WO2015181154A1 - Pharmaceutical combination comprising a class iii receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule edo-s101 together with its use in the treatment of cancer - Google Patents
Pharmaceutical combination comprising a class iii receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule edo-s101 together with its use in the treatment of cancer Download PDFInfo
- Publication number
- WO2015181154A1 WO2015181154A1 PCT/EP2015/061569 EP2015061569W WO2015181154A1 WO 2015181154 A1 WO2015181154 A1 WO 2015181154A1 EP 2015061569 W EP2015061569 W EP 2015061569W WO 2015181154 A1 WO2015181154 A1 WO 2015181154A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- combination
- tyrosine kinase
- compound
- cancer
- formula
- Prior art date
Links
- 0 C*(C(CCCCCCC(*O)=O)=*1)c2c1cc(*(CCCl)CCCl)cc2 Chemical compound C*(C(CCCCCCC(*O)=O)=*1)c2c1cc(*(CCCl)CCCl)cc2 0.000 description 1
Classifications
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- 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
- A61K31/41—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
- A61K31/433—Thidiazoles
-
- 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
- A61K31/4709—Non-condensed quinolines 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
- A61K31/495—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
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the present invention relates to combinations that are of use in the treatment of cancer such as hematologic cancer and breast cancer.
- Cancer is one of the most life threatening diseases. Cancer is a condition in which cells in a part of the body experience out-of-control growth. According to latest data from American Cancer Society, it is estimated there will be 1 .67 million new cases of cancer in USA in 2014. Cancer is the second leading cause of death in the United States (second only to heart disease) and will claim more than 585,000 lives in 2014. In fact, it is estimated that 50% of all men and 33% of all women living in the United States will develop some type of cancer in their lifetime. Therefore cancer constitutes a major public health burden and represents a significant cost in the United States. These figures are reflected elsewhere across most countries globally, although the types of cancer and relative proportions of the population developing the cancers vary depending upon many different factors such including genetics and diet.
- Chemotherapy involves the disruption of cell replication or cell metabolism. It is used most often in the treatment of breast, lung, and testicular cancer.
- One of the main causes of failure in this treatment of cancer is the development of drug resistance by the cancer cells, a serious problem that may lead to recurrence of disease or even death. Thus, more effective cancer treatments are needed.
- Multiple myeloma is a significant and growing problem. It is a cancer arising from plasma cells. Normal plasma cells produce immunoglobulins to fight infection. In myeloma, the plasma cells become abnormal, multiply uncontrollably and release only one type of anttibody - known as paraprotein - which has no useful function.
- multiple myeloma (or myeloma as it is also referred to) are active myeloma, plasmacytoma, light chain myeloma and non-secretory myeloma.
- the number of new cases of myeloma in the US in 2011 was 6.1 per 100,000 men and women per year and the percentage survival rate beyond five years was 45%. It is estimated that the number of new cases in the US in 2014 will be over 24,000 (1.4% of all cancer cases), while the number of deaths in 2014 will be just over 1 1 ,000 (1.9% of all cancer cases).
- the compound of formula I was shown to have excellent in vitro activity against multiple myeloma cell lines, with activities in the range of ⁇ 35-100 greater than the activity shown by bendamustin.
- Leukemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Instead of producing normal, functioning white blood cells to fight infection the body produces large numbers of these non-functional blasts.
- Leukemia is a broad term covering a spectrum of diseases. In turn, it is part of the even broader group of diseases affecting the blood, bone marrow and lymphoid system, which are all known as hematological neoplasms.
- ALL acute lymphoblastic leukemia
- CLL chronic lymphocytic leukemia
- AML acute myeloid leukemia
- CML chronic myeloid leukemia
- HCL hairy cell leukemia
- T-PLL T-cell prolymphocytic leukemia
- T-cell acute lymphoblastic leukemia It is estimated that the number of new cases in the United States in 2014 will be over 52,000 (3.1 % of all new cancers in the US) with over 24,000 deaths (4.1 % of all cancer deaths in the US). The percentage survival rate over five years is currently 57.2%, a figure significantly lower than for many other cancers, with the survival rate over five years for acute myeloid leukemia being particularly low at only 20%.
- Lymphoma is a cancer of the lymphatic system.
- lymphoma There are two main types of lymphoma, namely Hodgkin lymphoma and non Hodgkin lymphoma.
- Non Hodgkin lymphoma is the more common form of lymphoma.
- the lymphatic system runs throughout the body, and it is therefore possible to find non Hodgkin lymphoma in almost all parts of the body.
- lymphocytes white blood cells
- All the abnormal lymphocytes start to collect in the lymph nodes or other places such as the bone marrow or spleen. They can then grow into tumours and begin to cause problems within the lymphatic system or the organ in which they are growing. For example, if a lymphoma starts in the thyroid gland it can affect the normal production of thyroid hormones.
- non Hodgkin lymphoma There are many different types of non Hodgkin lymphoma. They can be classified in several different ways. One way is by the type of cell affected. In non Hodgkin lymphoma two types of lymphocyte can be affected - B cells and T cells. This is classified as B cell lymphoma or a T cell lymphoma. Most people with non Hodgkin lymphoma have B cell lymphomas. T cell lymphomas are more common in teenagers and young adults.
- Hodgkin lymphoma The cells of Hodgkin lymphoma have a particular appearance under the microscope. These cells are called Reed Sternberg cells. Non Hodgkin lymphomas do not have Reed Sternberg cells. It is important for doctors to be able to tell the difference between Hodgkin lymphoma and non Hodgkin lymphoma cells as they are two different diseases. In Hodgkin lymphoma, it is cells in the lymph nodes that have become cancerous.
- the % survival rate over 5 years in 2009 for patients with non Hodgkin lymphoma was 63%, while the survival rate for those with Hodgkin lymphoma over the same period was 83%.
- Breast cancer is a cancer that forms in tissues of the breast.
- the most common type of breast cancer is ductal carcinoma, which begins in the lining of the milk ducts (thin tubes that carry milk from the lobules of the breast to the nipple).
- Another type of breast cancer is lobular carcinoma, which begins in the lobules (milk glands) of the breast.
- Breast cancers can be classified into sub-groups as claudin-low tumors, basal-like tumors, human epidermal growth factor receptor 2 (HER2) positive tumors, luminal A tumors and luminal B tumors.
- Invasive breast cancer is breast cancer that has spread from where it began in the breast ducts or lobules to surrounding normal tissue.
- breast cancer occurs in both men and women, although male breast cancer is rare. In 2014, it is estimated that there will be nearly 233,00 new cases in women and 2,400 in men, with 40,00 female deaths and just over 400 male deaths. Approximately 15 out of every 100 women with breast cancer have triple-negative breast cancer, i.e. are estrogen negative, are progesterone negative and are HER2 negative.
- Recurrent triple-negative breast cancer is a condition of high unmet medical need, due to its aggressive biology, fast development of drug resistance and lack of molecular targets.
- chemotherapy remains the standard of care for advanced triple-negative breast cancer with a poor median overall survival.
- WO-A-2010/085377 the compound of formula I below is disclosed. It is a first-in-class dual-functional alkylating-HDACi fusion molecule which potently inhibits the HDAC pathway. ⁇
- HDAC1 IC 5 o of 9 nM HDAC1 IC 5 o of 9 nM
- a combination comprising a class III receptor tyrosine kinase inhibitor and a compound of formula I or a pharmaceutically acceptable salt thereof:
- a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and a combination according to the first aspect of the invention.
- kits comprising a combination according to the first aspect of the present invention and, optionally, instructions for treating a patient.
- a combination, composition or kit according to the first, second or third aspect of the present invention for use in the treatment of cancer, such as hematologic cancers and breast cancer.
- a method of treating cancer in a patient in need thereof comprising administering to said patient a combination, composition or kit according to the first, second or third aspect of the present invention.
- Figure 1 is a plot of the % surviving in vitro MV-4-1 1 acute myeloid leukemia cells as a % of control versus log IC50 for each of the tested compounds in single compound tests (EDO-S101 versus cisplatin and quizartinib versus cisplatin);
- Figure 2 is a plot of the % surviving in vitro MV-4-1 1 acute myeloid leukemia cells as a % of control versus log IC50 for each of the tested compounds in single compound tests and also for the combination (EDO-S101 , quizartinib and the combination thereof);
- Figure 3 is a plot of the % surviving in vitro Molm-13 acute myeloid leukemia cells as a % of control versus log IC50 for each of the tested compounds in single compound tests (EDO-S101 versus cisplatin and quizartinib and EDO-S101 versus quizartinib); and
- Figure 4 is a plot of the % surviving in vitro Molm-13 acute myeloid leukemia cells as a % of control versus log IC50 for each of the tested compounds in single compound tests and also for the combination (EDO-S101 , quizartinib and the combination thereof).
- Animal includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
- non-human mammals e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like
- non-mammals e.g., birds, and the like.
- “Pharmaceutically acceptable salts” means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired
- Such salts include acid addition salts formed with inorganic acids, or with organic acids.
- Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
- such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.
- non-aqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
- acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, salicylate, tosylate, lactate, naphthalenesulphonae, malate, mandelate,
- mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, sulfamate, nitrate, phosphate
- organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, salicylate, tosylate, lactate, naphthalene
- alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N- dialkylenethanolamine, triethanolamine and basic aminoacids salts.
- the pharmaceutically acceptable salt of the compound of formula I may preferably be the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate or acetate, and more prefereably the acetate.
- the class III receptor tyrosine kinase inhibitor is preferably an inhibitor of a class III tyrosinse receptor kinase selected from FMS-related tyrosine kinase 3 (FLT3/STK1 ), colony-stimulating factor 1 receptor (CSF-1 R), stem cell factor receptor (SCFR) and platelet derived growth factor receptors (PDGFRs).
- FMS-related tyrosine kinase 3 FMS-related tyrosine kinase 3
- CSF-1 R colony-stimulating factor 1 receptor
- SCFR stem cell factor receptor
- PDGFRs platelet derived growth factor receptors
- the class III receptor tyrosine kinase inhibitor is an FMS-related tyrosine kinase 3 (FLT3) inhibitor selected from the group consisting of quizartinib, sunitinib, linifanib, foretinib, staurosporine and tandutinib, and more preferably it is quizartinib.
- FLT3 FMS-related tyrosine kinase 3
- said combination may further comprise one or more additional pharmaceutically active agents.
- Particularly suitable pharmaceutically active agents are anti-tumor agents having a different mode of action to the compound of formula I or a pharmaceutically acceptable salt thereof and the class III receptor tyrosine kinase inhibitor, e.g.
- alkylating agents such as nitrosureas, ethylenimines, alkylsulfonates, hydrazines and triazines, and platinum based agents; plant alkaloids, taxanes, vinca alkaloids; anti-tumor antibiotics such as chromomycins, anthracyclines, and miscellaneous antibiotics such as Mitomycin and Bleomycin; anti-metabolites such as folic acid antagonists, pyrimidine antagonists, purine antagonists and adenosine deaminase inhibitors; glucocorticoids such as dexamethasone; proteasome inhibitors such as bortezomib and carfilzomib, topoisomerase inhibitors such as topoisomerase I inhibitors, topoisomerase II inhibitors, miscellaneous anti-neoplastics such as ribonucleotide reductase inhibitors, adrenocortical steroid inhibitor, anti-microtub
- the compound of formula I or a pharmaceutically acceptable salt thereof and the class III receptor tyrosine kinase inhibitor of the combination are adapted for administration concurrently, sequentially or separately.
- the compound of formula I or a pharmaceutically acceptable salt thereof and the class III receptor tyrosine kinase inhibitor of the combination are adapted for administration concurrently.
- the class III receptor tyrosine kinase inhibitor is quizartinib and the compound of formula I or a pharmaceutically acceptable salt thereof is
- the molar ratio of the class III receptor tyrosine kinase inhibitor to the compound of formula I or a pharmaceutically acceptable salt thereof in the combination of the present invention is typically from 1 :2000 to 2000: 1.
- the molar ratio of class III receptor tyrosine kinase inhibitor to compound of formula I or a pharmaceutically acceptable salt thereof in said combination is from 1 :2000 to 1 :100, more preferably the molar ratio of class III receptor tyrosine kinase inhibitor to compound of formula I or a pharmaceutically acceptable salt thereof in said combination is from 1 : 1000 to 1 :500, and most preferably it is from 1 :900 to 1 :500, e.g.
- One particularly preferred combination of the present invention comprises the compound of formula I or the acetate salt thereof and quizartinib, wherein the molar ratio of the quizartinib to the compound of formula I or the acetate salt thereof in said combination is from 1 :900 to 1 :500, e.g. 1 :900, 1 :800, 1 :700, 1 :600 or 1 :500.
- CI has been found to be less than 1 , indicating synergy.
- composition according to the second aspect of the present invention comprises a pharmaceutically acceptable diluent or carrier and a combination according to the first aspect of the present invention.
- Preferred compositions of the second invention include those comprising the preferred combinations of the present invention as described and exemplified above.
- the pharmaceutically acceptable diluent or carrier of the pharmaceutical composition according to the second aspect of the present can be any suitable dispersant, excipient, adjuvant, or other material which acts as a carrier for the active agents of the combination of the present invention and which does not interfere with the active agents present in said combination.
- suitable dispersant, excipient, adjuvant, or other material which acts as a carrier for the active agents of the combination of the present invention and which does not interfere with the active agents present in said combination.
- typical pharmaceutically acceptable carriers and diluents may be found in "Remington's
- Cremophor a cyclopolysaccharide (e.g hydroxypropyl-3-cyclodextrin or sulfobutyl ether ⁇ - cyclodextrins), a polymer, a liposome, a micelle, a nanosphere, etc.
- a cyclopolysaccharide e.g hydroxypropyl-3-cyclodextrin or sulfobutyl ether ⁇ - cyclodextrins
- a polymer e.g hydroxypropyl-3-cyclodextrin or sulfobutyl ether ⁇ - cyclodextrins
- a polymer e.g hydroxypropyl-3-cyclodextrin or sulfobutyl ether ⁇ - cyclodextrins
- a polymer e.g hydroxypropyl-3-cyclodextrin or sulfobutyl ether
- kits comprising a combination according to the first aspect of the present invention and, optionally, instructions for treating a patient.
- a kit can comprise a compound of formula I or pharmaceutically acceptable salt thereof and a class III receptor tyrosine kinase inhibitor together with instructions for treating a patient.
- Each active agent can be provided in a suitable container.
- the kit may further comprise a delivery system, e.g. for the compound of formula I or pharmaceutically acceptable salt thereof and a class III receptor tyrosine kinase inhibitor or a combination thereof.
- the instructions may advise administering the class III receptor tyrosine kinase inhibitor and the compound of formula I or a pharmaceutically acceptable salt thereof concurrently, sequentially or separately according to variables such as the specific condition being treated, the state of that condition, the activity of the specific compounds employed; the specific combination employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compounds employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compounds employed; and like factors well known in the medical arts.
- kits according to the third aspect of the present invention include those comprising the preferred combinations of the present invention as described and exemplified above.
- the combination, composition or kit according to the first, second or third aspect of the present invention for use in the treatment of cancer.
- a method of treating cancer in a patient in need thereof comprising administering to said patient the combination, composition or kit according to the first, second or third aspect of the present invention.
- cancers which are treatable by the combinations, compositions and kits of the present invention include hematologic cancers such as multiple myeloma, lymphoma and leukemia, breast cancer, lung cancer, colorectal cancer, prostate cancer, testicular cancer, pancreatic cancer, liver cancer, stomach cancer, biliary tract cancer, esophageal cancer, gastrointestinal stromal tumor, cervical cancer, ovarian cancer, uterine cancer, renal cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, bladder cancer, sarcoma, mesothelioma, thymoma, myelodysplasia syndrome, glioblastoma and myeloproliferative disease.
- the combinations, compositions and kits of the present invention are effective against hematologic cancer such as multiple myeloma, lymphoma and leukemia, and breast cancer.
- the cancer is selected from a hematologic cancer and breast cancer.
- composition or kit of the present invention is for use in the treatment of a hematologic cancer
- this may preferably be selected from multiple myeloma (e.g. active myeloma, plasmacytoma, light chain myeloma or non-secretory myeloma), lymphoma (e.g. Hodgkin lymphoma or non-Hodgkin lymphoma) and leukemia [acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML, including ALL, ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML, including
- myeloblasts leukemia acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia and acute megakaryotic leukemia, with all forms being treatable in all phases including relapsed and refractory phases), chronic myeloid leukemia (CML), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia or T-cell acute lymphoblastic leukemia].
- CML chronic myeloid leukemia
- HCL hairy cell leukemia
- T-PLL T-cell prolymphocytic leukemia
- AML acute myeloid leukemia
- AML acute myeloid leukemia
- the breast cancer may typically be selected from claudin-low tumors, basal-like tumors, human epidermal growth factor receptor 2 (HER2) positive tumors, luminal A tumors and luminal B tumors, and it is preferably a triple-negative breast cancer.
- HER2 human epidermal growth factor receptor 2
- the class III receptor tyrosine kinase inhibitor and the compound of formula I or a pharmaceutically acceptable salt thereof are administered concurrently, sequentially or separately. More preferably, the class III receptor tyrosine kinase inhibitor and the compound of formula I or a pharmaceutically acceptable salt thereof are administered concurrently.
- the compound of formula I or a pharmaceutically acceptable salt thereof is typically administered to the patient in need thereof at a dosage range of 10 to 100 mg/kg body weight patient, and preferably at a dosage range of 40 to 80 mg/kg body weight.
- the class III receptor tyrosine kinase inhibitor is administered at a dosage range of from 0.01 to 1 mg/kg body weight patient, and preferably, it is administered at a dosage range of from 0.1 to 0.25 mg/kg body weight patient.
- the therapeutically effective amount of a combination, composition or kit according to the present invention is an amount of the combination, composition or kit which confers a therapeutic effect in accordance with the fourth and fifth aspects of the present invention on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
- the therapeutic effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. subject gives an indication of or feels an effect).
- An effective amount of the combination, composition or kit according to the present invention is believed to be one wherein the compound of formula I or a salt thereof is included in the combination at a dosage range of from 10 to 100 mg/kg body weight patient (e.g.
- 40 to 80 mg/kg body weight such as 40, 50, 60, 70 or 80 mg/kg body weight
- the class III receptor tyrosine kinase inhibitor is administered at a dosage range of from 0.1 to 0.25 mg/kg body weight patient (e.g. 0.1 , 0.15, 0.2 or 0.25 mg/kg body weight patient).
- Effective doses will vary depending on route of administration, as well as the possibility of co- usage with other active agents. It will be understood, however, that the total daily usage of the combinations, compositions and kits of the present invention will be decided by the attending physician within the scope of sound medical judgment.
- the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
- the present invention is also directed to the use of a combination, composition or kit according to the first, second or third aspect of the present invention in the manufacture of a medicament for the treatment of cancer, e.g. for the treatment of a hematologic cancer or breast cancer.
- Suitable examples of the administration form of the combination, composition or kit of the present invention include without limitation oral, topical, parenteral, sublingual, rectal, vaginal, ocular, and intranasal.
- Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
- the combinations, compositions and kits are administered parenterally.
- Combinations, compositions and kits of the invention can be formulated so as to allow a combination or composition of the present invention to be bioavailable upon administration of the combination, composition or kit to an animal, preferably human.
- Compositions can take the form of one or more dosage units, where for example, a tablet can be a single dosage unit, and a container of a combination or composition of the present invention in aerosol form can hold a plurality of dosage units.
- kits Preferably the combinations of the present invention are provided in the form of kits.
- a kit includes a compound of formula I or a pharmaceutically acceptable salt thereof and a class III receptor tyrosine kinase inhibitor.
- a kit can include one or more delivery systems, e.g. the class III receptor tyrosine kinase inhibitor, the compound of formula I or a pharmaceutically acceptable salt thereof, or a combination thereof, and directions for the use of the kit (e.g. instructions for treating a subject).
- These directions/instructions may advise administering the class III receptor tyrosine kinase inhibitor and the compound of formula I or a pharmaceutically acceptable salt thereof of the combination concurrently, sequentially or separately according to variables such as the specific condition being treated, the state of that condition, the activity of the specific compounds employed; the specific combination employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compounds employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compounds employed; and like factors well known in the medical arts.
- the pharmaceutically acceptable diluent or carrier can be particulate, so that the compositions are, for example, in tablet or powder form.
- the carrier(s) can be liquid, with the combinations, compositions or kits being, for example, an oral syrup or injectable liquid.
- the carrier(s) can be gaseous, so as to provide an aerosol composition useful in, for example, inhalatory administration.
- Such pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
- the carriers can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
- auxiliary, stabilizing, thickening, lubricating and coloring agents can be used.
- the combination, composition or kit of the present invention and the pharmaceutically acceptable carriers are sterile.
- Water is a preferred carrier when the combination, composition or kit of the present invention is administered intravenously.
- Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
- Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
- the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
- the combination, composition or kit When intended for oral administration, the combination, composition or kit may be in solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
- the combination, composition or kit can be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
- a solid composition typically contains one or more inert diluents, either as a single tablet comprising all active agents or as a number of separate solid compositions, each comprising a single active agent of the combination of the present invention (in the case of the kit).
- binders such as
- composition or kit is in the form of a capsule (e. g. a gelatin capsule), it can contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol, cyclodextrin or a fatty oil.
- a liquid carrier such as polyethylene glycol, cyclodextrin or a fatty oil.
- the combination, composition or kit can be in the form of a liquid, e. g. an elixir, syrup, solution, emulsion or suspension.
- the liquid can be useful for oral administration or for delivery by injection.
- a combination, composition or kit can comprise one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
- a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent can also be included.
- the preferred route of administration is parenteral administration including, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, intranasal, intracerebral, intraventricular, intrathecal, intravaginal or transdermal.
- the preferred mode of administration is left to the discretion of the practitioner, and will depend in part upon the site of the medical condition (such as the site of cancer).
- the present combinations, compositions and kits of the present invention are administered intravenously.
- liquid combinations and compositions of the invention can also include one or more of the following: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides, polyethylene glycols, glycerin, or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
- sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides, polyethylene glycols, glycerin, or other solvents
- antibacterial agents such as benzyl alcohol or methyl paraben
- agents for the adjustment of tonicity such as sodium chloride or dextrose.
- a parenteral combination or composition can be enclosed in
- the combination or composition may typically comprise the compound of formula I or a salt thereof at a dosage range of from 10 to 100 mg/kg body weight patient and preferably from 40 to 80 mg/kg body weight patient.
- the combination or composition may comprise the class III receptor tyrosine kinase inhibitor at a dosage range of from 0.1 to 1 mg/kg body weight patient, and preferably of from 0.1 to 0.25 mg/kg body weight patient.
- the combinations of the inventions may be formulated such that the class III receptor tyrosine kinase inhibitor and the compound of formula I or a pharmaceutically acceptable salt thereof of the combination are adapted for administration concurrently, sequentially or separately.
- they are administered concurrently.
- the combination, composition or kit of the present invention can be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings.
- administration can be by direct injection at the site (or former site) of a cancer, tumor or neoplastic or pre-neoplastic tissue.
- Pulmonary administration can also be employed, e. g. by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
- the combination, composition or kit of the present invention or compositions can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
- the present combination, composition or kit can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained- release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
- suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin.
- compositions or kits can be prepared using methodology well known in the pharmaceutical art.
- a composition intended to be administered by injection can be prepared by combining a combination or composition of the present invention with water so as to form a solution.
- a surfactant can be added to facilitate the formation of a homogeneous solution or suspension.
- the combinations, compositions and kits of the present invention are particularly effective in the treatment of cancer. It has been shown that the combinations, compositions and kits of the present invention are highly active both in vitro and in vivo against a wide variety of tumour cell types making them particularly interesting for development for use in the treatment of cancer, e.g. hematologic cancer and breast cancer.
- the acute myeloid leukemia cell line MV-4-1 1 (obtained from the ATCC) was cultured in media supplemented with 10% fetal bovine serum (FBS) at a temperature of 37°C, 5% C0 2 and 95% humidity. Culture media was purchased from GIBCO, USA. The cells were plated out in 96- Well Flat Clear Bottom Black Polystyrene TC-Treated Microplates (Cat# 3603, Corning ® ).
- the compounds tested were EDO-S101 and quizartinib, as well as the reference control cisplatin.
- Equipment used was the EnVision Multi Label Reader, PerkinElmer (USA). C0 2 Water Jacketed Incubator, Therma (USA). Reverse microscope, Chongguang XDS-1 B, Chongqing Guangdian Corp. (Chongqing, P.R.China).
- the cells were harvested respectively during the logarithmic growth period and counted with a hemocytometer.
- the cell viability is over 98 % by trypan blue exclusion.
- the cell concentrations were adjusted to 4.44x 10 4 cells/ml with the medium supplemented with 10% FBS.
- 90 ⁇ cell suspensions were added to 96-well plates, such that the final cell density was 4x 10 3 cells/well. The appropriate cell density was determined and adjusted according to the results of our first test.
- the cell concentrations were adjusted to 5.00x10 4 /ml with the medium supplemented with 10% FBS.
- 80 ⁇ cell suspensions were added to 96-well plates, such that the final cell densities were 4x10 3 cells/well. The appropriate cell density was determined and adjusted according to the results of our first test.
- IC 5 o The data were displayed graphically using GraphPad Prism 5.0.
- a dose-responsive curve was fitted using nonlinear regression model with a sigmoidal dose response.
- the formula of surviving rate is shown below, and the IC 50 was automatically produced by GraphPad Prism 5.0.
- the Surviving rate (%) (Lum T est article-Lum M edium control)/ (Lum No netreated-Lum M edium control) x 100%.
- the CI was calculated from the mean affected fraction at each drug ratio concentration of each drug.
- the combination of EDO-S101 and quizartinib shows synergy in its activity against the acute myeloid leukemia MV-4-1 1 cell line.
- the acute myeloid leukemia cell line MOLM-13 (obtained from the ATCC) was cultured in media supplemented with 10% FBS at a temperature of 37°C, 5% C0 2 and 95% humidity. Culture media was purchased from GIBCO, USA. The cells were plated out in 96-Well Flat Clear Bottom Black Polystyrene TC-Treated Microplates (Cat# 3603, Corning ® ).
- the compounds tested were EDO-S101 and quizartinib, as well as the reference control cisplatin.
- Equipment used was the EnVision Multi Label Reader, PerkinElmer (USA). C0 2 Water Jacketed Incubator, Therma (USA). Reverse microscope, Chongguang XDS-1 B, Chongqing Guangdian Corp. (Chongqing, P.R.China).
- the cells were harvested respectively during the logarithmic growth period and counted with a hemocytometer.
- the cell viability is over 98 % by trypan blue exclusion.
- the cell concentrations were adjusted to 4.44x 10 4 cells/ml with the medium supplemented with 10% FBS.
- 90 ⁇ cell suspensions were added to 96-well plates, such that the final cell density was 4x10 3 cells/well. The appropriate cell density was determined and adjusted according to the results of our first test.
- the cell concentrations were adjusted to 5.00x10 4 /ml with the medium supplemented with 10% FBS.
- 80 ⁇ cell suspensions were added to 96-well plates, such that the final cell densities were 4x10 3 cells/well. The appropriate cell density was determined and adjusted according to the results of our first test.
- IC 50 The data was displayed graphically using GraphPad Prism 5.0.
- a dose-responsive curve was fitted using nonlinear regression model with a sigmoidal dose response.
- the formula of surviving rate is shown below, and the IC 50 was automatically produced by GraphPad Prism 5.0.
- the Surviving rate (%) (LumTest article-LumMedium control)/ (LumNone treated-LumMedium control )x100%.
- the CI was calculated from the mean affected fraction at each drug ratio concentration of each drug.
- Figure 4 showing a plot of % surviving cells versus log IC 50 for the tested compounds shows excellent combined activity for the EDO-S101 and quizartinib combination. This is confirmed in the CI values in Table 2 below:
- the compound of formula I (EDO-S101 ) show excellent activity in combination with class III receptor tyrosine kinase inhibitors such as quizartinib in acting both in vitro and in vivo against acute myeloid leukemia. Furthermore, it can be seen that the activity of these combinations is surprisingly synergistic. It is to be expected that these combinations will be active against a wide range of hematologic cancers, not just leukemia but other hematologic conditions such as lymphoma and multiple myeloma. We also believe that these combinations are likely to be active against other cancers such as breast cancer.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2016569664A JP2017519736A (en) | 2014-05-28 | 2015-05-26 | Pharmaceutical combination comprising a class III receptor tyrosine kinase inhibitor and an alkylated histone deacetylase inhibitor fusion molecule EDO-S101 and its use in the treatment of cancer |
US15/314,167 US9993482B2 (en) | 2014-05-28 | 2015-05-26 | Pharmaceutical combination comprising a class III receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule EDO-S101 together with its use in the treatment of cancer |
CN201580028027.4A CN106470701A (en) | 2014-05-28 | 2015-05-26 | Comprise III receptoroid tyrosine kinase inhibitor and the drug regimen of alkylation histone deacetylase inhibitor fusion molecule EDO S101 and its purposes in treating cancer |
AU2015266050A AU2015266050A1 (en) | 2014-05-28 | 2015-05-26 | Pharmaceutical combination comprising a class III receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule EDO-S101 together with its use in the treatment of cancer |
EA201692470A EA201692470A1 (en) | 2014-05-28 | 2015-05-26 | PHARMACEUTICAL COMBINATIONS |
KR1020167035842A KR20170005125A (en) | 2014-05-28 | 2015-05-26 | Pharmaceutical combination comprising a class iii receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule edo-s101 together with its use in the treatment of cancer |
SG11201609363RA SG11201609363RA (en) | 2014-05-28 | 2015-05-26 | Pharmaceutical combination comprising a class iii receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule edo-s101 together with its use in the treatment of cancer |
EP15723979.9A EP3148533A1 (en) | 2014-05-28 | 2015-05-26 | Pharmaceutical combination comprising a class iii receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule edo-s101 together with its use in the treatment of cancer |
CA2950625A CA2950625A1 (en) | 2014-05-28 | 2015-05-26 | Pharmaceutical combination comprising a class iii receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule edo-s101 together with its use in the treatment of cancer |
MX2016015435A MX2016015435A (en) | 2014-05-28 | 2015-05-26 | Pharmaceutical combination comprising a class iii receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule edo-s101 together with its use in the treatment of cancer. |
ZA2016/07425A ZA201607425B (en) | 2014-05-28 | 2016-10-27 | Pharmaceutical combination comprising a class iii receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule edo-s101 together with its use in the treatment of cancer |
PH12016502353A PH12016502353A1 (en) | 2014-05-28 | 2016-11-25 | Pharmaceutical composition |
IL249228A IL249228A0 (en) | 2014-05-28 | 2016-11-27 | Pharmaceutical combination comprising a class iii receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule edo-s101 together with its use in the treatment of cancer |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB1409488.2A GB201409488D0 (en) | 2014-05-28 | 2014-05-28 | Pharmaceutical composition |
GB1409488.2 | 2014-05-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015181154A1 true WO2015181154A1 (en) | 2015-12-03 |
Family
ID=51177590
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2015/061569 WO2015181154A1 (en) | 2014-05-28 | 2015-05-26 | Pharmaceutical combination comprising a class iii receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule edo-s101 together with its use in the treatment of cancer |
Country Status (16)
Country | Link |
---|---|
US (1) | US9993482B2 (en) |
EP (1) | EP3148533A1 (en) |
JP (1) | JP2017519736A (en) |
KR (1) | KR20170005125A (en) |
CN (1) | CN106470701A (en) |
AU (1) | AU2015266050A1 (en) |
CA (1) | CA2950625A1 (en) |
EA (1) | EA201692470A1 (en) |
GB (1) | GB201409488D0 (en) |
IL (1) | IL249228A0 (en) |
MX (1) | MX2016015435A (en) |
PH (1) | PH12016502353A1 (en) |
SG (1) | SG11201609363RA (en) |
TW (1) | TW201613578A (en) |
WO (1) | WO2015181154A1 (en) |
ZA (1) | ZA201607425B (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018068832A1 (en) * | 2016-10-11 | 2018-04-19 | Euro-Celtique S.A. | Hodgkin lymphoma therapy |
US9993482B2 (en) | 2014-05-28 | 2018-06-12 | Purdue Pharmaceutical Products L.P. | Pharmaceutical combination comprising a class III receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule EDO-S101 together with its use in the treatment of cancer |
US10118901B2 (en) | 2012-02-01 | 2018-11-06 | Purdue Pharmaceutical Products L.P. | Therapeutic agents |
WO2018229132A1 (en) * | 2017-06-13 | 2018-12-20 | Euro-Celtique S.A. | Tinostamustine for use in the treatment of t-cell prolymphocytic leukaemia |
US10406138B2 (en) | 2014-05-28 | 2019-09-10 | Purdue Pharmaceutical Products L.P. | Pharmaceutical combinations for treating cancer |
US10744120B2 (en) | 2014-05-28 | 2020-08-18 | Purdue Pharmaceutical Products L.P. | Combination comprising a glucocorticoid and EDO-S101 |
WO2022060831A1 (en) * | 2020-09-17 | 2022-03-24 | Mirati Therapeutics, Inc. | Combination therapies |
US11413276B2 (en) | 2017-06-13 | 2022-08-16 | Purdue Pharma L.P. | Compounds for treating TNBC |
US11576899B2 (en) | 2017-06-13 | 2023-02-14 | Purdue Pharma L.P. | Tinostamustine for use in treating sarcoma |
US11896583B2 (en) | 2017-06-13 | 2024-02-13 | Purdue Pharma L.P. | Tinostamustine for use in treating ovarian cancer |
US12048688B2 (en) | 2014-05-28 | 2024-07-30 | Purdue Pharmaceutical Products L.P. | Pharmaceutical combinations for treating cancer |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3124001A1 (en) * | 2018-12-18 | 2020-06-25 | Mundipharma International Corporation Limited | Compounds for treating lymphoma or a t-cell malignant disease |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013040286A2 (en) * | 2011-09-18 | 2013-03-21 | Euro-Celtique S.A. | Pharmaceutical compositions |
Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE34727C (en) | Ch. H. TH. HAVEMANN in Paris, 16 rue Bleue | Process for the direct extraction of metallic lead | ||
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US6407079B1 (en) | 1985-07-03 | 2002-06-18 | Janssen Pharmaceutica N.V. | Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation |
US5376645A (en) | 1990-01-23 | 1994-12-27 | University Of Kansas | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
KR0166088B1 (en) | 1990-01-23 | 1999-01-15 | . | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
US5369108A (en) | 1991-10-04 | 1994-11-29 | Sloan-Kettering Institute For Cancer Research | Potent inducers of terminal differentiation and methods of use thereof |
GB9126209D0 (en) | 1991-12-10 | 1992-02-12 | Orion Yhtymae Oy | Drug formulations for parenteral use |
US5602112A (en) | 1992-06-19 | 1997-02-11 | Supergen, Inc. | Pharmaceutical formulation |
US5882941A (en) | 1994-05-04 | 1999-03-16 | Massachusette Institute Of Technology | Programmable genotoxic agents and uses therefor |
US6046177A (en) | 1997-05-05 | 2000-04-04 | Cydex, Inc. | Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations |
US5874418A (en) | 1997-05-05 | 1999-02-23 | Cydex, Inc. | Sulfoalkyl ether cyclodextrin based solid pharmaceutical formulations and their use |
US6133248A (en) | 1997-06-13 | 2000-10-17 | Cydex, Inc. | Polar drug of prodrug compositions with extended shelf-life storage and a method of making thereof |
US6214852B1 (en) | 1998-10-21 | 2001-04-10 | Bristol-Myers Squibb Company | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases |
US6392053B2 (en) | 1999-12-15 | 2002-05-21 | Bristol-Myers Squibb Company | Process for preparing arylacetylaminothiazoles |
AU2001273413A1 (en) | 2000-07-12 | 2002-01-21 | Immunex Corporation | Method for treating cancer using an interleukin- 4 antagonist |
PE20020354A1 (en) | 2000-09-01 | 2002-06-12 | Novartis Ag | HYDROXAMATE COMPOUNDS AS HISTONE-DESACETILASE (HDA) INHIBITORS |
US7569724B2 (en) | 2000-09-29 | 2009-08-04 | Topotarget Uk Limited | Carbamic acid compounds comprising an amide linkage as HDAC inhibitors |
CN1764648A (en) | 2003-01-13 | 2006-04-26 | 安斯泰来制药有限公司 | hydroxamid acid derivatives as histone deacetylase (HDAC) inhibitors |
AU2004215624B2 (en) | 2003-02-25 | 2011-06-02 | Topotarget Uk Limited | Hydroxamic acid compounds comprising a bicyclic heteroaryl group as HDAC inhibitors |
JP4993374B2 (en) | 2004-04-05 | 2012-08-08 | メルク エイチディーエーシー リサーチ エルエルシー | Histone deacetylase inhibitor prodrug |
WO2007134169A2 (en) | 2006-05-10 | 2007-11-22 | Nuada, Llc | Indole, benzimidazole, and benzolactam boronic acid compounds, analogs thereof and methods of use thereof |
US8436190B2 (en) | 2005-01-14 | 2013-05-07 | Cephalon, Inc. | Bendamustine pharmaceutical compositions |
SI1901729T1 (en) | 2005-05-13 | 2012-05-31 | Topotarget Uk Ltd | Pharmaceutical formulations of hdac inhibitors |
EP2591775A1 (en) * | 2006-04-05 | 2013-05-15 | Novartis AG | Combinations comprising mtor inhibitors for treating cancer |
AU2007325576B2 (en) | 2006-10-20 | 2013-01-10 | Icos Corporation | Compositions of Chk1 inhibitors |
GB0621160D0 (en) | 2006-10-24 | 2006-12-06 | Imp College Innovations Ltd | Compounds and uses thereof |
TWI636795B (en) | 2006-11-20 | 2018-10-01 | 希佛隆公司 | Method of radio-sensitizing tumors using a radio-sensitizing agent |
CN101084876A (en) | 2007-07-11 | 2007-12-12 | 济南康泉医药科技有限公司 | Anti-cancer composition containing bendamustine |
TW200922564A (en) | 2007-09-10 | 2009-06-01 | Curis Inc | CDK inhibitors containing a zinc binding moiety |
US20090131367A1 (en) | 2007-11-19 | 2009-05-21 | The Regents Of The University Of Colorado | Combinations of HDAC Inhibitors and Proteasome Inhibitors |
US8987468B2 (en) | 2008-02-04 | 2015-03-24 | The Translational Genomics Research Institute | Compounds, pharmaceutical compositions and methods of use of hydroxamic acid derivatives |
CA2735899A1 (en) | 2008-09-25 | 2010-04-01 | Cephalon, Inc. | Liquid formulations of bendamustine |
WO2010042568A1 (en) | 2008-10-08 | 2010-04-15 | Cephalon, Inc. | Processes for the preparation of bendamustine |
WO2010075542A1 (en) | 2008-12-23 | 2010-07-01 | Curis, Inc. | Cdk inhibitors |
PL2389375T3 (en) | 2009-01-23 | 2015-11-30 | Euro Celtique Sa | Hydroxamic acid derivatives |
EP2792369B1 (en) | 2009-02-25 | 2018-04-18 | Softkemo Pharma Corp. | Bendamustine cyclopolysaccharide compositions |
WO2010120592A1 (en) * | 2009-04-16 | 2010-10-21 | Merck Sharp & Dohme Corp. | Combination therapy using an anti-egfr agent(s) and igf-1r specific inhibitors |
US8603521B2 (en) | 2009-04-17 | 2013-12-10 | Pharmacyclics, Inc. | Formulations of histone deacetylase inhibitor and uses thereof |
CN101928234B (en) | 2010-01-15 | 2012-12-12 | 北京欧凯纳斯科技有限公司 | 6/7-(hetero)aryl-N-hydroxyl hexanamide/heptamide compounds and method for preparing same |
JO3659B1 (en) | 2010-06-02 | 2020-08-27 | Astellas Deutschland Gmbh | Oral dosage forms of bendamustine and therapeutic use thereof |
ES2627820T3 (en) | 2011-09-13 | 2017-07-31 | Pharmacyclics, Inc. | Histone deacetylase inhibitor formulations in combination with bendamustine and uses thereof |
CN102993102B (en) | 2011-09-16 | 2016-08-24 | 杭州民生药业有限公司 | The synthetic method of [1-methyl-2-(hydroxamic acid base in 7 '-heptan)-5-N, N-bis-(2 '-chloroethyl)]-1H-benzimidazole |
JP6008972B2 (en) | 2011-09-28 | 2016-10-19 | ユーロ−セルティーク エス.エイ. | Nitrogen mustard derivatives |
TWI573792B (en) | 2012-02-01 | 2017-03-11 | 歐陸斯迪公司 | Novel therapeutic agents |
JP6525474B2 (en) | 2013-12-06 | 2019-06-05 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | Combination of Aurora kinase inhibitor and anti-CD30 antibody |
GB201409488D0 (en) | 2014-05-28 | 2014-07-09 | Euro Celtique Sa | Pharmaceutical composition |
GB201409471D0 (en) | 2014-05-28 | 2014-07-09 | Euro Celtique Sa | Pharmaceutical composition |
GB201409485D0 (en) | 2014-05-28 | 2014-07-09 | Euro Celtique Sa | Pharmaceutical composition |
WO2016087950A1 (en) | 2014-12-05 | 2016-06-09 | University of Modena and Reggio Emilia | Combinations of histone deacetylase inhibitors and bendamustine for use in the treatment of lymphoma |
-
2014
- 2014-05-28 GB GBGB1409488.2A patent/GB201409488D0/en not_active Ceased
-
2015
- 2015-05-26 MX MX2016015435A patent/MX2016015435A/en unknown
- 2015-05-26 US US15/314,167 patent/US9993482B2/en active Active
- 2015-05-26 KR KR1020167035842A patent/KR20170005125A/en unknown
- 2015-05-26 SG SG11201609363RA patent/SG11201609363RA/en unknown
- 2015-05-26 CA CA2950625A patent/CA2950625A1/en not_active Abandoned
- 2015-05-26 EP EP15723979.9A patent/EP3148533A1/en not_active Withdrawn
- 2015-05-26 JP JP2016569664A patent/JP2017519736A/en not_active Withdrawn
- 2015-05-26 CN CN201580028027.4A patent/CN106470701A/en active Pending
- 2015-05-26 TW TW104116782A patent/TW201613578A/en unknown
- 2015-05-26 AU AU2015266050A patent/AU2015266050A1/en not_active Abandoned
- 2015-05-26 WO PCT/EP2015/061569 patent/WO2015181154A1/en active Application Filing
- 2015-05-26 EA EA201692470A patent/EA201692470A1/en unknown
-
2016
- 2016-10-27 ZA ZA2016/07425A patent/ZA201607425B/en unknown
- 2016-11-25 PH PH12016502353A patent/PH12016502353A1/en unknown
- 2016-11-27 IL IL249228A patent/IL249228A0/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013040286A2 (en) * | 2011-09-18 | 2013-03-21 | Euro-Celtique S.A. | Pharmaceutical compositions |
Non-Patent Citations (8)
Title |
---|
BARENDSEN N ET AL: "Inhibition of TPA-Induced monocytic differentiation in THP-1 human monocytic leukemic cells by staurosporine, a potent protein kinase C inhibitor", LEUKEMIA RESEARCH, NEW YORK,NY, US, vol. 14, no. 5, 1 January 1990 (1990-01-01), pages 467 - 474, XP026297693, ISSN: 0145-2126, [retrieved on 19900101], DOI: 10.1016/0145-2126(90)90034-7 * |
D. J. DEANGELO ET AL: "Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics", BLOOD, vol. 108, no. 12, 1 December 2006 (2006-12-01), pages 3674 - 3681, XP055199576, ISSN: 0006-4971, DOI: 10.1182/blood-2006-02-005702 * |
HEDGETHORNE K ET AL: "Foretinib: c-Met and VEGFR-2 inhibitor oncolytic", DRUGS OF THE FUTURE, PROUS SCIENCE, ES, vol. 35, no. 11, 1 November 2010 (2010-11-01), pages 893 - 901, XP008166536, ISSN: 0377-8282, DOI: 10.1358/DOF.2010.35.11.1529012 * |
KERSTIN MARIA KAMPA-SCHITTENHELM ET AL: "Quizartinib (AC220) is a potent second generation class III tyrosine kinase inhibitor that displays a distinct inhibition profile against mutant-FLT3, -PDGFRA and -KIT isoforms", MOLECULAR CANCER, BIOMED CENTRAL, LONDON, GB, vol. 12, no. 1, 7 March 2013 (2013-03-07), pages 19, XP021145504, ISSN: 1476-4598, DOI: 10.1186/1476-4598-12-19 * |
SHAOYU YAN ET AL: "Abstract 2741: Synergistic inhibition of tumor growth and overcoming chemo-resistance by simultaneously targeting key components in DNA damage/repair, epigenetic, and putative cancer stem cell signaling pathways using novel dual-functional DNA-alkylating/HDAC inhibitor and tumor suppressor gene nano", CANCER RESEARCH, vol. 72, no. 8 Supplement, 15 April 2012 (2012-04-15), pages 2741 - 2741, XP055199507, ISSN: 0008-5472, DOI: 10.1158/1538-7445.AM2012-2741 * |
SHIPLEY J L ET AL: "Acute myelogenous leukemia", EXPERIMENTAL HEMATOLOGY, ELSEVIER INC, US, vol. 37, no. 6, 1 June 2009 (2009-06-01), pages 649 - 658, XP026128692, ISSN: 0301-472X, [retrieved on 20090520], DOI: 10.1016/J.EXPHEM.2009.04.002 * |
WALID K RASHEED ET AL: "Histone deacetylase inhibitors in cancer therapy", EXPERT OPINION ON INVESTIGATIONAL DRUGS, vol. 16, no. 5, 1 May 2007 (2007-05-01), pages 659 - 678, XP055199693, ISSN: 1354-3784, DOI: 10.1517/13543784.16.5.659 * |
WANG E S ET AL: "Phase 1 trial of linifanib (ABT-869) in patients with refractory or relapsed acute myeloid leukemia", LEUKEMIA AND LYMPHOMA, INFORMA HEALTHCARE, US, vol. 53, no. 8, 1 August 2012 (2012-08-01), pages 1543 - 1551, XP009176722, ISSN: 1042-8194 * |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10118901B2 (en) | 2012-02-01 | 2018-11-06 | Purdue Pharmaceutical Products L.P. | Therapeutic agents |
US11419853B2 (en) | 2014-05-28 | 2022-08-23 | Purdue Pharmaceutical Products L.P. | Compounds for treating brain cancer |
US9993482B2 (en) | 2014-05-28 | 2018-06-12 | Purdue Pharmaceutical Products L.P. | Pharmaceutical combination comprising a class III receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule EDO-S101 together with its use in the treatment of cancer |
US12048688B2 (en) | 2014-05-28 | 2024-07-30 | Purdue Pharmaceutical Products L.P. | Pharmaceutical combinations for treating cancer |
US10406138B2 (en) | 2014-05-28 | 2019-09-10 | Purdue Pharmaceutical Products L.P. | Pharmaceutical combinations for treating cancer |
US11559516B2 (en) | 2014-05-28 | 2023-01-24 | Purdue Pharmaceutical Products L.P. | Pharmaceutical combinations for treating cancer |
US11541038B2 (en) | 2014-05-28 | 2023-01-03 | Purdue Pharmaceutical Products L.P. | Combination comprising a glucocorticoid and EDO-S101 |
US10744120B2 (en) | 2014-05-28 | 2020-08-18 | Purdue Pharmaceutical Products L.P. | Combination comprising a glucocorticoid and EDO-S101 |
US11766424B2 (en) | 2016-10-11 | 2023-09-26 | Purdue Pharmaceutical Products L.P. | Hodgkin lymphoma therapy |
WO2018068832A1 (en) * | 2016-10-11 | 2018-04-19 | Euro-Celtique S.A. | Hodgkin lymphoma therapy |
AU2016426574B2 (en) * | 2016-10-11 | 2023-07-13 | Euro-Celtique S.A. | Hodgkin lymphoma therapy |
US11266631B2 (en) | 2016-10-11 | 2022-03-08 | Purdue Pharmaceutical Products L.P. | Hodgkin lymphoma therapy |
US11413276B2 (en) | 2017-06-13 | 2022-08-16 | Purdue Pharma L.P. | Compounds for treating TNBC |
JP7195283B2 (en) | 2017-06-13 | 2022-12-23 | ユーロ-セルティーク エス.エイ. | Tinostamstine for use in the treatment of T-cell prolymphocytic leukemia |
JP2020523359A (en) * | 2017-06-13 | 2020-08-06 | ユーロ−セルティーク エス.エイ. | Tinostamustine for use in the treatment of T cell prolymphocytic leukemia |
KR20200015563A (en) * | 2017-06-13 | 2020-02-12 | 유로-셀띠끄 소시에떼 아노님 | Tinostamustine for use in the treatment of T-cell prelymphocytic leukemia |
US11576899B2 (en) | 2017-06-13 | 2023-02-14 | Purdue Pharma L.P. | Tinostamustine for use in treating sarcoma |
US11318117B2 (en) | 2017-06-13 | 2022-05-03 | Purdue Pharma L.P. | Tinostamustine for use in the treatment of t-cell prolymphocytic leukaemia |
US11786509B2 (en) | 2017-06-13 | 2023-10-17 | Purdue Pharma L.P. | Compounds for treating TNBC |
US11896583B2 (en) | 2017-06-13 | 2024-02-13 | Purdue Pharma L.P. | Tinostamustine for use in treating ovarian cancer |
US11918558B2 (en) | 2017-06-13 | 2024-03-05 | Purdue Pharma L.P. | Tinostamustine for use in the treatment of T-cell prolymphocytic leukaemia |
KR102655833B1 (en) | 2017-06-13 | 2024-04-08 | 유로-셀띠끄 소시에떼 아노님 | Tinostamustine for use in the treatment of T-cell prolymphocytic leukemia |
WO2018229132A1 (en) * | 2017-06-13 | 2018-12-20 | Euro-Celtique S.A. | Tinostamustine for use in the treatment of t-cell prolymphocytic leukaemia |
WO2022060831A1 (en) * | 2020-09-17 | 2022-03-24 | Mirati Therapeutics, Inc. | Combination therapies |
Also Published As
Publication number | Publication date |
---|---|
US20170095482A1 (en) | 2017-04-06 |
IL249228A0 (en) | 2017-02-28 |
PH12016502353A1 (en) | 2017-02-13 |
CA2950625A1 (en) | 2015-12-03 |
KR20170005125A (en) | 2017-01-11 |
US9993482B2 (en) | 2018-06-12 |
MX2016015435A (en) | 2017-06-23 |
GB201409488D0 (en) | 2014-07-09 |
EP3148533A1 (en) | 2017-04-05 |
TW201613578A (en) | 2016-04-16 |
CN106470701A (en) | 2017-03-01 |
AU2015266050A1 (en) | 2016-11-10 |
ZA201607425B (en) | 2019-04-24 |
EA201692470A1 (en) | 2017-08-31 |
JP2017519736A (en) | 2017-07-20 |
SG11201609363RA (en) | 2016-12-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9993482B2 (en) | Pharmaceutical combination comprising a class III receptor tyrosine kinase inhibitor and the alkylating histone-deacetylase inhibitor fusion molecule EDO-S101 together with its use in the treatment of cancer | |
US11559516B2 (en) | Pharmaceutical combinations for treating cancer | |
US11541038B2 (en) | Combination comprising a glucocorticoid and EDO-S101 | |
US12048688B2 (en) | Pharmaceutical combinations for treating cancer |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15723979 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2015266050 Country of ref document: AU Date of ref document: 20150526 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2016/015435 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2950625 Country of ref document: CA Ref document number: 2016569664 Country of ref document: JP Kind code of ref document: A |
|
REEP | Request for entry into the european phase |
Ref document number: 2015723979 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12016502353 Country of ref document: PH Ref document number: 2015723979 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 249228 Country of ref document: IL |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15314167 Country of ref document: US |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112016027045 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 20167035842 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: NC2016/0005602 Country of ref document: CO |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201692470 Country of ref document: EA Ref document number: A201613405 Country of ref document: UA |
|
ENP | Entry into the national phase |
Ref document number: 112016027045 Country of ref document: BR Kind code of ref document: A2 Effective date: 20161118 |