromethyl—pyridin2—ylamine; 5-(2,6~Di—4—m01pholinyl-4—pyrimidinyl)—4— trifluoromethylpyridin-Z-amine; or CAS name 5—(2,6-di~4—mOIpholinylpyrimidinyl) — 4- (trifluoromethyl)pyrimidinamine.

Alternatively, the second agent that inhibits PI3Kinase is nd B2 described by Formula B2: \ YH/ri Formula B2 or pharmaceutically acceptable salt(s) thereof.

Compound B2 is known as (S)—Pyrrolidine—1,2-dicarboxylic acid 2—amide l-( {4— methyl-S— [2—(2,2,2—triflu0ro- 1 , 1—dimethyl—ethyl)—pyridin—4—yl]—thiazol~2-yl} —amide).

The present invention therefore provides a combination comprising a first agent that is a cyclin dependent kinase 4 or cyclin dependent kinase 6 (CDK4/6) inhibitor, n the first agent is Compound A described by Fonnula A: N \ \ .134N O | C H a A, or a pharmaceutically acceptable salt thereof, and a second agent that is a PI3Kinase inhibitor, wherein the second agent is (i) Compound B1 described by Fon’nula B1: Formula B l, or a pharmaceutically acceptable salt thereof, (ii) Compound B2 described by Formula B2: \ THY“ O/\NH2 Formula B2, or a ceutically acceptable salt thereof.

The t invention also provides these ations for use in the treatment of cancer, and these combinations for use in the treatment of s cancers as described herein.

The present invention also provides the use of these combinations in the manufacture of a medicament for treating cancer and the use of these combinations in the manufacture of a medicament for treating various cancers as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the results when the combination of Compound A and Compound B1 or Compound B2, is used to treat MDA—MB—453 cells. The resulting inhibition values were used by CHALICE software to generate Inhibition and ADD Excess Inhibition matrices, as well as the isobolograms.

Figure 2 illustrates the results when the combination of nd A and Compound B1 or nd B2, is used to treat HCT—l 16 cells. The resulting inhibition values were used by CHALICE software to generate Inhibition and ADD Excess tion matrices, as well as the isobolograms.

Figure 3 illustrates the results when the combination of Compound A and Compound B1 or Compound B2, is used to treat MCF-7 cells. The resulting inhibition values were used by CHALICE software to generate Inhibition and ADD Excess Inhibition es, as well as the isobolograms.

Figure 4 illustrates the results when the combination of Compound A and Compound B2, is used to treat T47—D cells. The resulting inhibition values were used by CHALICE software to generate Inhibition and ADD Excess Inhibition matrices, as well as the isobolograms.

DETAILED DESCRIPTION OF THE DISCLOSURE The disclosure provides a combination comprising a first agent that inhibits the CDK4/6 pathway and a second agent that ts PI3Kinase. In another aspect, the disclosure provides combinations including pharmaceutical compositions comprising a therapeutically effective amount of a first agent that inhibits CDK4/6, a second agent that inhibits PI3Kinase, and a pharmaceutically acceptable carrier.

Furthermore, the present disclosure provides for the use of a eutically effective amount of a combination comprising a first agent that inhibits the CDK4/6 pathway and a second agent that inhibits PI3 Kinase, or a pharmaceutically acceptable salt or ceutical composition thereof, in the manufacture of a medicament for treating cancer.

The present sure has a therapeutic use in the treatment of various proliferative diseases.

The above combinations and compositions can be administered to a system comprising cells or tissues, as well as a human patient or and animal t.

The first agent that inhibits the CDK4/6 pathway is Compound A which is 7- Cyclopentyl—2-(5—piperazin- l -yl-pyridinylamino)—7H—pyrrolo [2,3 -d]pyrimidine carboxylic acid dimethylamide or ceutically acceptable salt(s) f.

Compound A is bed by Formula A: a A.

The second agent that inhibits PBKinase is Compound Bl described by Formula B 1: Formula B1 or pharmaceutically acceptable salt(s) f.

Compound B1 has been described with several names, such as 4—(trifluoromethyl)—5- (2,6-dimorpholinopyrimidin—4—yl)pyridin-2—amine; 5—(2,6-di—morpholin—4—yl-pyrimidin— 4—yl)-4—trifluoromethyl—pyridin2~ylamine; 5-(2,6-Di—4-morpholinylpyrimidinyl)—4- trifluoromethylpyridin-Z-amine; or CAS name 5-(2,6-di—4-morpholinyl—4—pyrimidinyl) — 4— (trifluoromethyl)pyrimidinamine.

Alternatively, the second agent that inhibits P13Kinase is Compound B2 descn'bed by Formula B2: [followed by page 6a] Formula B2 or pharmaceutically acceptable salt(s) thereof.

Compound BZ is known as (S)—Pyrrolidine-1,2-dicarboxylic acid 2—amide l—( {4— methyl-S-[2—(2,2,2-trifluoro- l , l -dimethyl-ethyl)-pyridin—4—yl]—thiazol—2~yl} —amide).

The present disclosure includes a method of treating a hyperproliferative disease, preferably cancer. The compounds of the t sure inhibitors of CDK4/6 and P13K, and therefore may be capable of treating diseases wherein the underlying ogy is (at least in part) mediated by activated CDK4/6 and/or PI3K pathway. Such es include cancer and other diseases in which there is a disorder of cell proliferation, apoptosis, or differentiation.

Thus the combination of the present disclosure may be useful in the treatment of RB+W (retinoblastoma protein positive) tumours, including tumours harbouring activating mutations in Ras, Raf, Growth Factor Receptors, P13K,or over-expression of Growth Factor Receptors, or inactivation of p16. The compounds of the t disclosure may also be useful in the treatment of tumours with amplifications of CDK4 and CDK6 genes as well as, tumours over-expressing cyclin partners of the cyclin dependent kinases. The compounds of the present disclosure may also be useful in the treatment of RB—ve tumours.

The combination of the t disclosure may also be useful in the treatment tumours with genetic tions that te the CDK4/6 kinase activity. These include, but are not limited to, cancers with D-cyclin ocations such as mantle cell lymphoma [followed by page 6b] and multiple myeloma, D-cyclin amplifications such as breast cancer and squamous cell esophageal , CDK4 amplifications such as rcoma, CDK6 amplifications or overexpressions such as T—cell lymphoma and p16 inactivation such as melanoma, non— small cell lung cancer and pancreatic cancer.

The combination of the present disclosure may be useful in the ent of cancers that have genetic aberrations in the upstream regulators of D-cyclins, where the defect results in an se of D—cyclins abundance, can also be considered for treatment.

These include, but are not limited to, acute myeloid leukemia with FLT3 tion, breast cancers with Her2/neu overexpression, ER ency or triple negative phenotype, colon cancers with activating mutations of the MAPK, PI3K or WNT pathway, melanomas with activating mutations of MAPK pathway, non small cell lung cancers with activating aberrations of EGFR pathway and pancreatic cancers with activating aberrations of MAPK pathway including K—Ras mutations. [followed by page 7] 2012/045199 The combination of the present sure may be useful in the treatment of cancers that have activating mutations of PI3K. These include, but not limited to, breast cancer, endometrium cancer, urinary track cancer, melanoma, colon cancer, stomach cancer, cervical cancer, prostate cancer and ovarian .

Examples of cancers which may be d With a compound of the present disclosure include but are not limited to, oma, for example a carcinoma of the bladder, breast, colon (e.g. ctal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermis, liver, lung (e.g. adenocarcinoma, small cell lung cancer and non-small cell lung omas), oesophagus, gall bladder, ovary, as (e.g; exocrine pancreatic carcinoma), stomach, cervix, thyroid, nose, head and neck, prostate, and skin (e.g. squamous cellcarcinoma). Other examples of s that may be treated with a compound ofthe t disclosure include hematopoietic tumours of lymphoid lineage (e.g. leukemia, acute lymphocytic leukemia, mantle cell ma, chronic lymphocytic leukaemia, B-cell lymphoma(such as diffuse large B cell - lymphoma), T-cell lymphoma, multiple myeloma, n’s lymphoma, non-Hodgkin’s lymphoma, hairy cell lymphoma, and Burkett‘s lymphoma; hematopoietic tumours of myeloid lineage, for example acute and chronic myelogenous leukemias, myelodysplastic syndrome, and locytic leukemia. Other cancers include thyroid follicular cancer; a tumour ofmesenchymal origin, for example fibrosarcoma or habdomyosarcoma; a tumour ofthe central or peripheral nervous system, for example astrocytoma, lastoma, glioma or schwannoma; neuroendocrine cancer; melanoma; prostate cancer; ovarian cancer; id cancer; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; retinoblastoma; keratoctanthoma; thyroid follicular cancer; and Kaposi's sarcoma.

One group of cancers includesihuman breast cancers (e.g. ER positive breast cancer, Her2 positive breast cancer, PI3K mutated breast cancer, y breast tumours, node-negative breast cancer, invasive duct adenocarcinomas of the breast, non- trioid breast cancers); and endometrial cancers. Another sub-set of cancers wherein compounds having CDK4/6 and/or PI3K inhibitory activity may be of particular therapeutic benefit comprises glioblastoma multiforme, T cell ALL, sarcomas, familial melanoma and melanoma.

W0 2013(006532 The combination of the t disclosure could also be useful in the ent of viral infections, for example herpes Virus, pox virus, n-Barr virus, Sindbis Virus, adenovirus, HIV, HPV, HCV and HCMV; prevention ofAIDS developmentin HIV- infected individuals; chronic inflammatory diseases, for example systemic lupus erythematosus, autoirmnune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus; cardiovascular diseases for example cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, for example Alzheimer’s disease, AIDS-related dementia, Parkinson’s disease, amyotropic lateral sclerosis, retinitis pigmentosa, spinal muscular atropy and llar degeneration; glomerulonephritis; myelodysplastic syndromes, ischemic injury associated myocardial infarctions, stroke and reperfusion injury, arrhythmia, sclerosis, toxin- induced or l related liver diseases, haematological diseases, for example, chronic anemia and ic anemia; degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, aspirin-senstive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases, ophthalmic diseases including age related macular degeneration, uveitis, and cancer pain.

The phrase “pharmaceutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. Preferably, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the US. Pharmacopeia or other lly recognized pharmacopeia for use in animals, and more particularly in .

The term er” refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical rs can be sterile liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, l 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 inj ectable ons. Suitable ceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.

The phrase “therapeutically effective amount” is used herein to mean an amount ent to reduce by at least about 15 t, preferably by at least 50 percent, more preferably by at least 90 percent, and most preferably prevent, a clinically cant deficit in the activity, on and response of the host. Alternatively, a therapeutically effective amount is sufficient to cause an improvement in a clinically significant condition/symptom in the host.

“Agent” refers to all materials that may be used to prepare pharmaceutical and diagnostic compositions, or that may be compounds, nucleic acids, polypeptides, fragments, isoforms, variants, or other materials that may be used independently for such purposes, all in accordance with the present disclosure.

The present disclosure includes all pharmaceutically acceptable isotopically-labeled compounds ofthe disclosure, i.e. compounds of a (I), wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in .

Examples of isotopes suitable for inclusion in the compounds of the disclosure ses isotopes ofhydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, e, such as 18F, iodine, such as 123I and 125I, nitrogen, such as ’ 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32F, and sulphur, such as 358.

Certain isotopically-labelled compounds of Formula (I), for e, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, 1'. e. 3H, and carbon-l4, z'. e. 14C, are particularly useful for this purpose in View of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, z‘. e. 2H, may afford certain therapeutic ages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage ements, and hence may be preferred in some circumstances.

Substitution with on emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of Formula (I) can lly beprepared by conventional techniques known to those skilled in the art or by processes analogous to those bed in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non—labeled reagent usly employed.

Compound A can be synthesized, for example, as described in W02010/020675 or Compound Bl can be synthesized, for example, as described in W02007/084786.

Compound B2 can be synthesized, for example, as described in W02010/029082.

EXAMPLES Example 1 Potential synergistic interactions n Compound A and Compound B lor BZ combinations were assessed relative to the Loewe additivity model using CHALICE software, via a synergy score calculated from the differences n the ed and Loewe model values across the se matrix. Briefly, 9 ing concentration ranging from 20 MM diluted serially three folds for Compound A and 10 uM diluted serially 3 folds for Compound B1 or B2, including 0 uM, were used. In a 96 well plate, the 9 concentration points for'each agent were mixed‘in a matrix format, generating 81 combinations. This plate was used to treat MDA-MB—453 cells, and the resulting inhibition values were used by CHALICE software to generate Inhibition and ADD Excess Inhibition matrices, as well as the isobolograms. A more detailed explanation of the que and calculation can be found in Lehar et al. “Synergistic drug combinations improve therapeutic selectivity”, Nat. Biotechnol. 2009, July; 27(7), 659-666, which is hereby incorporated by reference.

As illustrated by Figure 1, inhibition matrix shows the actual inhibition observed by the CTG assay at the respective concentrations of the compounds. ADD Excess inhibition shows the excess inhibition observed over the inhibition ted by the Loewe additivity model. In addition to the es, one can Use isobolograms to observe ' synergy. The inhibition level for each isobologram was chosen manually so as to observe W0 2013f006532 2012/045199 the best synergistic effects. Isobologram was generated with Compound A concentrations shown on the x-axis and Compound B1 or BZ concentrations shown on the y-axis. A straight line connecting the Compound A and the Compound B1 or B2 concentrations which produce the chosen level of inhibition represented growth inhibitions that were strictly additive for the combinations. Plots placed below the line of additivity (more growth inhibition) ented synergistic growth tions, while plots above the line of additivity (less growth tion) represented antagonistic growth inhibitions.

Synergic interaction is observed for the combination of Compound A and - Compound B1 or B2 in the MDA—MB—453 cells.

Example 2 Potential synergistic interactions between Compound A and Compound B1 or B2 combinations were assessed relative to the Loewe additivity model using CHALICE software, via a synergy score calculated from the ences between the ed and Loewe model values across the response . Briefly, 9 titrating concentration ranging from 20 MM diluted serially three folds for Compound A and 20 uM diluted serially 3 folds for nd B1 or B2, including 0 uM, were used. In a 96 well plate, the 9 concentration points for each agent were mixed in a matrix format, generating 81 ations. This plate was used to treat breast cancer HGT-116 cells, and the resulting inhibition values were used by CHALICE software to generate Inhibition and ADD Excess Inhibition matrices, as well as the isobolograms. A more detailed explanation of the" technique and calculation can be found in Lehar et a1. “Synergistic drug combinations improve therapeutic selectivity”, Nat. Biotechnol. 2009, July; 27(7), 6, which is hereby incorporated by reference.

As illustrated by Figure 2, inhibition matrix shows the actual inhibition observed by the CTG assay at the respective concentrations of the compounds. ADD Excess inhibition shows the excess inhibition observed over the inhibition predicted by the Loewe additivity model. In addition to the matrices, one can use isobolograms to observe synergy. The tion level for each isobologram was chosen manually so as to observe the best istic effects. Isobologram was generated with Compound A concentrations PCT/U82012/045199 shown on the x-axis and Compound B1 or B2 concentrations shown on the y-axis. A straight line connecting the Compound A and the Compound B1 or B2 concentrations which produce the chosen level of inhibition represented growth inhibitions that were strictly additive for the, combinations. Plots placed below the line of additivity (more growth inhibition) represented synergistic growth inhibitions, while plots above the line of additivity (less growth inhibition) represented antagonistic growth tions.

Synergic interaction is observed for the combination of Compound A and Compound B1 or B2 in the HGT-116 cells.

- Example 3 Potential synergistic interactions between nd A and COmpound B1 or B2 combinations were assessed relative to the Loewe additivity model using CHALICE software, via a synergy score calculated from the differences between the observed and Loewe model values across the response matrix. Briefly, 9 titrating concentration ranging from 20 uM diluted serially three folds for Compound A and 20 uM diluted serially 3 folds for Compound B1 or B2, including 0 uM, were used. In a 96 well plate, the 9 concentration points for each agent were mixed in a matrix format, generating 81 combinations. This plate was used to treat ER positive breast cancer MCF-7 cells, and the ing inhibition values were used by CHALICE re to generate Inhibition and ADD Excess Inhibition matrices, as well as the ograms. A more ed explanation ofthe technique and calculation can be found in Lehar et al. “Synergistic drug combinations improve therapeutic selectivity”, Nat. Biotechnol. 2009, July; 27(7), 659-666, whichsis hereby incorporated by reference.

As illustrated by Figure 3, inhibition matrix shows the actual inhibition observed by the BrdU assay at the respective concentrations of the compounds. ADD Excess tion shows the excess inhibition observed OVCI‘ the inhibitionpredicted by the Loewe vity model. In addition to the matrices, one can use isobolograms to observe synergy. The inhibition level for each isobologram was chosen ly so as to observe the best synergistic effects. Isobologram was generated with Compound A concentrations shown on the x-axis and Compound B1 or B2 trations shown on the y—axis. A PCT/U82012/045199 straight line connecting the Compound A and the Compound B1 or B2 concentrations which produce the chosen level of inhibition represented growth inhibitions that were ly additive for the combinations. Plots placed below the line of additivity (more growth tion) represented synergistic growth inhibitions, while plots above the line of additivity (less growth-inhibition) ented antagonistic growth inhibitions.

Synergic interaction is observed for the combination of Compound A and Compound B1 or B2 in the MCF-7 cells.

Example 4 Potential synergistic interactions between Compound A and Compound B2 combinations were assessed relative to the Loewe additivity model using E software, via a synergy score calculated from the differences between the observed and Loewe model values across the response matrix. Briefly, 9 titrating tration ranging from 20 uM diluted serially three folds for Compound A and 20 uM diluted serially 3 folds for Compound B2, including 0 uM, were used. In a 96 well plate, the 9 concentration points for each agent were mixed in a matrix , generating 81 combinations. This plate was used to treat ER positive breast cancer T47-D cells, and the resulting inhibition values were used by CHALICE re to te Inhibition and ADD Excess Inhibition es, as well as the isobolograms. A more detailed explanation of the technique and calculation can be found in Lehar et a1. “Synergistic drug combinations improve therapeutic selectivity”, Nat. Biotechnol. 2009, July; 27(7), 659-666, which is hereby incorporated by reference.

As illustrated by Figure 4, inhibition matrix shows the actual inhibition observed by the BrdU assay at the tive concentrations of the compounds. ADD Excess inhibition shows the excess inhibition observed over the inhibition predicted by the Loewe additivity model. In addition to the matrices, one can use isobolograms to observe synergy. The inhibition level for each isobologram was chosen manually so as to observe the best synergistic effects. Isobologram was generated with Compound A trations shown on the x-axis and Compound B2 concentrations shown on the y-axis. A straight line connecting the Compound A and the Compound 82 concentrations which produce PCT/U82012/045199 the chosen level of tion represented growth inhibitions that were strictly additive for the combinations. Plots placed below the line of additivity (more growth inhibition) represented synergistic growth inhibitions, while plots above the line of vity (less grth inhibition) represented antagonistic growth inhibitions.

Synergic interaction is observed for the combination of Compound A and Compound B2 in the T47-D cells.

Claims (1)

What is claimed is:

1. A combination comprising a first agent that is a cyclin dependent kinase 4 or cyclin dependent kinase 6 (CDK