WO2008120004A1 - Combinaison d'un inhibiteur de mek et d'un inhibiteur de b-raf pour le traitement du cancer - Google Patents

Combinaison d'un inhibiteur de mek et d'un inhibiteur de b-raf pour le traitement du cancer Download PDF

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Publication number
WO2008120004A1
WO2008120004A1 PCT/GB2008/001184 GB2008001184W WO2008120004A1 WO 2008120004 A1 WO2008120004 A1 WO 2008120004A1 GB 2008001184 W GB2008001184 W GB 2008001184W WO 2008120004 A1 WO2008120004 A1 WO 2008120004A1
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Prior art keywords
methyl
amino
oxo
phenyl
benzamide
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PCT/GB2008/001184
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English (en)
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Alex Adjei
Lisa Drew
Bret Friday
Jackson B. Gibbs
Patricia Elizabeth Mccoon
Paul David Smith
Chunrong Yu
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2008120004A1 publication Critical patent/WO2008120004A1/fr

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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
    • A61K31/41—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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

  • This invention relates to a combination product comprising a MEK inhibitor and a B- raf inhibitor, and to methods for the production of an anti-cancer effect in a patient, which is accordingly useful in the treatment of cancer in a patient. More specifically the present invention relates to: a combination product comprising a MEK inhibitor and a B-raf inhibitor; a combination product comprising a kit of parts comprising a MEK inhibitor and a B-raf inhibitor; the use of the combination product in the treatment of cancer; a method of treating cancer comprising administering the combination product to a patient.
  • the combination product and methods of the invention are also useful in the treatment of other diseases associated with the activity of MEK, and/or B-raf.
  • the Ras, Raf, MAP protein kinase/extracellular signal-regulated kinase kinase (MEK), extracellular signal-regulated kinase (ERK) pathway plays a central role in the regulation of a variety of cellular functions dependent upon cellular context, including cellular proliferation, differentiation, survival, immortalization, invasion and angiogenesis (reviewed in Peyssonnaux and Eychene, Biology of the Cell, 2001, 93,3-62).
  • the ras-dependent raf-MEK-MAPK cascade is one of the key signalling pathways responsible for conveying both mitogenic and invasive signals from the cell surface to the nucleus resulting in changes in gene expression and cell fate.
  • the Ras/Raf/MEK/ERK pathway has been reported to contribute to the tumorigenic phenotype by inducing immortalisation, growth factor-independent growth, insensitivity to growth-inhibitory signals, ability to invade and metastasis, stimulating angiogenesis and inhibition of apoptosis (reviewed in Kolch et al., Exp.Rev. MoI. Med., 2002, 25 April, http://www.expertreviews.org/02004386h.htm).
  • ERK phosphorylation is enhanced in approximately 30% of all human tumours (Hoshino et al., Oncogene, 1999, 18, 813-822). This may be a result of overexpression and/or mutation of key members of the pathway, including RAS and BRAF genes.
  • B-Raf is reportedly the major isoform involved in cell proliferation and the primary target of oncogenic Ras. Activating somatic missense mutations have been identified exclusively for B-Raf, occurring with a frequency of 66% in malignant cutaneous melanomas (Davies et al., Nature, 2002, 417, 949-954) and also present in a wide range of human cancers, including but not limited to papillary thyroid tumours (Cohen et al., J. Natl.
  • an inhibitor of a protein of the MAPK kinase pathway should be of value both as an anti-proliferative, pro-apoptotic and anti-invasiveo agent for use in the containment and/or treatment of proliferative or invasive disease.
  • the present invention provides a combination product comprising a MEK inhibitor and a B-raf inhibitor.
  • the combination product of the invention is useful in a method for the production of an anti-cancer effect in a patient, which is accordingly useful in the treatment of cancer in a patient.
  • a combination0 product comprising a MEK inhibitor, or a pharmaceutically acceptable salt thereof, and a B-raf inhibitor, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the combination product of the present invention provides for the administration of a MEK inhibitor in conjunction with a B-raf inhibitor.
  • the combination product may be in the form of a combined preparation of a MEK inhibitor and a B-raf inhibitor.
  • the combination product may comprise a kit of parts comprising separate formulations of a MEK inhibitor and a B-raf inhibitor.
  • the separate formulations of a MEK inhibitor and a B-raf inhibitor may be administered sequentially, separately and/or simultaneously.
  • the separate formulations of a MEK inhibitor and a B-raf inhibitor of the combination product are administered simultaneously (optionally repeatedly).
  • the separate formulations of a MEK inhibitor and a B-raf inhibitor of the combination product are administered sequentially (optionally repeatedly).
  • the separate formulations of a MEK inhibitor and a B-raf inhibitor of the combination product are administered separately (optionally repeatedly).
  • the delay in administering the second formulation should not be such as to lose the beneficial effect of the combination therapy.
  • the present invention provides a combination product comprising a MEK inhibitor, or a pharmaceutically- acceptable salt thereof, and a B-raf inhibitor, or a pharmaceutically-acceptable salt thereof, for use sequentially, separately and/or simultaneously in the treatment of cancer.
  • a combination product which comprises a kit of parts comprising the following components: a MEK inhibitor, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier; and a B-raf inhibitor, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, wherein the components are provided in a form which is suitable for sequential, separate and/or simultaneous administration.
  • the kit of parts comprises a first container comprising a MEK inhibitor, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier; and a second container comprising a B-raf inhibitor, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, and a container means for containing said first and second containers.
  • kit of parts further comprises instructions on how to administer the components sequentially, separately and/or simultaneously. In one embodiment the kit of parts further comprises instructions indicating that the combination product can be used in the treatment of cancer.
  • the MEK inhibitor is a small molecular weight compound. In one embodiment the MEK inhibitor is selected from any one of an ATP-competitive MEK inhibitor, a non-ATP competitive MEK inhibitor, or an ATP-uncompetitive MEK inhibitor.
  • the MEK inhibitor is selected from any one of AZD6244 (Example 10 of International Patent Publication Number WO03/077914) or a pharmaceutically acceptable salt thereof, 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 JS- dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof, 4-(4-Bromo-2- fluorophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihydropyridazine-3- carboxamide or a pharmaceutically acceptable salt thereof, PD-0325901 (Pfizer), PD- 184352 (Pfizer), XL-518 (Exelixis), AR-119 (Ardea Biosciences, Valeant Pharmaceuticals), AS- 701173 (Merck Serono), AS-701255 (Merck
  • the MEK inhibitor is selected from AZD6244 or a pharmaceutically acceptable salt thereof, 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 JS- dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof or 4-(4-Bromo- 2-fluorophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihydropyridazine-3- carboxamide or a pharmaceutically acceptable salt thereof as described below.
  • the MEK inhibitor is selected from AZD6244 or a pharmaceutically acceptable salt thereof or 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 JS- dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof, as described below.
  • the MEK inhibitor is AZD6244 hydrogen sulphate salt. AZD6244 hydrogen sulphate salt may be synthesised according to the process described in
  • the MEK inhibitor may inhibit gene expression, for example by interfering with mRNA stability or translation.
  • the MEK inhibitor is selected from small interfering RNA (siRNA), which is sometimes known as short interfering
  • RNA or silencing RNA or short hairpin RNA (shRNA), which is sometimes known as small hairpin RNA.
  • shRNA short hairpin RNA
  • the B-raf inhibitor is a small molecular weight compound. In one embodiment the B-raf inhibitor is selected from any one of an ATP-competitive B-raf inhibitor, a non-ATP competitive B-raf inhibitor, or an ATP -uncompetitive B-raf inhibitor. In one embodiment the B-raf inhibitor is selected from any one of the small molecular weight compounds disclosed in International Patent Publication Number WO2006/024834 or
  • WO2006/067446 or International Patent Application Number PCT/GB2006/004756, or is selected from any one of CHIR-265 (Novartis), XL281 (Exelixis) or PLX4032 (Plexxikon, Roche).
  • the B-raf inhibitor is selected from any one of
  • the B -raf inhibitor is selected from any one of
  • the B-raf inhibitor is selected from any one of
  • the B-raf inhibitor is selected from XL281 or PLX4032.0 In a further embodiment, the B-raf inhibitor is selected from any one of 3-( 1 -Cyano- 1 -methylethyl)-N- ⁇ 4-methyl-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)amino]phenyl ⁇ benzamide;
  • the B-raf inhibitor is a mutant B-raf selective inhibitor. Examples of mutant B-raf selective inhibitors are described in International Patent Publication Number WO2008020203.
  • Particular mutant B-raf selective inhibitors include (R)-N-( 1 -(4-(6-(Pyridin-4-yl)quinazolin-2-ylamino)phenyl)ethyl)acetamide; and 3-Methoxy-N-(( 1 R)- 1 - ⁇ 4-[(6-pyridin-4-ylquinazolin-2-yl)amino]phenyl ⁇ ethyl)propanamide.
  • the B-raf inhibitor may inhibit gene expression, for example by interfering with mRNA stability or translation.
  • the B-raf inhibitor is selected from for example siRNA or shRNA.
  • a combination product comprising AZD6244, or a pharmaceutically acceptable salt thereof, and a B-raf inhibitor, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, wherein the B-raf inhibitor is selected from any one of XL281 ; PLX4032; 3-( 1 -cyano- 1 -methylethyl)-N- ⁇ 4-methyl-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6- yi)amino]phenyl ⁇ benzamide;
  • a combination product comprising 4-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 ,6- dihydropyridazine-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a B-raf inhibitor, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, wherein the B-raf inhibitor is selected from any one of XL281; PLX4032; 3-(l -cyano- l-methylethyl)-N- ⁇ 4-methyl-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6- y l)amino] phenyl ⁇ benzamide;
  • AZD6244 or a pharmaceutically acceptable salt thereof
  • XL281 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a combination product comprising AZD6244, or a pharmaceutically acceptable salt thereof, and
  • PLX4032 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a combination product comprising AZD6244, or a pharmaceutically acceptable salt thereof, and 3-(l-cyano-l-methylethyl)-N- ⁇ 4-methyl-3-[(3-methyl-4-oxo-3,4-dihyd ⁇ oquinazolin-6- yl)amino]phenyl ⁇ benzamide, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a combination product comprising AZD6244, or a pharmaceutically acceptable salt thereof, and
  • a combination product comprising AZD6244, or a pharmaceutically acceptable salt thereof, and
  • a combination product comprising 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-l,5-dimethyl-6-oxo-l,6- dihydropyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof, and
  • XL281 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a combination product comprising 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 ,6- dihydropyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof, and
  • PLX4032 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a combination product comprising 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 ,6- dihydropyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof, and
  • a combination product comprising 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 ,6- dihydropyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof, and
  • a combination product comprising 4-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 ,6- dihydropyridazine-3-carboxamide, or a pharmaceutically acceptable salt thereof, and XL281 , or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a combination product comprising 4-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 ,6- dihydropyridazine-3-carboxamide, or a pharmaceutically acceptable salt thereof, and PLX4032, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a combination product comprising 4-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxyethoxy)-l,5-dimethyl-6-oxo-l,6- dihydropyridazine-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-(l-cyano-l-methylethyl)-N- ⁇ 4-methyl-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)amino]phenyl ⁇ benzamide, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a combination product comprising 4-(4-Bromo-2-fluorophenylamino)- ⁇ -(2-hydroxyethoxy)-l,5-dimethyl-6-oxo-l,6- dihydropyridazine-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (R)-N-( 1 -(4-(6-(Pyridin-4-yl)quinazolin-2-ylamino)phenyl)ethyl)acetamide, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a combination product comprising 4-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 ,6- dihydropyridazine-3-carboxamide, or a pharmaceutically acceptable salt thereof, and
  • a combination product comprising a AZD6244, or a pharmaceutically acceptable salt thereof, and a mutant B-raf inhibitor, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a combination product comprising a AZD6244, or a pharmaceutically acceptable salt thereof, and a mutant B-raf inhibitor, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, wherein the mutant B-raf inhibitor is selected from any one of
  • a combination product comprising 4-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxyethoxy)-l,5-dimethyl-6-oxo-l,6- dihydropyridazine-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a mutant B -raf inhibitor, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, wherein the mutant B-raf inhibitor is selected from any one of
  • a suitable pharmaceutically-acceptable salt of a MEK inhibitor or a B-raf inhibitor may be, for example, an acid-addition salt which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid.
  • a suitable pharmaceutically-acceptable salt of a MEK inhibitor or a B-raf inhibitor may be, for example, a salt which is sufficiently acidic, for example an alkali or alkaline earth metal salt.
  • a combination product comprising a MEK inhibitor, or a pharmaceutically acceptable salt thereof, linked to a B-raf inhibitor, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the combination product of the present invention is expected to produce a synergistic or beneficial effect through the production of an anti-cancer effect in a patient, which is accordingly useful in the treatment of cancer in a patient.
  • a beneficial effect is achieved if the effect is therapeutically superior, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, to that achievable on dosing one or other of the components of the combination treatment at its conventional dose.
  • the beneficial effect may be synergistic, if the combined effect is therapeutically superior to the sum of the individual effect achievable with a MEK inhibitor or a B-raf inhibitor.
  • a beneficial effect is obtained if an effect is achieved in a group of patients that does not respond (or responds poorly) to an antagonist of the biological activity of a MEK inhibitor or a B-raf inhibitor alone.
  • the effect is defined as affording a beneficial effect if one of the components is dosed at its conventional dose and the other component(s) is/are dosed at a reduced dose and the therapeutic effect, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, is equivalent to that achievable on dosing conventional amounts of the components of the combination treatment.
  • a beneficial effect is deemed to be achieved if a conventional dose of a MEK inhibitor or a B-raf inhibitor may be reduced without detriment to one or more of the extent of the response, the response rate, the time to disease progression and survival data, in particular without detriment to the duration of the response, but with
  • a method of treating cancer which comprises administration of a therapeutically effective amount of a combination product of the invention to a patient having or suspected of having cancer.
  • the MEK inhibitor, or a pharmaceutically acceptable salt thereof is administered sequentially, separately and/or simultaneously with the B-raf inhibitor, or a pharmaceutically acceptable salt thereof.
  • the method additionally comprises selecting a patient in need of treatment of cancer, and administration to the patient of a therapeutically effective dose of a combination product of the invention. 5
  • MEK and B-raf which comprises administration of a therapeutically effective amount of a combination product of the invention to a patient.
  • the MEK inhibitor, or a pharmaceutically acceptable salt thereof is administered sequentially, separately and/or simultaneously with the B-raf inhibitor, or a pharmaceutically acceptable salt thereof.
  • the method additionally comprises selecting a patient in need of MEK and/or B-raf inhibition, and administration to the patient of a therapeutically effective dose of a combination product of the invention.
  • a combination product of the invention in the production of an anti-cancer effect in a patient, which is5 accordingly useful in the treatment of cancer.
  • use of a combination product of the invention in the treatment of cancer in the treatment of cancer.
  • a combination product of the invention in the inhibition of MEK and/or B-raf in a patient, which is accordingly useful in the treatment of cancer.
  • a0 combination product of the invention for the inhibition of MEK and/or B-raf.
  • a method or use as described hereinabove wherein the patient is not resistant to MEK inhibition.
  • the dosage of the MEK inhibitor and/or the B-raf inhibitor for a given patient will be determined by the attending physician, taking into consideration various factors known to modify the action of drugs including severity and type of disease, body weight, sex, diet, time and route of administration, other medications and other relevant clinical factors.
  • Therapeutically effective dosages may be determined by either in vitro or in vivo methods.
  • the therapeutically effective amount of a MEK inhibitor or a B-raf inhibitor, as described herein, to be used will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the patient. Accordingly, it is preferred for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.
  • a typical daily dosage might range from about 0.000 lmg/kg to up to 100mg/kg or more, depending on the factors mentioned above.
  • the clinician will administer the combination product until a dosage is reached that achieves the desired effect.
  • the sequence in which the MEK inhibitor, or pharmaceutically acceptable salt thereof, and the B-raf inhibitor, or pharmaceutically acceptable salt thereof, may be administered i.e. whether and at what point sequential, separate and/or simultaneous administration takes place) may be determined by the physician or skilled person.
  • the combination product of the present invention is expected to be particularly useful for the treatment of patients with cancers, including, but not limited to, non-solid tumours such as leukaemia, for example acute myeloid leukaemia, multiple myeloma, haematologic malignancies or lymphoma, and also solid tumours and their metastases such as melanoma, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, carcinoma of the thyroid, bile duct, bone, gastric, brain/CNS, head and neck, hepatic, stomach, prostate, breast, renal, testicular, ovarian, skin, cervical, lung, muscle, neuronal, oesophageal, bladder, lung, uterine, vulval, endometrial, kidney, colorectal, pancreatic, pleural/peritoneal membranes, salivary gland, and epidermoid tumours and haematological malignancies.
  • non-solid tumours
  • the combination product of the invention is expected to be especially useful for the treatment of patients with lung cancer, melanoma, gastric cancer, colorectal cancer, ovarian cancer, thyroid cancer, pancreatic cancer, liver cancer, and their metastases, and also for the treatment of patients with acute myeloid leukaemia or multiple myeloma.
  • the combination product of the present invention is also expected to be particularly useful for the treatment of patients with a tumour which is associated with the Ras-Raf-MEK- ERK pathway or which is dependent alone, or in part, on the biological activity of the Ras- Raf-MEK-ERK pathway.
  • the combination product of the present invention is also expected to be particularly useful for the treatment of patients with a tumour which is associated with MEK or which is dependent alone, or in part, on the biological activity of MEK.
  • the combination product of the present invention is also expected to be particularly useful for the treatment of patients with a tumour which is associated with B-raf or which is dependent alone, or in part, on the biological activity of B-raf.
  • the combination product of the present invention may be used as a sole therapy or may involve additional surgery or radiotherapy or an additional chemotherapeutic agent or a therapeutic antibody in addition.
  • Such chemotherapeutic agents may include one or more of the following categories of anti tumor agents: (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithra
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-mo ⁇ holinopropoxy)quinazolin-4-amine (gefitinib, ZD 1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the epidermal growth factor family (for
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRC A2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Anti-cancer effects which are accordingly useful in the treatment of cancer in a patient include, but are not limited to, anti-tumour effects, the response rate, the time to disease progression and the survival rate.
  • Anti-tumour effects of a method of treatment of the present invention include but are not limited to, inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to regrowth of tumour on cessation of treatment, slowing of disease progression. It is expected that when a combination product of the present invention is administered to a patient in need of treatment for cancer, said combination product will produce an effect, as measured by, for example, one or more of: the extent of the anti-tumour effect, the response rate, the time to disease progression and the survival rate.
  • Anti-cancer effects include prophylactic treatment as well as treatment of existing disease.
  • An inhibitor may be a polypeptide, nucleic acid, carbohydrate, lipid, small molecular weight compound, an oligonucleotide, an oligopeptide, siRNA, antisense, a recombinant protein, an antibody, a peptibody, or conjugates or fusion proteins thereof.
  • siRNA see Milhavet O, Gary DS, Mattson MP. (Pharmacol Rev. 2003 Dec;55(4):629-48.
  • antisense see Opalinska JB, Gewirtz AM. Sci STKE. 2003 Oct 28; 2003 (206) : pe47.
  • a small molecular weight compound refers to a compound with a molecular weight of less than 2000 Daltons, 1000 Daltons, 700 Daltons or 500 Daltons.
  • a B-raf inhibitor is any inhibitor of the biological activity of wild-type or any mutant form of B-raf, including inhibitors that inhibit the biological activity of B-raf and other wild- type or mutant Raf serine/threonine protein kinase family members including Raf-1 /c-Raf, and/or A-Raf.
  • a B-raf inhibitor may additionally inhibit VEGFR-2 and/or c-kit.
  • a patient is any warm-blooded animal, such as a human.
  • treatment includes therapeutic and/or prophylactic treatment.
  • the MEK inhibitor 4-(4-Bromo -2-fluorophenylamino)-N-(2-hydroxyethoxy)-l,5- dimethyl-6-oxo-l,6-dihydropyridazine-3-carboxamide can be prepared according to the following method
  • Step A Preparation of diethyl 2-(2-methylhydrazono)malonate: To a solution of diethyl ketomalonate (95 g, 546 mmol) in EtOH (600 mL) (2 L 3-neck flask equipped with thermocouple, °C (internal temperature, heated by a heating mantle) and stirred for 6 hours. The reaction mixture was cooled to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give the crude material along with solid precipitates that was purified by a silica gel plug (3:2 hexanes:EtOAc) to afford 81 g (74%) of the desired product. N 2 line, condenser and mechanical stirrer) was added MeNHNH 2 (32 mL, 5 600 mmol) in one portion at room temperature. The reaction mixture was warmed to 60
  • Step B Preparation of diethyl 2-(2-methyl-2-propionylhvdrazono ' )malonate: To a solution of 2-(2-methylhydrazono)malonate (100 g, 494 mmol) in THF (1 L) at 0 0 C was added LiHMDS (643 mL, 643 mmol) by an addition funnel over 45 minutes. The reaction mixture was stirred for 45 minutes at 0 0 C. Propionyl chloride (51.6 mL, 593 mmol) waso added in one portion). The resulting mixture was warmed to room temperature and stirred for 20 hours. The reaction mixture was quenched with saturated aqueous NH 4 Cl (85 mL) and water (85 mL).
  • Step C Preparation of 4-hvdroxy- 1 ,5-dimethyl-6-oxo- 1 ,6-dihydropyridazine-3- carboxylic acid: To a solution of LiHMDS (331 mL, 331 mmol, 1 M solution in THF) ino THF (430 mL) at -78 °C was added a solution of 2-(2-methyl-2- propionylhydrazono)malonate (21.40 g, 82.86 mmol) in THF (10 mL). The resulting mixture was slowly warmed to -40 0 C over 1 hour and stirred for 1.5 hours at -40 0 C. To the reaction mixture was added water (500 mL) at -40 0 C.
  • LiHMDS 331 mL, 331 mmol, 1 M solution in THF
  • 2-(2-methyl-2- propionylhydrazono)malonate 21.40 g, 82.86 mmol
  • the reaction mixture was warmed to room temperature and stirred for 3 hours.
  • the reaction mixture was concentrated under reduced5 pressure, quenched with 6 N aqueous HCl at 0 0 C, and acidified to pH 1 to 2.
  • the resulting mixture was stirred for 16 hours at room temperature.
  • the precipitates were filtered off and triturated with CH 2 Cl 2 to afford 7.21 g (47%) of the desired product.
  • the filtrate was extracted with EtOAc (3x).
  • the combined organic layers were washed with water, dried over MgSO 4 , filtered, and concentrated under reduced pressure to give the crude material that was0 triturated with CH 2 Cl 2 to afford additional 3.56 g (23%) of the desired product.
  • the aqueous layer was extracted again with EtOAc (3x).
  • Step D Preparation of 4-chloro- 1 ,5-dimethyl-6-oxo- 1 ,6-dihvdropyridazine-3- carboxylic acid: A mixture of 4-hydroxy-l,5-dimethyl-6-oxo-l,6-dihydropyridazine-3- carboxylic acid (35.4 g, 192 mmol), catalytic amount of DMF (3 drop), and POCI 3 ( 178 mL, 1.92 mol) was heated for 2 days at 90 0 C, and then the POCI 3 was removed under reduced pressure. The crude material was quenched with ice, and the reaction mixture was stirred for 2 hours at room temperature. The precipitates formed out of the solution was filtered off and washed with ether.
  • Step E Preparation of 4-(4-bromo-2-fluorophenylamino)- 1 ,5-dimethyl-6-oxo- 1 ,6- dihydropyridazine-3 -carboxylic acid: To a solution of 4-bromo-2-fluoroaniline (22.6 g, 1 16 mmol) in THF (165 mL) at -78 0 C was slowly added a solution of LiHMDS (174 mL, 174 mmol, 1 M solution in THF). The resulting mixture was stirred for 1 hour at -78 0 C.
  • Step G Preparation of 4-(4-bromo-2-fluorophenylaminoVN-(2-hydroxyethoxy ' )-l ,5- dimethyl-6-oxo- 1 ,6-dihvdropyridazine-3-carboxamide: A mixture of 4-(4-bromo-2- fluorophenylamino)-l,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-l,6-dihydropyridazine-3- carboxamide (17.98 g, 40.75 mmol) and 6 N aqueous HCl (13.58 mL, 81.50 mmol) in EtOH/THF (50 mL/50 mL) was stirred for 3 hours at room temperature.
  • reaction mixture5 was concentrated under reduced pressure and diluted with water (50 mL). The resulting mixture was extracted with EtOAc (2x). The combined organic layers were dried over MgSO 4 , filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% CH 2 Cl 2 to 2.5% MeOH in CH 2 Cl 2 ) to afford 9.41 g (56% for two steps) of the desired product.
  • the MEK inhibitor 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-l,5- dimethyl-6-oxo-l,6-dihydropyridine-3-carboxamide can be prepared according to the5 following method
  • Step A Preparation of 2-chloro-6-oxo- 1 ,6-dihydro-pyridine-3-carboxylic acid: 2- Chloro- ⁇ -oxo-lj ⁇ -dihydro-pyridine-S-carboxylic acid was prepared from dichloronicotinic acid (3.00 g, 15.6 mmol, Aldrich) according to the procedure described in U.S. Patent No. 3,682,932 to yield 1.31 g (48%) of the desired product. 0 Step B.
  • Step C Preparation of methyl 5-bromo-2-chloro-l-methyl-6-oxo-L6- dihydropyridine-3 -carboxylate : To a solution of methyl 2-chlorq- 1 -methyl-6-oxo- 1,6- dihydropyridine-3-carboxylate (0.100 g, 0.496 mmol) in DMF (5 mL) was added N- bromosuccinimide (0.177 g, 0.992 mmol) and the reaction mixture was stirred for 4 hours at room temperature under N 2 . The reaction mixture was quenched with saturated sodium bisulfite and then diluted with EtOAc and H 2 O and the layers separated. The aqueous layer was back extracted with EtOAc (2x). The combined organic layers were dried (Na 2 SO 4 ) and concentrated under reduced pressure to yield a yellow solid in quantitative yield.
  • Step D Preparation of methyl 2-chloro- 1 ,5-dimethyl-6-oxo- 1 ,6-dihydropyridine-3- carboxylate: To a suspension of methyl 5-bromo-2-chloro-l -methyl-6-oxo- 1,6- dihydropyridine-3 -carboxylate (0.400 g, 1.43 mmol) and 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.0587 g, 0.0713 mmol) in dioxane (8 mL) at 0 0 C under N 2 was added dimethylzinc (0.713 mL, 1.43 mmol, 2 M solution in toluene).
  • reaction mixture was immediately heated to 100 0 C for 30 minutes.
  • the reaction mixture was cooled to 0 0 C and quenched with MeOH (0.800 mL).
  • the reaction mixture was diluted with EtOAc and washed with 1 M HCl.
  • the aqueous layer was back extracted with EtOAc (Ix).
  • the combined organic layers were washed with saturated NaCl, dried (Na 2 SO 4 ) and concentrated under reduced pressure to a dark yellow gum. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave 0.164 g (53%) pure desired product as a yellow crystalline solid.
  • Step E Preparation of methyl - (2-fluoro-4-iodophenylamino)-L5-dimethyl-6-oxo- L6-dihvdropyridine-3-carboxylate: To a solution of 2-fluoro-4-iodobenzenamine (0.058 g, 0.31 mmol) in THF (2 mL) at -78 0 C under N 2 was added lithium bis(trimethylsilyl)amide (0.56 mL, 0.56 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for one hour at -78 0 C. Methyl 2-chloro-l,5-dimethyl-6-oxo-l,6-dihydropyridine-3-
  • reaction mixture was warmed to room temperature. After stirring for 10 minutes the reaction mixture was quenched by the addition of 1 M HCl and partitioned between EtOAc and saturated NaCl. The layers were separated and the organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure to yield a crude yellow solid that was used without purification in the next step.
  • Step G Preparation of 2-(2-fluoro-4-iodophenylamino)-N-(2-hvdroxyethoxyV 1,5- dimethyl-6-oxo- 1 ,6-dihvdropyridine-3-carboxamide: To a solution of crude 2-(2-fluoro-4- iodophenylamino)-l,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-l,6-dihydropyridine-3- carboxamide (0.585 g, 1.20 mmol) in ethanol (10 mL) was added aqueous 2 M HCl (3 mL). The reaction mixture was stirred for 45 minutes at room temperature.
  • the pH of the reaction0 mixture was adjusted to pH 7 with 1 M NaOH.
  • the reaction mixture was diluted with EtOAc and H 2 O.
  • the organic layer was separated and washed with saturated NaCl.
  • the combined aqueous layers were back extracted with EtOAc (Ix).
  • the combined organic layers were dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • Purification by silica gel flash column chromatography (methylene chloride/MeOH, 15:1) gave 2-(2-fluoro-4- iodophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihydropyridine-3- carboxamide (0.421 g; 76% over two steps) as a pale yellow solid.
  • Figure 4 Shows dose response curves for combination of AZD6244 and B-raf inhibitor Compound A in the A549 cell line (concentration vs. fraction unaffected (Fu)).
  • Figure 5 Shows dose response curves for combination of AZD6244 and B-raf inhibitor Compound A in the A549 cell line (concentration vs. % cell viability).
  • Figure 6. Shows dose response curves for combination of 4-(4-Bromo-2- fluorophenylamino)-N-(2-hydroxyethoxy)-l,5-dimethyl-6-oxo-l,6-dihydropyridazine-3- carboxamide_and B-raf inhibitor Compound A in the A549 cell line (concentration vs. % cell viability).
  • Figure 7 Shows dose response curves for 2-(2-fluoro-4-iodophenylamino)-N-(2- hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihydropyridine-3-carboxamide and B-raf inhibitor Compound A plotting concentration vs. % cell viability in the A549 cell line.
  • the circles represent AZD6244 monotherapy;
  • the triangles represent AZD6244 plus 2OnM B-raf inhibitor Compound A;
  • the inverted triangles represent AZD6244 plus 167nM B-raf inhibitor Compound A;
  • the diamonds represent AZD6244 plus 333nM B-raf inhibitor Compound A.
  • Figure 18 Shows dose response curves for AZD6244 and (R)-N-(I -(4-(6-(Pyridin-4- yl)quinazolin-2-ylamino)phenyl)ethyl)acetamide plotting concentration vs. % cell growth in the COLO-205 cell line.
  • the closed circles represent 20OnM AZD6244 monotherapy; the closed diamonds represent 2OnM AZD6244 monotherapy; the open triangles represent (R)-N- (l-(4-(6-(Pyridin-4-yl)quinazolin-2-ylamino)phenyl)ethyl)acetamide monotherapy; the closed squares represent 2OnM AZD6244 plus (R)-N-(I -(4-(6-(Pyridin-4-yl)quinazolin-2- ylamino)phenyl)ethyl)acetamide; the closed triangles represent 20OnM AZD6244 plus (R)-N-
  • Figure 19 Shows dose response curves for AZD6244 and 3-Methoxy-N-((lR)-l- ⁇ 4- [(6-pyridin-4-ylquinazolin-2-yl)amino]phenyl ⁇ ethyl)propanamide plotting concentration vs. % cell growth in the COLO-205 cell line.
  • the closed circles represent 20OnM AZD6244 monotherapy; the closed diamonds represent 2OnM AZD6244 monotherapy; the openo triangles represent 3-Methoxy-N-((lR)-l- ⁇ 4-[(6-pyridin-4-ylquinazolin-2- yl)amino]phenyl ⁇ ethyl)propanamide monotherapy; the closed squares represent 2OnM AZD6244 plus 3-Methoxy-N-((lR)-l- ⁇ 4-[(6-pyridm-4-ylquinazolin-2- yl)amino]phenyl ⁇ ethyl)propanamide; the closed triangles represent 20OnM AZD6244 plus 3- Methoxy-N-((1 R)- 1 - ⁇ 4-[(6-pyridin-4-ylquinazolin-2-yl)amino]phenyl ⁇ ethyl)propanamide.5
  • Example 1 In vitro combination study of AZD6244 with 3-(l-Cyano-l-methylethyl)-N- ⁇ 4- methyl-3-F(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)aminolphenyUbenzamide, a B-raf inhibitor
  • B-raf inhibitor Compound A 3-(l-Cyano-l-methylethyl)-N- ⁇ 4-methyl-3-[(3-methyl-4- oxo-3,4-dihydroquinazolin-6-yl)amino]pheny! ⁇ benzamide
  • COLO-205, SW620, and A375 cell lines with the MEK inhibitor and B-raf inhibitor were beneficial. At the ratios tested, combined treatment resulted in synergy at all concentrations >IC15.
  • a CI could not be determined because the compounds do not have single agent activity at the concentrations tested.
  • the dose-response curves for the single agents were compared to that for the combination.
  • Fu fraction unaffected
  • the combined drug treatment had an IC50 (Inhibitory Concentration producing 50% inhibition) of ⁇ 0.6uM (0.3 uM AZD6244 + 0.3 uM B-raf Inhibitor Compound A) whereas the cells were unaffected by either single agent at this concentration, indicating that the compounds acted synergistically.
  • Example data for the A549 cell line is shown in Figure 4.
  • the combination of a MEK inhibitor and a B-raf inhibitor was found to be synergistic in all cell lines tested, regardless of B-raf and K-ras mutational status.
  • the combination of a MEK inhibitor and a B-raf inhibitor showed synergy even in a cell line A549, which is relatively insensitive to both inhibitors when used as single agents.
  • Example 2 In vitro combination study of AZD6244 or 2-(2-fluoro-4-iodophenylamino)-N- f2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihvdropyridine-3-carboxamide or 4-(4-Bromo-2- fluorophenylamino)-N-(2-hvdroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihydropyridazine-3- carboxamide with B-raf inhibitor Compound A
  • Cell viability was measured on day 5 using an MTS assay. A dose response curve was generated for each drug alone and in combination. For cell lines COLO-205, SW620, and 5 A375, a combination index, which compares the response of single agents to the combination, was calculated from the dose response curves, and a CI curve generated which indicates whether the drug combinations were antagonistic.
  • Figures 8-16 show the representative CI curves for treatment of the COLO-205, SW620, and A375 cell lines with a MEK inhibitor and B-raf inhibitor Compound A. In allo cases, treatment of cells with the MEK inhibitor and B-raf inhibitor did achieve synergy.
  • a CI could not be determined because the compounds do not have single agent activity at the concentrations tested.
  • the dose-response curves for the single agents were compared to that for the combination.
  • Fu fraction unaffected is lower for the combination than for5 either single agent.
  • Fu fraction unaffected
  • the combination of a MEK inhibitor and a B-raf inhibitor was found to be synergistic in all cell lines tested, regardless of B-raf and K-ras mutational status.
  • This combination of a MEK inhibitor and a B-raf inhibitor showed synergyo even in a cell line A549, which is relatively insensitive to both inhibitors when used as single agents.
  • Example data for the A549 cell line is shown in Figures 5, 6 and 7.
  • CIR Confidence Interval Ratio
  • n number of replicate experiments.
  • Example 3 In vitro combination study of AZD6244 with a mutant B-raf inhibitor in a homozygous mutant B-raf (V600E * ) cell line
  • Figure 17 shows the Combination Index curves for treatment of A375 cells with the MEK inhibitor and the B-raf inhibitor. Treatment with the combination achieves synergy.
  • Example 4 In vitro combination study of AZD6244 with mutant B-raf inhibitors in a cell line heterozygous for mutant B-raf (V600E)
  • the COLO-205 cell line is sensitive to the MEK inhibitor AZD6244, and to the mutant B-raf inhibitors (R)-N-(I -(4-(6-(Pyridin-4-yl)quinazolin-2- ylamino)phenyl)ethyl)acetamide and 3 -Methoxy-N-(( 1 R)- 1 - ⁇ 4-[(6-pyridin-4-ylquinazolin-2- yl)amino]phenyl ⁇ ethyl)propanamide.
  • Cells were seeded in 96-well plates on day 0 and treated with either a single drug or simultaneously with both drugs for 72 hours beginning on day 1.
  • AZD6244 was used at two different concentrations, 2OnM and 20OnM.
  • the dose of 20OnM AZD6244 was selected as previous experiments had shown this dose can completely inhibit phosphorylation of ERK, a MEK substrate, in a number of cell lines by western blot analysis. Cell viability was measured on day 4 using an MTS assay. A dose response curve was generated for each drug alone and in combination. Dose response curves for the single agents were compared to that for the combination.
  • FIGS 18 and 19 show the results of this experiment using COLO-205 cells. Treatment of cells with the combined drugs was more beneficial than monotherapy.

Abstract

Cette invention porte sur un produit de combinaison comprenant un inhibiteur de MEK et un inhibiteur de B-raf, et sur des procédés pour la production d'un effet anticancer dans un patient, qui est en conséquence utile dans le traitement du cancer chez un patient. Plus spécifiquement, la présente invention porte sur : un produit de combinaison comprenant un inhibiteur de MEK et un inhibiteur de B-raf; un produit de combinaison comprenant un coffret de partie comprenant un inhibiteur de MEK et un inhibiteur de B-raf; l'utilisation du produit de combinaison dans le traitement du cancer; un procédé de traitement du cancer comprenant l'administration du produit de combinaison à un patient. Le produit de combinaison et les procédés de l'invention sont également utiles dans le traitement d'autres maladies associées à l'activité de MEK et/ou de B-raf.
PCT/GB2008/001184 2007-04-02 2008-04-02 Combinaison d'un inhibiteur de mek et d'un inhibiteur de b-raf pour le traitement du cancer WO2008120004A1 (fr)

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