WO2018158225A1 - Combinaison d'un inhibiteur de bcl-2 et d'un inhibiteur de mcl-2, utilisations et compositions pharmaceutiques associées - Google Patents

Combinaison d'un inhibiteur de bcl-2 et d'un inhibiteur de mcl-2, utilisations et compositions pharmaceutiques associées Download PDF

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WO2018158225A1
WO2018158225A1 PCT/EP2018/054764 EP2018054764W WO2018158225A1 WO 2018158225 A1 WO2018158225 A1 WO 2018158225A1 EP 2018054764 W EP2018054764 W EP 2018054764W WO 2018158225 A1 WO2018158225 A1 WO 2018158225A1
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group
compound
branched
linear
combination
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Ensar HALILOVIC
Youzhen Wang
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Les Laboratoires Servier
Novartis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • 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

Definitions

  • the present invention relates to a combination of a Bcl-2 inhibitor and a Mdm2 inhibitor, as defined below.
  • the invention also relates to said combination for use in the treatment of cancer, in particular acute myeloid leukaemia, and a pharmaceutical formulation suitable for the administration of such combination.
  • the Bcl-2 inhibitor is a compound of formula (I) as described herein.
  • Said compounds of formula (I), their synthesis, their use in the treatment of cancer and pharmaceutical formulations thereof, are described in WO 2013/110890, WO 2015/011397, WO 2015/011399 and WO 2015/011400, the content of which is incorporated by reference.
  • the Bcl-2 inhibitor is Compound 1 : N-(4-hydroxyphenyl)-3- ⁇ 6-[((35)-3-(4- morpholinylmethyl)-3,4-dihydro-2(lH)-isoquinolinyl)carbonyl]-l,3-benzodioxol-5-yl ⁇ -N- phenyl-5,6,7,8-tetrahydro-l-indolizine carboxamide, or a pharmaceutically acceptable salt thereof.
  • Said Compound 1, its synthesis, its use in the treatment of cancer and pharmaceutical formulations thereof, are described in WO 2013/110890.
  • Compound 1 is a potent and selective Bcl-2 inhibitor which is specifically disclosed in Example 1 of WO 2013/110890, which is incorporated by reference.
  • the Mdm2 inhibitor of the combination of the invention is Compound 2: (S)-5-(5-Chloro- 1 -methyl-2-oxo- 1 ,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy- pyrimidin-5-yl)-l-isopropyl-5,6-dihydro-lH-pyrrolo[3,4-(i]imidazol-4-one
  • Apoptosis is a distinct cell death pathway that is highly regulated and initiated by various stimuli including DNA damage; however evasion of the programmed cell death is a hallmark of cancer.
  • the efficacy of many chemotherapeutic agents is dependent upon the activation of the intrinsic mitochondrial pathway which is mainly regulated by B-cell like protein-2 (Bcl-2).
  • Bcl-2 has been shown to be up-regulated in many cancers, particularly hematological malignancies such as mantle cell lymphoma (MCL) and follicular lymphoma/diffuse large B-cell lymphoma (FL/D) (Adams and Cory The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 2007 Vol 26: 1324-1337).
  • AML Acute myeloid leukaemia
  • AML is a rapidly fatal blood cancer arising from clonal transformation of hematopoietic stem cells resulting in paralysis of normal bone marrow function and deaths due to complications from profound pancytopenia.
  • AML accounts for 25% of all adult leukaemias, with the highest incidence rates occurring in the United States, Australia and Europe (WHO. GLOBOCAN 2012. Estimated cancer incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer). Globally, there are approximately 88,000 new cases diagnosed annually.
  • AML continues to have the lowest survival rate of all leukaemias, with expected 5-year survival of only 24%.
  • ⁇ X and Y represent a carbon atom or a nitrogen atom, it being understood that they may not simultaneously represent two carbons atoms or two nitrogen atoms,
  • ⁇ Ai and A 2 together with the atoms carrying them, form an optionally substituted, aromatic or non-aromatic heterocycle Het composed of 5, 6 or 7 ring members which may contain, in addition to the nitrogen represented by X or by Y, from one to 3 hetero atoms selected independently from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (Ci-C 6 )alkyl group or a group -C(0)-0-Alk wherein Alk is a linear or branched (Ci-Ce)alkyl group,
  • Ai and A 2 independently of one another represent a hydrogen atom, a linear or branched (Ci-C 6 )polyhaloalkyl, a linear or branched (Ci-Ce)alkyl group or a cycloalkyl,
  • ⁇ T represents a hydrogen atom, a linear or branched (Ci-Ce)alkyl group optionally substituted by from one to three halogen atoms, a group (Ci-C 4 )alkylene-NRiR 2 , or a group (Ci-C4)alkylene-OR6,
  • ⁇ Ri and R 2 independently of one another represent a hydrogen atom or a linear or branched (Ci-Ce)alkyl group
  • Ri and R 2 form with the nitrogen atom carrying them a heterocycloalkyl
  • R 3 represents a linear or branched (Ci-Ce)alkyl group, a linear or branched (C 2 -C 6 )alkenyl group, a linear or branched (C 2 -C 6 )alkynyl group, a cycloalkyl group, a (C 3 -Cio)cycloalkyl-(Ci-C 6 )alkylene group wherein the alkyl moiety is linear or branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, it being understood that one or more of the carbon atoms of the preceding groups, or of their possible substituents, may be deuterated,
  • ⁇ R4 represents an aryl group, a heteroaryl group, a cycloalkyl group or a linear or branched (Ci-Ce)alkyl group, it being understood that one or more of the carbon atoms of the preceding groups, or of their possible substituents, may be deuterated,
  • ⁇ R 5 represents a hydrogen or halogen atom, a linear or branched (Ci-Ce)alkyl group, or a linear or branched (Ci-Ce)alkoxy group,
  • ⁇ 5 represents a hydrogen atom or a linear or branched (Ci-Ce)alkyl group
  • R a , R b , R c and Rj each independently of the others, represent R 7 , a halogen atom, a linear or branched (Ci-C 6 )alkoxy group, a hydroxy group, a linear or branched (Ci-C 6 )polyhaloalkyl group, a trifluoromethoxy group, -NR 7 R 7 ', nitro, R 7 -CO-(C 0 -C 6 )alkylene-, R 7 -CO-NH-(C 0 -C 6 )alkylene-, NR 7 R 7 * -CO-(C 0 - C 6 )alkylene-, NR 7 R 7 * -CO-(C 0 -C 6 )alkylene-O-, R 7 -SO 2 -NH-(C 0 -C 6 )alkylene-, R 7 -NH-CO-NH-(C 0 -C 6 )alkylene-, R
  • R 7 and R 7 ' independently of one another represent a hydrogen, a linear or branched
  • (Ci-C 6 )alkyl a linear or branched (C 2 -C6)alkenyl, a linear or branched (C 2 -C 6 )alkynyl, an aryl or a heteroaryl, or R 7 and R 7 ' together with nitrogen atom carrying them form a heterocycle composed of from 5 to 7 ring members, it being understood that when the compound of formula (I) contains a hydroxy group, the latter may be optionally converted into one of the following groups: -OPO(OM)(OM'), -OPO(OM)(0 " Mi + ), -OPO(0 " Mi + )(0 " M 2 + ), -OPO(0 " )(0 " )M 3 2+ ,
  • M and M' independently of one another represent a hydrogen atom, a linear or branched (Ci-Ce)alkyl group, a linear or branched (C 2 -Ce)alkenyl group, a linear or branched (C 2 -Ce)alkynyl group, a cycloalkyl or a heterocycloalkyl, both composed of from 5 to 6 ring members, while Mi + and M 2 + independently of one another represent a pharmaceutically acceptable monovalent cation, M 3 2+ represents a pharmaceutically acceptable divalent cation, and n is an integer from 1 to 5,
  • aryl means a phenyl, naphthyl, biphenyl or indenyl group
  • heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 4 hetero atoms selected from oxygen, sulphur and nitrogen (including quaternary nitrogens),
  • cycloalkyl means any mono- or bi-cyclic, non-aromatic, carbocyclic group containing from 3 to 10 ring members,
  • heterocycloalkyl means any mono- or bi-cyclic, non-aromatic, condensed or spiro group composed of 3 to 10 ring members and containing from 1 to 3 hetero atoms selected from oxygen, sulphur, SO, S0 2 and nitrogen,
  • -(Co-C 6 )alkylene- refers either to a covalent bond (-Coalkylene-) or to an alkylene group containing 1 , 2, 3, 4, 5 or 6 carbon atoms, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the groups alkyl, alkenyl, alkynyl and alkoxy to be substituted by from 1 to 3 groups selected from: linear or branched (Ci-Ce)alkyl optionally substituted by a hydroxyl, a morpholine, 3-3-difluoropiperidine or a 3-3-difluoropyrrolidine; (C3-Ce)spiro; linear or branched (Ci-Ce)alkoxy optionally substituted by a morpholine; (Ci-C 6 )alkyl-S-; hydroxyl; oxo; N-oxide; nitro; cyano; -COOR';
  • a Bcl-2 inhibitor Compound 1 N-(4-hydroxyphenyl)-3- ⁇ 6-[((35)-3-(4- morpholinylmethyl)-3,4-dihydro-2(lH)-isoquinolinyl)carbonyl]-l,3-benzodioxol-5-yl ⁇ -N- phenyl-5,6,7,8-tetrahydro-l-indolizine carboxamide, or a pharmaceutically acceptable salt thereof,
  • the invention provides a combination as described herein, for use in the treatment of cancer, in particular acute myeloid leukaemia.
  • the invention provides a pharmaceutical composition comprising the combination as described herein, and at least one pharmaceutically acceptable carrier.
  • Figure 1 shows the anti-tumor effect in Acute Myeloid Leukaemia Xenograft Model 7781HAMLX5340-XEF.
  • Figure 2 shows the anti-tumor effect in Acute Myeloid Leukaemia Xenograft Model 7560HAMLX5343-XEF.
  • Figure 3 shows the body weight changes in Acute Myeloid Leukaemia Xenograft Model 7781HAMLX5340-XEF.
  • Figure 4 shows the body weight changes in Acute Myeloid Leukaemia Xenograft Model 7560HAMLX5343-XEF.
  • Combination refers to either a fixed dose combination in one unit dosage form (e.g., capsule, tablet, or sachet), non-fixed dose combination, or a kit of parts for the combined administration where a compound of the present invention and one or more combination partners (e.g. another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
  • a combination partners e.g. another drug as explained below, also referred to as "therapeutic agent” or "co-agent”
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • fixed dose combination means that the active ingredients, e.g. a compound of formula (I) and one or more combination partners, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed dose combination means that the active ingredients, e.g. a compound of the present invention and one or more combination partners, are both administered to a patient as separate entities either simultaneously or sequentially, with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • Cancer means a class of disease in which a group of cells display uncontrolled growth. Cancer types include haemato logical cancer (lymphoma and leukaemia). In particular “cancer” refers to haematological cancer, in particular acute myeloid leukaemia.
  • 'AML' means acute myeloid leukaemia.
  • joint therapeutically effective means that the therapeutic agents may be given separately (in a chronologically staggered manner, especially a sequence-specific manner) in such time intervals that they prefer, in the warm-blooded animal, especially human, to be treated, still show a (preferably synergistic) interaction (joint therapeutic effect). Whether this is the case can, inter alia, be determined by following the blood levels, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals.
  • “Synergistically effective” or “synergy” means that the therapeutic effect observed following administration of two or more agents is greater than the sum of the therapeutic effects observed following the administration of each single agent.
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • a subject is "in need of a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • “Medicament” means a pharmaceutical composition, or a combination of several pharmaceutical compositions, which contains one or more active ingredients in the presence of one or more excipients.
  • El l The combination according to any of El to El 0, for use in medicine.
  • El 2. The combination for use according to El l, wherein said use is in the treatment of cancer.
  • E15 The combination for use according to El 4, wherein the acute myeloid leukaemia comprises one or more of FLT3-ITD mutation.
  • E16 The combination for use according to E14, wherein the acute myeloid leukaemia carries one or more of KRAS mutation and wild type FLT3.
  • El 7. The combination for use according to any of El l to El 6, wherein Compound 1 and Compound 2 are provided in amounts which are jointly therapeutically effective for the treatment of cancer.
  • El 8. The combination for use according to any of El l to El 6, wherein Compound 1 and Compound 2 are provided in amounts which are synergistically effective for the treatment of cancer.
  • E20 A pharmaceutical composition comprising the combination according to any of El to E8, and at least one pharmaceutically acceptable carrier.
  • E22 The use according to E21, wherein the cancer is acute myeloid leukaemia.
  • E23 The use according to E22, wherein the acute myeloid leukaemia comprises one or more of FLT3-ITD mutation.
  • E24 The use according to E22, wherein the acute myeloid leukaemia carries one or more of KRAS mutation and wild type FLT3.
  • Compound 2 as disclosed herein can be in the form of a pharmaceutically acceptable salt, a complex, a co-crystal, a solvate (including hydrate), or a mixture of such forms.
  • Compound 2 can be in the form of a pharmaceutically acceptable salt, a solvate (including hydrate), or co-crystal thereof.
  • Co-crystals of Compound 2 may be formed with acids such as succinic acid, lactic acid, tartaric acid and malonic acid.
  • Solvates may be formed with solvents such as ethanol, propanol, butanol or water.
  • the solvate of Compound 2 is ethanolate or hydrate.
  • Compound 2 is the free molecule. In another embodiment, Compound 2 is a co-crystal. In a particular embodiment, Compound 2 is the succinic acid. In particular, when Compound 2 is the succinic acid, it is the succinic acid co-crystal. In a further embodiment, Compound 2 is the hydrate.
  • the proportion of active ingredients by weight is from 5 to 50 %.
  • compositions according to the invention there will be more especially used those which are suitable for administration by the oral, parenteral and especially intravenous, per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory route, more specifically tablets, dragees, sublingual tablets, hard gelatin capsules, glossettes, capsules, lozenges, injectable preparations, aerosols, eye or nose drops, suppositories, creams, ointments, dermal gels etc.
  • the pharmaceutical compositions according to the invention comprise one or more excipients or carriers selected from diluents, lubricants, binders, disintegration agents, stabilisers, preservatives, absorbents, colourants, sweeteners, flavourings etc.
  • binders magnesium aluminium silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone,
  • ⁇ as disintegrants agar, alginic acid and its sodium salt, effervescent mixtures.
  • the compounds of the combination may be administered simultaneously, separately or sequentially.
  • the administration route is preferably the oral route, and the corresponding pharmaceutical compositions may allow the instantaneous or delayed release of the active ingredients.
  • the compounds of the combination may moreover be administered in the form of two separate pharmaceutical compositions, each containing one of the active ingredients, or in the form of a single pharmaceutical composition, in which the active ingredients are in admixture.
  • the pharmaceutical composition of Compound 1 is a tablet.
  • the dose of N-(4-hydroxyphenyl)-3- ⁇ 6-[((35)-3-(4-morpholinylmethyl)-3,4-dihydro- 2(lH)-isoquinolinyl)carbonyl]-l,3-benzodioxol-5-yl ⁇ -N-phenyl-5,6,7,8-tetrahydro-l- indolizine carboxamide during the combination treatment is from 50 mg to 1500 mg.
  • N-(4-hydroxyphenyl)-3- ⁇ 6-[((35)-3-(4-morpholinylmethyl)-3,4-dihydro-2(lH)- isoquinolinyl)carbonyl]- 1 ,3-benzodioxol-5-yl ⁇ -N-phenyl-5,6,7,8-tetrahydro- 1 -indolizine carboxamide is administered during the combination treatment once a day.
  • Compound 2 may be administered orally.
  • oral administration is by solid form.
  • the oral administration may use a high-dose intermittent regimen [e.g.
  • Regimen A 50 mg - 400 mg Compound 2 administered on day 1 of a 3-week cycle or Regimen B (50 mg - 150 mg Compound 2 administered on days 1 and 8 of a 4-wk cycle) or regimen C (50 mg - 500 mg Compound 2 administered on day 1 of a 4-week cycle], or a low-dose extended regimen [e.g. Regimen D (10 mg - 30 mg Compound 2 once daily for the first 2 weeks of a 4-week cycle) or Regimen E (15 mg - 50 mg Compound 2 once daily for the first week of a 4-week cycle)].
  • Regimen D 10 mg - 30 mg Compound 2 once daily for the first 2 weeks of a 4-week cycle
  • Regimen E 15 mg - 50 mg Compound 2 once daily for the first week of a 4-week cycle
  • composition of Compound 1 HCl salt film-coated tablet containing 50 mg and 100 mg of drug substance
  • the drug product may consist of the drug substance compound 2 succinic acid filled directly into hard gelatin capsules (HGC), and may not need to contain any other excipients.
  • the capsule filling may be done manually.
  • the drug product may be provided in four dosage strengths: 1 mg, 2.5 mg, 10 mg and 100 mg (based on the weight of the free form), intended for oral use.
  • the 1 mg strength capsule may be a "Size 3" yellow HGC
  • the 2.5 mg strength capsule may be a "Size 3" Swedish Orange HGC
  • the 10 mg strength capsule may be a "Size 1" Grey HGC
  • the 100 mg may be a "Size 0" Swedish Orange HGC.
  • the drug product may be packaged in child resistant, induction sealed High Density Polyethylene (HDPE) bottles.
  • HDPE High Density Polyethylene
  • NOD scid gamma NSG female mice weighing 17-27 grams (Jackson Laboratories) were allowed to acclimate in an animal facility with access to food and water ad libitum for 3 days prior to manipulation.
  • Compound 2 succinic acid was formulated in 0.5% methylcellulose.
  • Compound 1 HC1 salt was formulated in PEG300/EtOH/water (40/10/50). Vehicle and compound dosing solutions were prepared as needed. All animals were dosed at 10 mL/kg.
  • Compound 2 and Compound 1 were administered by oral gavage (po) at 40 mg/kg with 3 consecutive doses (3 hour interval between each dose) once a week and 200 mg/kg once a week, respectively, for 14 days.
  • Both drugs were administered at 10 mL/kg. Animals were weighed daily and the dose was body weight adjusted. Bodyweights were recorded twice/week and tumor burden was recorded once/week.
  • mice were implanted with primary AML line HAMLX5340 or HAMLX5343. Mice were injected intravenously with 2.0 million leukemia cells. When the tumor burden was between 5%-30%, animals were randomized into four groups of four or five mice each for vehicle, Compound 2, Compound 1, or combination treatment. After 14-22 days of treatment, the study was terminated when the tumor burden reached 80- 100% or when excessive bodyweight loss would result in the loss of the majority of the animals in one group. Tumor burden was measured by FACS analysis.
  • mice Animal well-being and behavior, including grooming and ambulation were monitored twice daily. General health of mice was monitored and mortality recorded daily. Any moribund animals were sacrificed.
  • mice were bled via tail snip once per week.
  • Blood was split into an IgG control well and a CD33/CD45 well of a 96-well plate. Blood was lysed with 200 ⁇ 1 RBC lysis buffer (eBioscience # 00-4333-57) twice at RT, then washed once with FACS buffer (5% FBS in PBS). Samples were then incubated for 10-30 minutes at 4C in ⁇ blocking buffer (5% mouse Fc Block [Miltenyi #130-092-575] + 5% human Fc Block [Miltenyi #130-059-091] + 90% FACS buffer).
  • ⁇ blocking buffer 5% mouse Fc Block [Miltenyi #130-092-575] + 5% human Fc Block [Miltenyi #130-059-091] + 90% FACS buffer.
  • T/C Percent treatment/control
  • T mean tumor burden of the drug-treated group on the final day of the study
  • ⁇ mean tumor burden of the drug-treated group on the final day of the study - mean tumor burden of the drug-treated group on initial day of dosing;
  • i b i al mean tumor burden of the drug-treated group on initial day of dosing
  • AC mean tumor burden of the control group on the final day of the study - mean tumor burden of the control group on initial day of dosing.
  • the mean tumor burden for each treatment group is plotted against time for the 22 day treatment period, as shown in Figure 1.
  • the change in tumor burden, %T/C or %Regression is presented in Table 4.
  • the mean body weight (BW) change is shown in Figure 3. All treatments were well tolerated. Mice treated with Compound 1 and Compound 2 exhibited body weight gain (1.27% and 2.81%, respectively). A minimal body weight loss was observed with combination treatment (- 1.52%).
  • Figure 1 shows anti-tumor activity in 7781HAMLX5340-XEF study.
  • Figure 2 shows anti-tumor activity in 7560HAMLX5343-XEF study.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une combinaison comprenant un composé inhibiteur de Bcl-2 de formule (I) : ou un énantiomère, un diastéréoisomère ou un sel d'addition de celui-ci avec un acide ou une base pharmaceutiquement acceptables, et un composé inhibiteur de Mdm2 : (S)-5-(5-chloro-1-méthyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phényl)-2-(2,4-diméthoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one, ou un sel pharmaceutiquement acceptable de celui-ci, ou un complexe de ceux-ci, ou un co-cristal de celui-ci, ou un solvate, comprenant un hydrate, de celui-ci et des compositions et des utilisations de ladite combinaison.
PCT/EP2018/054764 2017-02-28 2018-02-27 Combinaison d'un inhibiteur de bcl-2 et d'un inhibiteur de mcl-2, utilisations et compositions pharmaceutiques associées WO2018158225A1 (fr)

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WO2019161221A3 (fr) * 2018-02-16 2019-11-07 Abbvie Inc. Inhibiteurs sélectifs de bcl-2 en association avec un anticorps anti-pd-1 ou anti-pd-l1 pour le traitement de cancers
WO2020128894A1 (fr) * 2018-12-20 2020-06-25 Novartis Ag Combinaisons d'inhibiteur d'interaction hdm2-p53 et d'inhibiteur de bcl2 et leur utilisation dans le traitement du cancer
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11419870B2 (en) 2014-06-26 2022-08-23 Novartis Ag Intermittent dosing of MDM2 inhibitor
WO2019161221A3 (fr) * 2018-02-16 2019-11-07 Abbvie Inc. Inhibiteurs sélectifs de bcl-2 en association avec un anticorps anti-pd-1 ou anti-pd-l1 pour le traitement de cancers
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2020128894A1 (fr) * 2018-12-20 2020-06-25 Novartis Ag Combinaisons d'inhibiteur d'interaction hdm2-p53 et d'inhibiteur de bcl2 et leur utilisation dans le traitement du cancer
RU2793123C2 (ru) * 2018-12-20 2023-03-29 Новартис Аг Комбинации ингибитора взаимодействия hdm2-p53 и ингибитора bcl2 и их применение для лечения рака
EP3897647B1 (fr) 2018-12-20 2023-11-01 Novartis AG Combinaisons d'inhibiteur d'interaction hdm2-p53 et d'inhibiteur de bcl2 et leur utilisation dans le traitement du cancer
EP4249513A3 (fr) * 2018-12-20 2023-12-20 Novartis AG Combinaisons pharmaceutiques

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