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
  • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • 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
  • 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

• FIG. 1 A is a graph depicting efficacy of Compound 1 in the HEL xenograft model, tumor volume (mm 3 ) vs. days post inoculation.
• FIG. IB is a graph depicting tolerability of Compound 1 in the HEL xenograft model, tumor corrected body weight change (%) vs. days post inoculation.
• FIG. 2A is a graph depicting efficacy of the combination of Compound 1 and ruxolitinib in the SET-2 model, tumor volume (mm 3 ) vs. days post inoculation.
• FIG. 2B is a graph depicting tolerability of the combination of Compound 1 and ruxolitinib in the SET -2 model, tumor corrected body weight change (%) vs. days post inoculation.
• FIG. 3 A is a graph depicting efficacy of the combination of Compound 1 and ruxolitinib in the SET-2 model, tumor volume (mm 3 ) vs. days post inoculation.
• FIG. 4A is a graph depicting spleen weight and white blood cell counts as measures of efficacy of Compound 1 and ruxolitinib in the MPLW515L mouse model of MPN.
• FIG. 4B is a graph depicting spleen weight and white blood cell counts as measures of efficacy of Compound 1 and ruxolitinib in the MPLW515L mouse model of MPN.
• FIG. 5 is a table (Table 3) depicting a summary of Compound 1 pharmacokinetic parameters for Compound 1 as monotherapy (part 1 and 2) at steady-state (cycle 1 day 8).
• FIG. 6 is a graph depicting inhibition of cMyc protein expression in the pharmacodynamics spiked cell assay versus plasma levels of Compound 1.
• FIG. 7 is a graph depicting Compound 1 steady-state plasma concentrations (mean ⁇ se) in participants following once daily dosing of Compound 1 as monotherapy.
• FIG. 8 is a graph depicting probability of response (hyperglycemia) versus Compound 1 steady-state AUC following once daily dosing of Compound 1 as monotherapy.
• the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).
• solid form refers to a compound provided herein in either an amorphous state or a crystalline state (“crystalline form” or “crystalline solid” or “crystalline solid form”), whereby a compound provided herein in a crystalline state may optionally include solvent or water within the crystalline lattice, for example, to form a solvated or hydrated crystalline form.
• hydrated is meant to refer to a crystalline form that includes water molecules in the crystalline lattice.
• Example “hydrated” crystalline forms include hemihydrates, monohydrates, dihydrates, and the like. Other hydrated forms such as channel hydrates and the like are also included within the meaning of the term.
• the present invention relates to the use of a JAK1/JAK2 inhibitor, ruxolitinib, in combination with a BET protein inhibitor for treatment of a myeloproliferative neoplasm.
• Ruxolitinib (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yljpropanenitrile, is an inhibitor of JAK1 and JAK2.
• the IC50 of ruxolitinib was measured by Assay A infra at 1 mM ATP and found to be less than 10 nM at JAK1 and JAK2.
• the present application provides a method of treating a myeloproliferative neoplasm in a patient in need thereof, comprising administering to said patient 2,2,4-trimethyl-8-(6- methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-l,4- benzoxazin-3(4H)-one (Compound 1 below) is an inhibitor of BET proteins such as BRD2, BRD3, BRD4, and BRD-t. Compound 1 can be prepared as described in US Patent 9,540,368 or US Patent 10,189,832, each of which is incorporated herein by reference in its entirety.
• the present application provides a method of treating a myeloproliferative neoplasm in a patient in need thereof, comprising administering to said patient 2,2,4-trimethyl-8-(6- methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-l,4- benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof, and ruxolitinib, or a pharmaceutically acceptable salt thereof.
• Administering a combination of Compound 1 and ruxolitinib can provide an enhanced efficacy.
• combination of Compound 1 and ruxolitinib showed enhanced efficacy in in vivo models and significantly (p ⁇ 0.05) more efficacious than either ruxolitinib alone or Compound 1 alone. That is, the combination of ruxolitinib and Compound 1 provides efficacy better than the sum of the parts.
• the present application further provides a method of treating a myeloproliferative neoplasm in a patient in need thereof, comprising administering to said patient 2,2,4- trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)- 2H-l,4-benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of ruxolitinib, or a pharmaceutically acceptable salt thereof.
• the present application further provides a method of treating a myeloproliferative neoplasm in a patient in need thereof, comprising administering to said patient a dose from about 2 mg/day to about 20 mg/day on a free base basis of 2,2,4-trimethyl-8-(6-methyl-7- oxo-6, 7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-l,4-benzoxazin- 3(4H)-one, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of ruxolitinib, or a pharmaceutically acceptable salt thereof.
• the dose of 2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-l,4-benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof is about 2 mg/day to about 18 mg/day on a free base basis.
• the dose of 2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-6- (methylsulfonyl)-2H-l,4-benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof is about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 18, or about 20 mg/day on a free base basis.
• the dose of 2,2,4- trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)- 2H-l,4-benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof is about 2, about 4, about 6, about 8, about 10, or about 12 mg per day on a free base basis.
• the dose of 2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridin-4-yl)-6-(methylsulfonyl)-2H-l,4-benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof is about 4, about 6, or about 8 mg per day on a free base basis.
• the dose of 2,2, 4-trimethyl-8-(6-methyl-7-oxo-6, 7-dihydro- 1H- pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-l,4-benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof is about 8, about 10, about 12, about 14, or about 16 mg per day on a free base basis.
• the dose of 2,2,4-trimethyl-8-(6- methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-l,4- benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof is about 10, about 12, about 14, about 16 mg, or about 18 mg per day on a free base basis.
• the dose of 2,2,4- trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)- 2H-l,4-benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof is about 4 mg per day on a free base basis.
• the dose of 2,2,4-trimethyl-8-(6-methyl- 7-oxo-6, 7-dihydro- lH-pyrrolo[2, 3-c]pyri din-4-yl)-6-(methylsulfonyl)-2H-l, 4-benzoxazin- 3(4H)-one, or a pharmaceutically acceptable salt thereof is about 6 mg per day on a free base basis.
• the dose of 2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-l,4-benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof is about 8 mg per day on a free base basis.
• the dose of 2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridin-4-yl)-6-(methylsulfonyl)-2H-l,4-benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof is about 10 mg per day on a free base basis.
• the dose of 2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-6- (methylsulfonyl)-2H-l,4-benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof is about 12 mg per day on a free base basis.
• 2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-l,4-benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof, and ruxolitinib, or a pharmaceutically acceptable salt thereof are administered once daily (QD).
• the dose of ruxolitinib, or a pharmaceutically acceptable salt thereof is about 5 mg/day to about 60 mg/day on a free base basis.
• the dose of ruxolitinib, or a pharmaceutically acceptable salt thereof is about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or 60 mg/day on a free base basis.
• the dose of ruxolitinib, or a pharmaceutically acceptable salt thereof is about 2.5 mg BID to about 30 mg BID on a free base basis.
• the dose of ruxolitinib, or a pharmaceutically acceptable salt thereof is about 2.5, about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, about 20, about 25, or about 30 mg BID on a free base basis.
• the pharmaceutically acceptable salt of ruxolitinib is ruxolitinib phosphate.
• 2,2,4-trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-l,4-benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof is selected from the phosphoric acid salt, dihydrochlorlic acid salt, hydrochloric acid salt, maleic acid salt, adipic acid salt, hydrobromic acid salt, (R)-(-)-mandelic acid salt, salicylic acid salt, benzoic acid salt, benzenesulfonic acid salt, L-pyroglutamic acid salt, methanesulfonic acid salt, (lS)-(+)-10- camphorsulfonic acid salt, fumaric acid salt, sulfuric acid salt, L-tartaric acid salt, and D- tartaric acid salt of 2,2,4-trimethyl-8-(6-methyl-7-ox
• 2,2,4- trimethyl-8-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)- 2H-l,4-benzoxazin-3(4H)-one is a free base.
• the crystalline solid forms of Compound 1 can include solvent such as water (e.g., a hydrated form) or be substantially free of water and solvent (e.g., forming an anhydrate). In some embodiments, the crystalline solid form is an anhydrate. In further embodiments, the crystalline solid form is hydrated.
• Compound 1 can be obtained in a solid crystalline form referred to as Form I, Form II, Form III, Form IV, Form V, Form Va, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, and Form X, which are described in US Patent No. 10,626,114, which is incorporated herein by reference in its entirety.
• Form II is an anhydrate.
• Form II is characterized by its XRPD pattern and other solid state characteristics.
• Form II has one or more characteristic XRPD peaks, in terms of 2-theta, selected from about about 6.7, about
• Form III has one or more characteristic XRPD peaks, in terms of 2-theta, selected from about 7.8, about 12.4, about 13.1, about 15.2, about 15.5, about 16.9, about 17.5, and about 20.3 degrees.
• Form IV has one or more characteristic XRPD peaks, in terms of 2-theta, selected from about 11.2, about 16.3, about 18.7, and about 22.1 degrees.
• Form VI has one or more characteristic XRPD peaks, in terms of 2-theta, selected from about 8.5, about 9.6, about 11.4, about 12.1, about 13.5, about 14.5, about 15.2, about 17.1, about 17.7, about 18.1, about 19.2, and about 20.7 degrees.
• Form VII has one or more characteristic XRPD peaks, in terms of 2-theta, selected from about 9.9, about 12.2, about 14.8, about 15.7, about 17.0, about 17.5, and about 18.8 degrees.
• Form VIII has one or more characteristic XRPD peaks, in terms of 2-theta, selected from about 8.1, about 8.5, about 16.2, about 16.6, about 17.0, about
• Form IX has one or more characteristic XRPD peaks, in terms of 2-theta, selected from about 8.6, about 9.1, about 11.4, about 13.4, about 15.2, about 18.2, about 22.1, about 22.8, and about 23.9 degrees.
• Form X has one or more characteristic XRPD peaks, in terms of 2-theta, selected from about 14.9, about 15.3, about 15.8, about 17.0, about 17.7, about
• Form XI has one or more characteristic XRPD peaks, in terms of 2-theta, selected from about 8.9, about 12.8, about 18.0 about 21.5, about 22.6, and about 23.3 degrees.
• Form XII has one or more characteristic XRPD peaks, in terms of 2-theta, selected from about 5.6, about 11.7, about 13.8, about 14.5, about 16.9, about 17.7, about 18.7, about 23.5, about 24.6, about 34.3, about 44.2, and 44.6 degrees.
• Form XIII has one or more characteristic XRPD peaks, in terms of 2-theta, selected from about 5.7, about 8.6, about 9.8, about 11.8, about 12.6, about
• the present application provides a method of treating a myeloproliferative neoplasm in a patient in need thereof, comprising administering to said patient 2,2,4-trimethyl-8-(6- methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-l,4- benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of ruxolitinib, or a pharmaceutically acceptable salt thereof.
• the myeloproliferative neoplasm is selected from polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis, chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), chronic neutrophilic leukemia (CNL), and chronic eosinophilic leukemia.
• the myeloproliferative neoplasm is polycythemia vera (PV).
• the myeloproliferative neoplasm is essential thrombocythemia
• the myeloproliferative neoplasm is primary myelofibrosis.
• the myeloproliferative neoplasm is myelofibrosis.
• 2,2,4-trimethyl-8-(6- methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-6-(methylsulfonyl)-2H-l,4- benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof, is administered orally.
• ruxolitinib, or pharmaceutically acceptable salt thereof and 2, 2, 4-trimethyl-8-(6-methyl-7-oxo-6, 7-dihydro- lH-pyrrolo[2, 3-c]pyri din-4-yl)-6- (methylsulfonyl)-2H-l,4-benzoxazin-3(4H)-one, or a pharmaceutically acceptable salt thereof, are administered simultaneously or sequentially.
• All compounds, and pharmaceutically acceptable salts thereof can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.
• solvents e.g., hydrates and solvates
• the compounds described herein and salts thereof may occur in various forms and may, e.g, take the form of solvates, including hydrates.
• the compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound.
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
• pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
• examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• the pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, e.g ., from non-toxic inorganic or organic acids.
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
• such salts can be 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; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g, methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred.
• non-aqueous media like ether, ethyl acetate, alcohols (e.g, methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred.
• suitable salts are found in Remington's Pharmaceutical Sciences, 17 th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge etal., ./. Pharm. Sci ., 1977, 66( 1), 1-19, and in Stahl etal.,
• BID means two times a day.
• QD means once a day.
• Compound 1 can be used in additional combination treatments where Compound 1 is administered in conjunction with other treatments such as the administration of one or more additional therapeutic agents.
• the additional therapeutic agents are typically those which are normally used to treat the particular condition to be treated.
• the additional therapeutic agents can include, e.g ., chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, FAK, and JAK kinase inhibitors for treatment of BET protein-associated diseases, disorders or conditions.
• the one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.
• Compound 1 can be used in combination with a therapeutic agent that targets an epigenetic regulator.
• epigenetic regulators include the histone lysine methyltransferases, histone arginine methyl transferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases.
• Histone deacetylase inhibitors include, e.g. , vorinostat.
• Compound 1 can be used in combination with chemotherapeutic agents, or other anti-proliferative agents.
• Compound 1 can also be used in combination with medical therapy such as surgery or radiotherapy, e.g. , gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes.
• chemotherapeutic agents include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxe
• Compound 1 can be used in combination with ruxolitinib.
• Compound 1 can be used in combination with one or more immune checkpoint inhibitors.
• immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD 122, CD96, CD73, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4- IBB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2.
• the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, 0X40, GITR and CD137.
• the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA.
• the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD 160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
• the inhibitor of an immune checkpoint molecule is anti -PD 1 antibody, anti-PD-Ll antibody, or anti-CTLA-4 antibody.
• the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody.
• the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224.
• the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab.
• the anti-PDl antibody is pembrolizumab.
• the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonal antibody.
• the anti-PD-Ll monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C.
• the anti-PD-Ll monoclonal antibody is MPDL3280A or MEDI4736.
• the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
• the anti-CTLA-4 antibody is ipilimumab.
• the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody.
• the anti-LAG3 antibody is BMS-986016 or LAG525.
• the inhibitor of an immune checkpoint molecule is an inhibitor of 0X40, e.g., an anti-OX40 antibody or OX40L fusion protein.
• the anti-OX40 antibody is MEDI0562.
• the OX40L fusion protein is MEDI6383.
• Compound 1 can be used in combination with one or more agents for the treatment of diseases such as cancer.
• the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent.
• an alkylating agent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.
• the proteasome inhibitor is carfilzomib.
• the corticosteroid is dexamethasone (DEX).
• the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).
• Compound 1 can be administered in combination with a corticosteroid such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone.
• a corticosteroid such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone.
• Compound 1 can be administered in combination with an immune suppressant such as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol, Alcon), or cyclosporine (Restasis®).
• an immune suppressant such as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol, Alcon), or cyclosporine (Restasis®).
• Compound 1 can be administered in combination with one or more additional agents selected from DehydrexTM (Holies Labs), Civamide (Opko), sodium hyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603, Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P) (Argentis), ecabet sodium (Senju-Ista), gefamate (Santen), 15-(s)- hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine, doxycycline (ALTY-0501, Alacrity), minocycline, iDestrinTM (NP50301, Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali), oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101 (2S, 3S, 4R, 5R)-3, 4-d
• Compound 1 can be administered in combination with one or more agents selected from an antibiotic, antiviral, antifungal, anesthetic, anti-inflammatory agents including steroidal and non-steroidal anti-inflammatories, and anti-allergic agents.
• suitable medicaments include aminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin, netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin; paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines; rifampin and its derivatives ("rifampins”); cycloserine; beta-lactams;
• agents one or more of which a provided compound may also be combined with include: a treatment for Alzheimer's Disease such as donepezil and rivastigmine; a treatment for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta interferon (e.g ., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone; a treatment for asthma such as albuterol and montelukast; an agent for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; an anti-inflammatory agent such as a corticosteroid, such as dexamethasone or prednisone, a TNF blocker, IL-1 RA,
• mice At one week prior to bone marrow transplant, eight week old female Balb/c mice (Charles River Laboratories) were injected once intraperitoneally with 150 mg/kg 5- fluorouracil. Five days later, these mice were sacrificed, and bone marrow was harvested by aspiration of femurs. Red blood cells were lysed using BD Pharma Lyse buffer (BD Biosciences), then washed with PBS. The remaining marrow was plated in 10% FBS/RPMI overnight in standard cell culture incubation.
• BD Pharma Lyse buffer BD Biosciences
• the bone marrow was infected with ecotropic retrovirus (MSCV puromycin backbone) expressing the MPLW515L gene by adding 1 ml virus to 106 cells, then centrifugation at 1800 rpm, 37°C, 90 minutes in 6 well plates. Following centrifugation, infected cells were kept in the incubator until the following day when they were injected into recipients.
• ecotropic retrovirus MSCV puromycin backbone
• CBCs complete blood counts
• mice Female Balb/c mice were transplanted with MPLW515L expressing bone marrow in order to assess the ability of the BET inhibitor Compound 1 to improve upon the activity of ruxolitinib alone in a preclinical MPN model. On day 7 post transplant, mice were randomized into cohorts for dosing based on platelet levels, as determined by CBC. The following day oral dosing commenced, with mice receiving Compound 1 at 10 mg/kg QD, ruxolitinib at 60 mg/kg BID, the combination of Compound 1 and ruxolitinib, or vehicle control.
• Example 4 Clinical Study Protocol of Compound 1 as Monotherapy in Participants with Myelofibrosis Study Design
• Part 1 On a continuous basis. The study will be conducted in 2 parts. Part 1 will evaluate initial safety and tolerability of 4 mg QD of Compound 1 in participants with relapsed or refractory myelofibrosis. Study drug will be self-administered once daily every day for 28 days, which is 1 cycle. Participants will continue taking study drug as long as benefit is derived and discontinuation criteria is not met. If the starting dose of 4 mg QD is deemed tolerable in Part 1, the starting dose in Part
• Part 2 will be 4 mg QD; if not, the starting dose in Part 2 will be 2 mg QD. Part 2 will administer Compound 1 as monotherapy as well.
• Plasma samples for the determination of plasma concentrations of Compound 1 in Parts 1 and 2 were collected at predose on Cycle 1 Day 1, Cycle 1 Day 2, and Cycle 1 Day 8, and at 0.5, 1, 2, 4, 6, and 8 hours on Cycle 1 Day 1 and Cycle 1 Day 8.
• the plasma samples of Compound 1 were assayed by a validated LC-MS/MS method.
• Compound 1 plasma concentrations attained the peak values (Cmax) typically at 1-2 hours (median Tmax) postdose, and subsequently exhibited a monophasic decay, with a steady-state geometric mean t1 ⁇ 2 of approximately 10 hours that was not dose-dependent.
• the steady-state was predicted to be achieved after 2 days with once daily dosing, based on an effective half-life of 10 hours.
• the geometric mean (CV%) of t1 ⁇ 2, steady-state Cmax, and AUCo-24 were 9.17 h (49.7%), 272 nM (40.9%), and 2740 h*nM (43.2%), respectively.
• Pharmacodynamic analysis was performed using an ex vivo assay measuring protein levels of cMyc, a BRD4 target gene, in KMS12BM cells, which were spiked into participant plasma samples collected at predose and various postdose timepoints.
• Compound 1 demonstrated inhibition of total cMyc protein expression with maximal inhibition occurring between 1 and 4 hours.
• the selected clinical safety endpoints as deemed appropriate eg, frequently occurring TEAEs (treatment-emergent adverse events), incident rate > 20% for all AEs (adverse events) and clinically notable adverse events
• TEAEs treatment-emergent adverse events
• incident rate > 20% for all AEs acute events
• clinically notable adverse events were used to evaluate exposure-safety relationships.
• FIG. 8 shows model-predicted versus observed relationship of Compound 1 steady state AUC and probability of hyperglycemia.
• the predicted probability of hyperglycemia incidence at dose of 2 mg and 4 mg is 8.0% and 9.2%, respectively, based on AUC and hyperglycemia relationship (Note: Open squares represent first (893-2035 h*nM), second (2074-2605 nM), third (2622-3564 nM), and fourth (3606-9788 nM) quartiles of Compound 1 AUCss,o-24.).

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