WO2018066946A1 - Pharmaceutical combinations of histone deacetylase inhibitor and proteasome inhibitor or immunomodulatory drug for the treatment of hematological cancer - Google Patents

Pharmaceutical combinations of histone deacetylase inhibitor and proteasome inhibitor or immunomodulatory drug for the treatment of hematological cancer Download PDF

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WO2018066946A1
WO2018066946A1 PCT/KR2017/011015 KR2017011015W WO2018066946A1 WO 2018066946 A1 WO2018066946 A1 WO 2018066946A1 KR 2017011015 W KR2017011015 W KR 2017011015W WO 2018066946 A1 WO2018066946 A1 WO 2018066946A1
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active ingredient
combination
chemical formula
cancer
weight
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PCT/KR2017/011015
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French (fr)
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Soo Jin Kim
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Chong Kun Dang Pharmaceutical Corp.
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Priority to EP17858740.8A priority Critical patent/EP3522891A4/en
Priority to CN201780061019.9A priority patent/CN109789138A/en
Priority to RU2019108930A priority patent/RU2721409C1/en
Priority to AU2017338564A priority patent/AU2017338564B2/en
Priority to MX2019003907A priority patent/MX2019003907A/en
Priority to BR112019006633A priority patent/BR112019006633A2/en
Priority to JP2019537733A priority patent/JP2019529562A/en
Priority to CA3038019A priority patent/CA3038019A1/en
Publication of WO2018066946A1 publication Critical patent/WO2018066946A1/en
Priority to ZA2019/02340A priority patent/ZA201902340B/en

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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
    • A61K31/415—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
    • A61K31/435—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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/005—Enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • 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
    • 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
    • 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 a pharmaceutical combination for treating a hematological cancer, more specifically, multiple myeloma, particularly, a hematological cancer which is resistant to conventional therapies, and more specifically, relates to a pharmaceutical combination for treating myeloma comprising a histone deacetylase (HDAC) inhibitor, a proteasome inhibitor or an immunomodulatory drug and a steroidal anti-cancer agent together.
  • HDAC histone deacetylase
  • Myeloma of hematological cancers refers to a tumor consisting of cells of the type usually found in bone marrow.
  • multiple myeloma means disseminated malignant neoplasm of plasma cells characterized by secretion of multiple myeloid tumor lesions and M component (monoclonal immunoglobulin fragment), related to widespread osteolytic lesions that lead to bone pain, pathological fractures, hypercalcemia and normocytic normochromic anemia.
  • Multiple myeloma cannot be treated by conventional, high-dose chemotherapies.
  • acetylation status of nucleosomal histones plays an important role in the regulation of gene expression.
  • Deacetylation of nucleosomal histones is facilitated by a group of enzymes known as histone deacetylases (HDACs) with 11 known isoforms.
  • Histone deacetylation induces chromatin condensation leading to transcriptional repression, while acetylation allows approaching to transcriptional machinery which makes transcription easy by inducing localized relaxation within specific chromosomal regions.
  • HDACs histone deacetylases
  • Histone deacetylation induces chromatin condensation leading to transcriptional repression, while acetylation allows approaching to transcriptional machinery which makes transcription easy by inducing localized relaxation within specific chromosomal regions.
  • selective inhibitors of HDAC enzymes lead to histone hyperacetylation. It is known to alter transcriptional regulation of a subset of genes, including many tumor suppressor genes involved in cell cycle control, cell division and apoptos
  • HDAC inhibitors have been reported to inhibit tumor growth in vivo. Inhibition of tumor growth is accompanied by hyperacetylation of histone and tubulin and may include a number of mechanisms. HDAC inhibitors block cancer cell proliferation in both in vitro and in vivo. As described above, it has been known that HDAC inhibitors effectively inhibit cancer growth in multiple myeloma, but in case of drugs developed in the past, there is a problem that their use is limited due to severe toxicity.
  • proteasome inhibitors and immunomodulatory drugs are well known as the main agents for treating multiple myeloma.
  • immunomoduratory (IMiD) class of drugs exhibit significant anti-myeloma characteristics in various multiple myeloma models and have been shown to have significant clinical activity in patients with multiple myeloma.
  • bortezomib also known as Velcade or PS-341
  • PS-341 has been reported to have activity in NSCLS cell lines as an FDA-approved small molecule proteasome inhibitor in treatment of refractory multiple myeloma, where it was found to induce concentration and time-dependent G2/M cell cycle arrest.
  • the present inventors have conducted intensive studies on a more effective and less toxic hematological cancer drug, specifically multiple myeloma.
  • the present invention has been completed by confirming that in case of combining the compound of chemical formula 1 as a HDAC inhibitor and a proteasome inhibitor or an immunomodulatory drug and a steroidal anti-cancer agent. It is possible to obtain synergistic anti-cancer effect with reduced toxicity and comparable pharmaceutical effect to other HDAC inhibitors in multiple myeloma, which has been difficult to effectively treat due to various problems such as toxicity, etc. in the past.
  • the purpose of the present invention is to provide a composition for treating myeloma comprising the compound of the following chemical formula 1 as a histone deacetylase inhibitor, a proteasome inhibitor or an immunomodulatory drug, and a steroidal anti-cancer agent.
  • the present invention relates to a pharmaceutical combination for treating a hematological cancer comprising,
  • hydroxamic acid derivative represented by the following chemical formula 1, N-(7-(hydroxyamino)-7-oxoheptyl)-4-methyl-N-(4-(1-methyl-1H-indazol-6-yl)phenyl)piperazine-1-carboxamide methanesulfonate or its pharmaceutically acceptable salt as the first active ingredient;
  • the hematological cancer is multiple myeloma.
  • the improved efficacy of the combination according to the present invention can be demonstrated by measuring the therapeutic synergistic effect.
  • the combination of the present invention exhibits a synergistic effect when the first active ingredient, which is a HDAC inhibitor, is administered in combination with the second active ingredient and the third active ingredient, and thus has excellent anti-cancer activity against a hematological cancer, particularly multiple myeloma.
  • FIG. 1a is a graph of cancer growth of the control group and each experimental group in MM.1s xenograft mouse model.
  • FIG. 1b shows the tumor size change by individual of each experimental group on the last day of the experiment (day 57) in MM.1s xenograft mouse model.
  • FIG. 2a is a graph of cancer growth of the control group and each experimental group in MM.1s xenograft mouse model.
  • FIG. 2b shows the tumor size change by individual of each experimental group on the last day of the experiment (day 70) in MM.1s xenograft mouse model.
  • the first active ingredient of the pharmaceutical combination according to the present invention is the compound of the above chemical formula 1, and this compound has activity as a histone deacetylase (HDAC).
  • HDAC histone deacetylase
  • the description and preparation method of the compound of the above chemical formula 1 are described in detail in international patent publication No. WO 2010-110545, which is incorporated herein by reference.
  • the compound of the above chemical formula 1 can be prepared by the preparation method disclosed in the above document.
  • the compound of the above chemical formula 1 administered to humans varies in dosage depending on various administration factors including individual specific factors of patients, but for example, it can be administered in 10 to 210 mg/m 2 .
  • the second active ingredient of the pharmaceutical combination according to the present invention is a proteasome inhibitor or an immunomodulatory drug
  • the proteasome inhibitor is an agent inhibiting activity of a proteasome (i.e. a cell complex degrading a protein) degrading a cell division regulating protein reversely, and it is based on the fact that the normal cells regenerate cell division ability even if the activity of the proteasome is temporarily inhibited, but various cancer cells enter the death process as soon as the proteasome activity is temporarily inhibited.
  • the proteasome inhibitor that may be comprised in the pharmaceutical combination of the present invention may be various classes of known proteasome inhibitors.
  • bortezomib (INN, PS0341; Velcade) which is a compound approved in the United States for treating relapsed multiple myeloma.
  • CEP-18770 as another peptide boronate.
  • proteasome inhibitors there are peptide aldehyde (for example, MG132), peptide vinyl sulfone, peptide epoxyketone (for example, epoxomicin, carfilzomib), ⁇ lactone inhibitor (for example, lactocystine, MLN 519, NPI-0052, salinosporamide A), a compound which produces dithiocarbamate complex with a metal (for example, disulfiram which is also used in treatment of chronic alcoholism), and specific antioxidant (for example, epigallocatechin-3-gallate, catechin-3-galate, and salinosporamide A.
  • peptide aldehyde for example, MG132
  • peptide vinyl sulfone for example, peptide epoxyketone (for example, epoxomicin, carfilzomib)
  • ⁇ lactone inhibitor for example, lactocystine, MLN 519, NPI-0052, salinosporamide
  • the proteasome inhibitor comprised in the pharmaceutical combination of the present invention is preferably, bortezomib represented by the following chemical formula 2 or its pharmaceutically acceptable salt.
  • the bortezomib can be administered intravenously or subcutaneously in a dose of 0.3 ⁇ 1.5 mg/m 2 , 1 to 2 times per week, depending on the administration schedule, but is not limited thereto.
  • the immunomodulatory drug has effects such as expansion of immune cells and promotion of tumor cell death, etc. and specifically, a substance which regulates immunity by improving ADCC (antibody-dependent cell-mediated cytotoxicity).
  • the immunomodulatory drug comprised in the pharmaceutical combination of the present invention may be thalidomide lenalidomide, formalidomide, or a pharmaceutically acceptable salt, and preferably, lenalidomide represented by the following chemical formula 3 or its pharmaceutically acceptable salt.
  • Lenalidomide is generally orally administered in a dose of 10 mg to 30 mg depending on the administration schedule, but is not limited thereto.
  • the third active ingredient of the pharmaceutical combination according to the present invention is a steroidal anti-cancer agent, and for example, may be prednisone or dexamethasone, but is not limited thereto.
  • dexamethasone represented by the following chemical formula 4 that is, (8S, 9R, 10S, 11S, 13S, 14S, 16R, 17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene- 3-on or isotope variant; or its pharmaceutically acceptable salt, hydrate, or solvate.
  • dexamethasone is (8S, 9R, 10S, 11S, 13S, 14S, 16R, 17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-on.
  • dexamethasone is (8S, 9R, 10S, 11S, 13S, 14S, 16R, 17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17- dodecahydro-3H-cyclopenta[a]phenanthrene-3-on, wherein hydrogen atom is deuterated.
  • the pharmaceutically acceptable salt means a salt commonly used in the medical industry, and for example, there are inorganic ionic salts prepared with calcium, potassium, sodium and magnesium, etc., inorganic acid salts prepared with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, tartaric acid and sulfuric acid, etc., organic acid salts prepared with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc., amino acid salts prepared with methane sulfonic acid, ethane s
  • the first active ingredient, the second active ingredient, and the third active ingredient may be comprised per 100 parts by weight of the total pharmaceutical combination.
  • a proteasome inhibitor such as bortezomib
  • it is composed of 28.55 to 85.60 parts by weight of the first active ingredient, 1.28 to 8.63 parts by weight of the second active ingredient and 2.71 to 69.55 parts by weight of the third active ingredient.
  • an immunomodulatory drug such as lenalidomide is used as the second active ingredient, it is composed of 19.54 to 94.69 parts by weight of the first active ingredient, 2.46 to 52.63 parts by weight of the second active ingredient and 2.52 to 59.70 parts by weight of the third active ingredient.
  • the pharmaceutical combination may comprise 3 kinds of separate formulations, and may consist of two or one formulation.
  • the combination of the present invention may be administered orally or parenterally (For example, intravenously, subcutaneously, intraperitoneally or topically).
  • the first active ingredient and the second active ingredient may be administered orally or parenterally, and preferably, may be administered parenterally.
  • the third active ingredient may be parenterally or orally administered, preferably administered orally.
  • the range of appropriate dose of the first active ingredient to the third active ingredient varies according to the body weight, age, sex, health condition of patient, diet, administration time, administration method, excretion rate, and severity of disease, etc.
  • the daily dose of the first active ingredient is approximately 10 ⁇ 80 mg/kg, preferably 20 to 60 mg/kg.
  • the daily dose of the second active ingredient of the present invention is approximately 0.1 ⁇ 5 mg/kg, preferably 0.5 to 2 mg/kg.
  • the appropriate administration period of the first active ingredient and the second active ingredient and the third active ingredient may be determined according to the dose.
  • the first active ingredient may be administered once a day to once every two weeks, preferably once a week.
  • the second active ingredient of the present invention may be administered once a day to once a week, preferably twice a week.
  • the third active ingredient of the present invention may be administered once a day to once a week, preferably 4 times a week.
  • the first active ingredient of the present invention may be administered once a day to once every two weeks, preferably once a week, and the second active ingredient may be administered once a day to once a week, preferably once a day, and the third active ingredient may be administered once a day to once a week, preferable once a week.
  • the pharmaceutical combination of the present invention confirmed the combination effect of the first active ingredient, which is a HDAC inhibitor, the second active ingredient, which is a proteasome inhibitor or an immunomodulatory drug, and the third active ingredient, which is a steroidal anti-cancer agent, thereby exhibiting excellent anti-cancer activity.
  • the anti-cancer combination of the present invention can by usefully used as an anti-cancer treatment strategy, and it is preferable particularly for treating a hematological cancer.
  • the hematological cancer may preferably be multiple myeloma.
  • the first active ingredient, the second active ingredient, and the third active ingredient comprised in the combination of the present invention may be comprised in separate pharmaceutical composition respectively, and the pharmaceutical composition may be prepared in a unit dose form or prepared by introducing in a multi-dose container by formulating it using a pharmaceutically acceptable carrier, according to a method which can be easily carried out by a person having ordinary skill in the art.
  • the pharmaceutically acceptable carrier is conventionally used in formulation, and includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, etc., but not limited thereto.
  • the pharmaceutical combination of the present invention may comprise a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, etc. in addition to the above components.
  • the appropriate pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
  • the present invention provides a method for treating a cancer comprising administering the pharmaceutical combination into an individual who needs it.
  • the "individual” includes mammals, particularly humans.
  • MM.1s which is a human multiple myeloma cell line was purchased from ATCC (USA). MM.1s cell line was maintained with RPMI1640 (Gibco, USA) containing 10% fetal bovine serum (FBS; Gibco, Grand Island, NY, USA).
  • MM.1s cells which were mixed with matrigel were subcutaneously administered into NOD.CB17-Prkdcscid/NCrHsd male mouse (2x10 7 cell/head) to organize groups to uniformly distribute the tumor size and then used in the experiment.
  • the compound of the chemical formula 1 was prepared in the concentration of 4 mg/ml by dissolving with physiological saline solution.
  • Bortezomib was prepared in the concentration of 0.005 mg/ml by dissolving with physiological saline solution.
  • Dexamethasone was prepared in the concentration of 0.05 mg/ml by diluting 5 mg/mL original solution with physiological saline solution.
  • the using solution was prepared on the day of use, and the remaining solution was discarded.
  • the anti-cancer effect of the compound of the chemical formula 1 and bortezomib and dexamethasone was evaluated in MM.1s xenograft model.
  • the experimental groups were divided to the following different administration groups.
  • Chemical formula 1 the compound of the chemical formula 1 (40 mg/kg, once a week, injection)
  • bortezomib 0.05 mg/kg, twice a week, injection
  • dexamethasone 0.5 mg/kg, 4 times a week, injection
  • tumor volume (length ⁇ width 2 ) / 2
  • each substance was administered into xenograft mouse, and the weight and tumor growth were monitored for 57 days.
  • tumor growth inhibiting effect comparing the tumor sizes of group administering the compound of the chemical formula 1 and coadministration group of bortezomib and dexamethasone, and coadministration group of the compound of the chemical formula 1+bortezomib+dexamethasone to a group administering an excipient during administration period, the tumor growth was highly inhibited.
  • Example 2 Confirmation of anti-cancer effect of the combination of the present invention using lenalidomide as the second active ingredient, in MM.1s xenograft model >
  • MM.1s which is a human multiple myeloma cell line was purchased from ATCC (USA). MM.1s cell line was maintained with RPMI1640 (Gibco, USA) containing 10% fetal bovine serum (FBS; Gibco, Grand Island, NY, USA).
  • MM.1s cells which were mixed with matrigel were subcutaneously administered into NOD.CB17-Prkdcscid/NCrHsd male mouse (2x10 7 cell/head) to organize groups to uniformly distribute the tumor size and then used in the experiment.
  • the compound of the chemical formula 1 was prepared in the concentration of 6 mg/ml by dissolving with physiological saline solution.
  • Lenalidomide was prepared in the concentration of 1 mg/ml by dissolving with 1% HCl in PBS, and then titrating to a neutral pH.
  • Dexamethasone was prepared in the concentration of 0.2 mg/ml by diluting 5 mg/ml dexamethasone with saline.
  • the using solution was prepared on the day of use, and the remaining solution was discarded.
  • the anti-cancer effect of the compound of the chemical formula 1 and lenalidomide and dexamethasone was evaluated in MM.1s xenograft model.
  • the experimental groups were divided to the following different administration groups.
  • lenalidomide 10 mg/kg, once a day, injection
  • dexamethasone 2 mg/kg, once a week, injection
  • each substance was administered into xenograft mouse, and the weight and tumor growth were monitored for 70 days.
  • tumor growth inhibiting effect comparing the tumor sizes of group administering the compound of the chemical formula 1 and coadministration group of lenalidomide and dexamethasone, and coadministration group of the compound of the chemical formula 1+ lenalidomide+dexamethasone to a group administering an excipient during administration period, the tumor growth was highly inhibited.

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Abstract

The present invention relates to a pharmaceutical combination for treating a hematological cancer comprising the histone deacetylase (HDAC) inhibitor of the chemical formula 1, a proteasome inhibitor or an immunomodulatory drug and a steroidal anti-cancer agent together.The pharmaceutical combination of the present invention can be useful for treating a hematological cancer such as multiple myeloma, by reducing toxicity which is the problem of the conventional HDAC inhibitor and exhibiting an equivalent level of pharmaceutical effects due to a complex inhibitory mechanism against the cancer of the compound of chemical formula 1 and its pharmaceutically acceptable salt, the proteasome inhibitor or the immunomodulatory drug and the steroidal anti-cancer agent.

Description

PHARMACEUTICAL COMBINATIONS OF HISTONE DEACETYLASE INHIBITOR AND PROTEASOME INHIBITOR OR IMMUNOMODULATORY DRUG FOR THE TREATMENT OF HEMATOLOGICAL CANCER
The present invention relates to a pharmaceutical combination for treating a hematological cancer, more specifically, multiple myeloma, particularly, a hematological cancer which is resistant to conventional therapies, and more specifically, relates to a pharmaceutical combination for treating myeloma comprising a histone deacetylase (HDAC) inhibitor, a proteasome inhibitor or an immunomodulatory drug and a steroidal anti-cancer agent together.
Myeloma of hematological cancers refers to a tumor consisting of cells of the type usually found in bone marrow. Furthermore, multiple myeloma (MM) means disseminated malignant neoplasm of plasma cells characterized by secretion of multiple myeloid tumor lesions and M component (monoclonal immunoglobulin fragment), related to widespread osteolytic lesions that lead to bone pain, pathological fractures, hypercalcemia and normocytic normochromic anemia. Multiple myeloma cannot be treated by conventional, high-dose chemotherapies.
On the other hand, acetylation status of nucleosomal histones plays an important role in the regulation of gene expression. Deacetylation of nucleosomal histones is facilitated by a group of enzymes known as histone deacetylases (HDACs) with 11 known isoforms. Histone deacetylation induces chromatin condensation leading to transcriptional repression, while acetylation allows approaching to transcriptional machinery which makes transcription easy by inducing localized relaxation within specific chromosomal regions. In tumor cells, selective inhibitors of HDAC enzymes lead to histone hyperacetylation. It is known to alter transcriptional regulation of a subset of genes, including many tumor suppressor genes involved in cell cycle control, cell division and apoptosis. In addition, HDAC inhibitors have been reported to inhibit tumor growth in vivo. Inhibition of tumor growth is accompanied by hyperacetylation of histone and tubulin and may include a number of mechanisms. HDAC inhibitors block cancer cell proliferation in both in vitro and in vivo. As described above, it has been known that HDAC inhibitors effectively inhibit cancer growth in multiple myeloma, but in case of drugs developed in the past, there is a problem that their use is limited due to severe toxicity.
On the other hand, proteasome inhibitors and immunomodulatory drugs are well known as the main agents for treating multiple myeloma.
Meanwhile, immunomoduratory (IMiD) class of drugs exhibit significant anti-myeloma characteristics in various multiple myeloma models and have been shown to have significant clinical activity in patients with multiple myeloma. Among these, bortezomib (also known as Velcade or PS-341) has been reported to have activity in NSCLS cell lines as an FDA-approved small molecule proteasome inhibitor in treatment of refractory multiple myeloma, where it was found to induce concentration and time-dependent G2/M cell cycle arrest.
Due to various problems of these therapies including toxicity, there is a strong need for a combination and a method that are more effective and less toxic for treating multiple myeloma.
Under these circumstances, the present inventors have conducted intensive studies on a more effective and less toxic hematological cancer drug, specifically multiple myeloma. As a result, the present invention has been completed by confirming that in case of combining the compound of chemical formula 1 as a HDAC inhibitor and a proteasome inhibitor or an immunomodulatory drug and a steroidal anti-cancer agent. It is possible to obtain synergistic anti-cancer effect with reduced toxicity and comparable pharmaceutical effect to other HDAC inhibitors in multiple myeloma, which has been difficult to effectively treat due to various problems such as toxicity, etc. in the past.
Thus, the purpose of the present invention is to provide a composition for treating myeloma comprising the compound of the following chemical formula 1 as a histone deacetylase inhibitor, a proteasome inhibitor or an immunomodulatory drug, and a steroidal anti-cancer agent.
As one embodiment to achieve the above purpose, the present invention relates to a pharmaceutical combination for treating a hematological cancer comprising,
1) a hydroxamic acid derivative represented by the following chemical formula 1, N-(7-(hydroxyamino)-7-oxoheptyl)-4-methyl-N-(4-(1-methyl-1H-indazol-6-yl)phenyl)piperazine-1-carboxamide methanesulfonate or its pharmaceutically acceptable salt as the first active ingredient;
2) a proteasome inhibitor or an immunomodulatory drug as the second active ingredient; and
3) a steroidal anti-cancer agent as the third active ingredient. Preferably, the hematological cancer is multiple myeloma.
[Chemical formula 1]
Figure PCTKR2017011015-appb-I000001
The improved efficacy of the combination according to the present invention can be demonstrated by measuring the therapeutic synergistic effect. The combination of the present invention exhibits a synergistic effect when the first active ingredient, which is a HDAC inhibitor, is administered in combination with the second active ingredient and the third active ingredient, and thus has excellent anti-cancer activity against a hematological cancer, particularly multiple myeloma.
FIG. 1a is a graph of cancer growth of the control group and each experimental group in MM.1s xenograft mouse model.
FIG. 1b shows the tumor size change by individual of each experimental group on the last day of the experiment (day 57) in MM.1s xenograft mouse model.
FIG. 2a is a graph of cancer growth of the control group and each experimental group in MM.1s xenograft mouse model.
FIG. 2b shows the tumor size change by individual of each experimental group on the last day of the experiment (day 70) in MM.1s xenograft mouse model.
Hereinafter, the present invention will be described in more detail.
The first active ingredient of the pharmaceutical combination according to the present invention is the compound of the above chemical formula 1, and this compound has activity as a histone deacetylase (HDAC). The description and preparation method of the compound of the above chemical formula 1 are described in detail in international patent publication No. WO 2010-110545, which is incorporated herein by reference. In the present invention, the compound of the above chemical formula 1 can be prepared by the preparation method disclosed in the above document. Generally, it is known that the compound of the above chemical formula 1 administered to humans varies in dosage depending on various administration factors including individual specific factors of patients, but for example, it can be administered in 10 to 210 mg/m2.
On the other hand, the second active ingredient of the pharmaceutical combination according to the present invention is a proteasome inhibitor or an immunomodulatory drug, and the proteasome inhibitor is an agent inhibiting activity of a proteasome (i.e. a cell complex degrading a protein) degrading a cell division regulating protein reversely, and it is based on the fact that the normal cells regenerate cell division ability even if the activity of the proteasome is temporarily inhibited, but various cancer cells enter the death process as soon as the proteasome activity is temporarily inhibited. The proteasome inhibitor that may be comprised in the pharmaceutical combination of the present invention may be various classes of known proteasome inhibitors. For example, as a class of peptide boronate, there is bortezomib (INN, PS0341; Velcade) which is a compound approved in the United States for treating relapsed multiple myeloma. There is CEP-18770, as another peptide boronate. As other classes of proteasome inhibitors, there are peptide aldehyde (for example, MG132), peptide vinyl sulfone, peptide epoxyketone (for example, epoxomicin, carfilzomib), β lactone inhibitor (for example, lactocystine, MLN 519, NPI-0052, salinosporamide A), a compound which produces dithiocarbamate complex with a metal (for example, disulfiram which is also used in treatment of chronic alcoholism), and specific antioxidant (for example, epigallocatechin-3-gallate, catechin-3-galate, and salinosporamide A. The proteasome inhibitor comprised in the pharmaceutical combination of the present invention is preferably, bortezomib represented by the following chemical formula 2 or its pharmaceutically acceptable salt. The bortezomib can be administered intravenously or subcutaneously in a dose of 0.3~1.5 mg/m2, 1 to 2 times per week, depending on the administration schedule, but is not limited thereto.
[Chemical formula 2]
Figure PCTKR2017011015-appb-I000002
Meanwhile, the immunomodulatory drug has effects such as expansion of immune cells and promotion of tumor cell death, etc. and specifically, a substance which regulates immunity by improving ADCC (antibody-dependent cell-mediated cytotoxicity). Specifically, the immunomodulatory drug comprised in the pharmaceutical combination of the present invention may be thalidomide lenalidomide, formalidomide, or a pharmaceutically acceptable salt, and preferably, lenalidomide represented by the following chemical formula 3 or its pharmaceutically acceptable salt. Lenalidomide is generally orally administered in a dose of 10 mg to 30 mg depending on the administration schedule, but is not limited thereto.
[Chemical formula 3]
Figure PCTKR2017011015-appb-I000003
The third active ingredient of the pharmaceutical combination according to the present invention is a steroidal anti-cancer agent, and for example, may be prednisone or dexamethasone, but is not limited thereto. Preferably, dexamethasone represented by the following chemical formula 4 that is, (8S, 9R, 10S, 11S, 13S, 14S, 16R, 17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene- 3-on or isotope variant; or its pharmaceutically acceptable salt, hydrate, or solvate. In one embodiment, dexamethasone is (8S, 9R, 10S, 11S, 13S, 14S, 16R, 17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-on. In other embodiment, dexamethasone is (8S, 9R, 10S, 11S, 13S, 14S, 16R, 17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17- dodecahydro-3H-cyclopenta[a]phenanthrene-3-on, wherein hydrogen atom is deuterated.
[Chemical formula 4]
Figure PCTKR2017011015-appb-I000004
In the present invention, the pharmaceutically acceptable salt means a salt commonly used in the medical industry, and for example, there are inorganic ionic salts prepared with calcium, potassium, sodium and magnesium, etc., inorganic acid salts prepared with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, tartaric acid and sulfuric acid, etc., organic acid salts prepared with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc., amino acid salts prepared with methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid and naphthalene sulfonic acid, etc., and amine salts prepared with trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but the kinds of salts in the present invention are not limited by these listed salts.
In one specific embodiment, the first active ingredient, the second active ingredient, and the third active ingredient may be comprised per 100 parts by weight of the total pharmaceutical combination. When a proteasome inhibitor such as bortezomib is used as the second active ingredient, it is composed of 28.55 to 85.60 parts by weight of the first active ingredient, 1.28 to 8.63 parts by weight of the second active ingredient and 2.71 to 69.55 parts by weight of the third active ingredient. When an immunomodulatory drug such as lenalidomide is used as the second active ingredient, it is composed of 19.54 to 94.69 parts by weight of the first active ingredient, 2.46 to 52.63 parts by weight of the second active ingredient and 2.52 to 59.70 parts by weight of the third active ingredient.
The pharmaceutical combination may comprise 3 kinds of separate formulations, and may consist of two or one formulation.
The combination of the present invention may be administered orally or parenterally (For example, intravenously, subcutaneously, intraperitoneally or topically). In the present invention, the first active ingredient and the second active ingredient may be administered orally or parenterally, and preferably, may be administered parenterally. In addition, the third active ingredient may be parenterally or orally administered, preferably administered orally.
In the combination of the present invention, the range of appropriate dose of the first active ingredient to the third active ingredient varies according to the body weight, age, sex, health condition of patient, diet, administration time, administration method, excretion rate, and severity of disease, etc. The daily dose of the first active ingredient is approximately 10 ~ 80 mg/kg, preferably 20 to 60 mg/kg. In addition, the daily dose of the second active ingredient of the present invention is approximately 0.1 ~ 5 mg/kg, preferably 0.5 to 2 mg/kg.
In the combination of the present invention, the appropriate administration period of the first active ingredient and the second active ingredient and the third active ingredient may be determined according to the dose. For example, in case that the second active ingredient of the present invention is a proteasome inhibitor, the first active ingredient may be administered once a day to once every two weeks, preferably once a week. In addition, the second active ingredient of the present invention may be administered once a day to once a week, preferably twice a week. The third active ingredient of the present invention may be administered once a day to once a week, preferably 4 times a week. In addition, in case that the second active ingredient of the present invention is an immunomodulatory drug, the first active ingredient of the present invention may be administered once a day to once every two weeks, preferably once a week, and the second active ingredient may be administered once a day to once a week, preferably once a day, and the third active ingredient may be administered once a day to once a week, preferable once a week.
The pharmaceutical combination of the present invention confirmed the combination effect of the first active ingredient, which is a HDAC inhibitor, the second active ingredient, which is a proteasome inhibitor or an immunomodulatory drug, and the third active ingredient, which is a steroidal anti-cancer agent, thereby exhibiting excellent anti-cancer activity.
Therefore, the anti-cancer combination of the present invention can by usefully used as an anti-cancer treatment strategy, and it is preferable particularly for treating a hematological cancer. The hematological cancer may preferably be multiple myeloma.
In the present invention, the first active ingredient, the second active ingredient, and the third active ingredient comprised in the combination of the present invention may be comprised in separate pharmaceutical composition respectively, and the pharmaceutical composition may be prepared in a unit dose form or prepared by introducing in a multi-dose container by formulating it using a pharmaceutically acceptable carrier, according to a method which can be easily carried out by a person having ordinary skill in the art.
The pharmaceutically acceptable carrier is conventionally used in formulation, and includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, etc., but not limited thereto. The pharmaceutical combination of the present invention may comprise a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, etc. in addition to the above components. The appropriate pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
As another embodiment, the present invention provides a method for treating a cancer comprising administering the pharmaceutical combination into an individual who needs it. In the present invention, the "individual" includes mammals, particularly humans.
Hereinafter, the configuration and effect of the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.
<Example 1: Confirmation of anti-cancer effect of the combination of the present invention using bortezomib as the second active ingredient, in MM.1s xenograft model>
1-1) Experimental method
a. Preparation of animal tumor model
MM.1s which is a human multiple myeloma cell line was purchased from ATCC (USA). MM.1s cell line was maintained with RPMI1640 (Gibco, USA) containing 10% fetal bovine serum (FBS; Gibco, Grand Island, NY, USA).
After MM.1s cells which were mixed with matrigel were subcutaneously administered into NOD.CB17-Prkdcscid/NCrHsd male mouse (2x107 cell/head) to organize groups to uniformly distribute the tumor size and then used in the experiment.
b. Preparation of active ingredients
The compound of the chemical formula 1 was prepared in the concentration of 4 mg/ml by dissolving with physiological saline solution.
Bortezomib was prepared in the concentration of 0.005 mg/ml by dissolving with physiological saline solution.
Dexamethasone was prepared in the concentration of 0.05 mg/ml by diluting 5 mg/mL original solution with physiological saline solution.
The using solution was prepared on the day of use, and the remaining solution was discarded.
c. Confirmation of anti-tumor activity
The anti-cancer effect of the compound of the chemical formula 1 and bortezomib and dexamethasone was evaluated in MM.1s xenograft model. The experimental groups were divided to the following different administration groups.
- control group : vehicle
- Chemical formula 1 : the compound of the chemical formula 1 (40 mg/kg, once a week, injection)
- Combination group of bortezomib and dexamethasone : bortezomib (0.05 mg/kg, twice a week, injection), dexamethasone (0.5 mg/kg, 4 times a week, injection)
- Combination group of chemincal formula 1, bortezomib and dexamethasone : the compound of the chemical formula 1 (40 mg/kg, once a week, injection), bortezomib (0.05 mg/kg, twice a week, injection), dexamethasone (0.5 mg/kg, 4 times a week, injection)
All experimental groups were administered intraperitoneally for 57 days. The toxicity was monitored by measuring mouse weight, and the tumor growth was measured by using caliper during the experiment. The tumor volume was calculated according to the following mathematical equation 1.
[Mathematical equation 1]
tumor volume = (length × width2) / 2
d. Statistical analysis
For all the results of the present experiment, the comparison between experimental groups was performed by assuming normality of the data through parametric multiple comparison or nonparametric multiple comparison, and statistical analysis was performed by using Prism 5.03 (GraphPad Software Inc., San Diego, CA, USA), and the case where p value was below 0.05 was considered statistically significant.
1-2) Experimental result
In order to evaluate anti-tumor effect by coadministration of the compound of the chemical formula 1 and bortezomib, dexamethasone, each substance was administered into xenograft mouse, and the weight and tumor growth were monitored for 57 days.
In an aspect of tumor growth inhibiting effect, comparing the tumor sizes of group administering the compound of the chemical formula 1 and coadministration group of bortezomib and dexamethasone, and coadministration group of the compound of the chemical formula 1+bortezomib+dexamethasone to a group administering an excipient during administration period, the tumor growth was highly inhibited.
In the coadministration group of bortezomib and dexamethasone, there was a slight decrease in the size, but the number of mice reaching a complete remission was only 1, and most of the mice had an effect of reducing the cancer less than 50%. While, in the coadministration group of the compound of the chemical formula 1+bortezomib+dexamethasone, the complete remission was observed in 3 mice, and most of the mice had an effect of reducing the cancer more than 50%. It is a very surprising effect that cancer reaches complete remission, and the increase of the rate of complete remission suggests that the combination of these drugs is very beneficial.
These results suggest that the anti-cancer effect of 3-agent combination therapy of the compound of the chemical formula 1,bortezomib and dexamethasone is very exceptional.
<Example 2: Confirmation of anti-cancer effect of the combination of the present invention using lenalidomide as the second active ingredient, in MM.1s xenograft model>
2-1) Experimental method
a. Preparation of animal tumor model
MM.1s which is a human multiple myeloma cell line was purchased from ATCC (USA). MM.1s cell line was maintained with RPMI1640 (Gibco, USA) containing 10% fetal bovine serum (FBS; Gibco, Grand Island, NY, USA).
After MM.1s cells which were mixed with matrigel were subcutaneously administered into NOD.CB17-Prkdcscid/NCrHsd male mouse (2x107 cell/head) to organize groups to uniformly distribute the tumor size and then used in the experiment.
b. Preparation of active ingredients
The compound of the chemical formula 1 was prepared in the concentration of 6 mg/ml by dissolving with physiological saline solution.
Lenalidomide was prepared in the concentration of 1 mg/ml by dissolving with 1% HCl in PBS, and then titrating to a neutral pH.
Dexamethasone was prepared in the concentration of 0.2 mg/ml by diluting 5 mg/ml dexamethasone with saline.
The using solution was prepared on the day of use, and the remaining solution was discarded.
c. Confirmation of anti-tumor activity
The anti-cancer effect of the compound of the chemical formula 1 and lenalidomide and dexamethasone was evaluated in MM.1s xenograft model. The experimental groups were divided to the following different administration groups.
- control group : vehicle
- group administering only the compound of the chemical formula 1 : the compound of the chemical formula 1 (60 mg/kg, once a week, injection)
- coadministration group of lenalidomide and dexamethasone : lenalidomide (10 mg/kg, once a day, injection), dexamethasone (2 mg/kg, once a week, injection)
- coadministration group : the compound of the chemical formula 1 (60 mg/kg, once a week, injection), lenalidomide (10 mg/kg, once a day, injection), dexamethasone (2 mg/kg, once a week, injection)
All experimental groups were administered intraperitoneally for 70 days. The toxicity was monitored by measuring mouse weight, and the tumor growth was measured by using caliper during the experiment. The tumor volume was calculated according to the mathematical equation 1 in Example 1.
d. Statistical analysis
For all the results of the present experiment, the comparison between experimental groups was performed by assuming normality of the data through parametric multiple comparison or nonparametric multiple comparison, and statistical analysis was performed by using Prism 5.03 (GraphPad Software Inc., San Diego, CA, USA), and the case where p value was below 0.05 was considered statistically significant.
2-2) Experimental result
In order to evaluate anti-tumor effect by coadministration of the compound of the chemical formula 1 and lenalidomide, dexamethasone, each substance was administered into xenograft mouse, and the weight and tumor growth were monitored for 70 days.
In an aspect of tumor growth inhibiting effect, comparing the tumor sizes of group administering the compound of the chemical formula 1 and coadministration group of lenalidomide and dexamethasone, and coadministration group of the compound of the chemical formula 1+ lenalidomide+dexamethasone to a group administering an excipient during administration period, the tumor growth was highly inhibited.
In the coadministration group of lenalidomide and dexamethasone, there was a slight increase in the size of the first cancer, while in the coadministration group of the compound of the chemical formula 1+ lenalidomide+dexamethasone, most of the mice had an effect of reducing the cancer including complete remission.
These results suggest that the anti-cancer effect of 3-agent coadministration therapy of the compound of the chemical formula 1 and lenalidomide, dexamethasone is very high.

Claims (13)

  1. A combination for treating a hematological cancer comprising,
    1) a compound of the following chemical formula 1 or its pharmaceutically acceptable salt as the first active ingredient;
    2) a proteasome inhibitor or an immunomodulatory drug as the second active ingredient; and
    3) a steroidal anti-cancer agent as the third active ingredient:
    Figure PCTKR2017011015-appb-I000005
    .
  2. The combination of claim 1, wherein the proteasome inhibitor is bortezomib of the following chemical formula 2 or its pharmaceutically acceptable salt:
    [Chemical formula 2]
    Figure PCTKR2017011015-appb-I000006
    .
  3. The combination of claim 1, wherein the immunomodulatory drug is lenalidomide of the following chemical formula 3 or its pharmaceutically acceptable salt:
    [Chemical formula 3]
    Figure PCTKR2017011015-appb-I000007
    .
  4. The combination of claim 1, wherein the steroidal anti-cancer agent is dexamethasone of the following chemical formula 4 or its pharmaceutically acceptable salt:
    [Chemical formula 4]
    .
    Figure PCTKR2017011015-appb-I000008
  5. The combination of claim 1, wherein the pharmaceutically acceptable salt of the compound of the chemical formula 1 is methanesulfonate.
  6. The combination of claim 3, wherein the lenalidomide is lenalidomide free base.
  7. The combination of claim 1, wherein the second active ingredient is a proteasome inhibitor, and the first active ingredient, the second active ingredient, and the third active ingredient are comprised in an amount of 28.55~85.60 parts by weight of the first active ingredient, 1.28~8.63 parts by weight of the second active ingredient, and 2.71~69.55 parts by weight of the third active ingredient, per 100 parts by weight of the total pharmaceutical combination.
  8. The combination of claim 1, wherein the second active ingredient is an immunomodulatory drug, and the first active ingredient, the second active ingredient, and the third active ingredient are comprised in an amount of 19.54~94.69 parts by weight of the first active ingredient, 2.46~52.63 parts by weight of the second active ingredient, and 2.52~59.70 parts by weight of the third active ingredient, per 100 parts by weight of the total pharmaceutical combination.
  9. The combination of claim 1, wherein the hematological cancer is multiple myeloma.
  10. The combination of claim 1, wherein the first active ingredient, the second active ingredient, and the third active ingredient are comprised in the form of separate formulations respectively.
  11. The combination of claim 1, wherein the first active ingredient, the second active ingredient, and the third active ingredient are combined and comprised in the form of a single formulation.
  12. The combination of claim 10, wherein the first active ingredient and the second active ingredient are comprised as a formulation in a parenteral administration form, and the third active ingredient is comprised as a formulation in an oral administration form.
  13. The combination of claim 10 or claim 12, wherein the formulation comprising the first active ingredient and the formulation comprising the second active ingredient, and the formulation comprising the third active ingredient of the combination are in the form of a formulation that can be administered simultaneously or sequentially.
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CN109789138A (en) 2019-05-21
ZA201902340B (en) 2020-08-26
KR20180037507A (en) 2018-04-12
EP3522891A4 (en) 2020-04-15
MX2019003907A (en) 2019-08-05
BR112019006633A2 (en) 2019-07-02

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