Combinations of menin inhibitors and cyp3a4 inhibitors and methods of use thereof

Abstract

The present invention relates to combinations of menin inhibitors with one or more CYP3A4 inhibitors, pharmaceutical compositions thereof, and methods of treating cancers and other diseases mediated by the menin-MLL interaction.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to U.S. Provisional Application No. 63 / 006,574, filed April 7, 2020, the contents of which are incorporated herein by reference in their entirety. Invention Field

[0003] This invention relates to inhibitors of menin interacting with MLL and MLL fusion proteins in combination with one or more CYP3A4 inhibitors, pharmaceutical compositions containing the same, and their use in the treatment of cancers and other diseases mediated by menin-MLL interaction. Background of the Invention

[0005] Mixed lineage leukemia (MLL) protein is a histone methyltransferase that is mutated in a subpopulation of acute leukemia that is a clinical and biological feature of the disease. Recombinant mixed lineage leukemia (MLL-r) involves repeated translocations at the 11q23 chromosomal locus, resulting in an aggressive form of acute leukemia with limited treatment options. These translocations target the MLL gene, producing an oncogenic fusion protein containing an N-terminus of MLL that is fused to more than 60 different fusion protein chaperones within a framework. Menin, a widely expressed nuclear protein encoded by the tumor suppressor gene of multi-endocrine tumor type 1 (MEN1), has a high-affinity binding interaction with MLL fusion proteins and is an important cofactor of the oncogenic MLL-r fusion protein (Yokoyama et al., 2005, Cell, 123:207-18; Cierpicki & Grembecka, 2014, Future Med. Chem., 6:447-462). Disruption of this interaction leads to selective growth inhibition and apoptosis of MLL-r leukemia cells in vitro (Grembecka et al., 2012, Nat. Chem. Biol., 8:277-284) and in vivo (Yokoyama et al., 2005, op. cit.; Borkin et al., 2015, Cancer Cell, 27:589-602).

[0006] The Menin-MLL complex plays a role in castration-resistant / advanced prostate cancer and it has been shown that menin-MLL inhibitors reduce tumor growth in vivo (Malik et al., 2015, Nat. Med., 21 :344-352). In addition, it has been shown that menin-MLL inhibitors enhance human beta cell proliferation (Chamberlain et al., 2014, J. Clin. Invest., 124:4093-4101), supporting a role for inhibitors of menin-MLL interactions in the treatment of diabetes (Yang et al., 2010, Proc Natl Acad Sci U S A., 107:20358-20363). The interaction between menin and MLL or MLL fusion proteins is an attractive target for therapeutic intervention and there is a need for new combination therapies that inhibit menin-MLL interactions for the treatment of various diseases and conditions, including leukemia, other cancers, and diabetes. SUMMARY

[0008] The present invention provides a combination therapy comprising a menin inhibitor and a CYP3A inhibitor. In certain embodiments, the present invention provides a pharmaceutical composition comprising: (a) a menin inhibitor, and (b) a CYP3A inhibitor. In some embodiments, the present invention relates to a method of treating a patient comprising (a) administering a menin inhibitor, and (b) administering a CYP3A inhibitor.

[0009] Some embodiments of the present invention relate to a combination therapy designed to treat or manage cancer in a subject, wherein the combination therapy comprises administration of a menin inhibitor in combination with a CYP3A inhibitor. In particular, some embodiments of the present invention relate to a method of treating or managing cancer in a subject comprising administering a menin inhibitor in combination with a therapeutically effective amount of a CYP3A inhibitor, simultaneously, separately, or sequentially.

[0010] In some embodiments, the present invention provides a combination therapy comprising a menin inhibitor and a CYP3A4 inhibitor. In certain embodiments, the present invention provides a pharmaceutical composition comprising: (a) a menin inhibitor, and (b) a CYP3A4 inhibitor. In some embodiments, the present invention relates to a method of treating a patient comprising (a) administering a menin inhibitor, and (b) administering a CYP3A4 inhibitor.

[0011] Some embodiments of the present application relate to combination therapies designed for treating or managing cancer in a subject, wherein the combination therapy comprises administration of a menin inhibitor in combination with a CYP3A4 inhibitor. In particular, some embodiments of the present application relate to methods of treating or managing cancer in a subject comprising administering a menin inhibitor in combination with a therapeutically effective amount of a CYP3A4 inhibitor, simultaneously, separately, or sequentially.

[0012] In some embodiments, the CYP3A inhibitor is: an antiarrhythmic agent; an antihistamine; an azole antifungal agent; a benzodiazepine; a calcium channel blocker; an HIV antiviral agent; an HMG CoA reductase inhibitor; a macrolide antibiotic; a prokinetic agent; a protease inhibitor; or any combination thereof. In some embodiments, the CYP3A inhibitor is: posaconazole, alprazolam; amiodarone; amlodipine; aprepitant; aripiprazole; astemizole; atorvastatin; boceprevir; buspirone; chloramphenicol; chlorpheniramine; cimetidine; ciprofloxacin; cisapride; clarithromycin; cobiprostone (GS-9350); an analog or derivative of cobiprostone (GS-9350); cyclosporine; delavirdine; diazepam -> 3-OH; diethyl dithiocarbamate; diltiazem; erythromycin; felodipine; fluconazole; fluvoxamine; gestodene; gleevec; grapefruit juice; haloperidol; imatinib; indinavir; itraconazole; ketoconazole; lovastatin; methadone; mibefradil; midazolam; mifepristone; nefazodone; nelfinavir; nifedipine; nisoldipine; nilvadipine; norfluoxetine; pimozide; quinine; quinidine -> 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; starfruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; triazolam; triazolam; verapamil; telaprevir; vincristine; voriconazole; or any combination thereof.

[0013] In some embodiments, the CYP3A4 inhibitor is posaconazole, cobiprostone (GS-9350), or an analog or derivative of cobiprostone (GS-9350). In some embodiments, the CYP3A4 inhibitor is ketoconazole. In some embodiments, the CYP3A4 inhibitor is ritonavir. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are in separate dosage forms. In some embodiments, the pharmaceutical composition is a combination dosage form. In some embodiments, the CYP3A4 inhibitor is posaconazole.

[0014] In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor effective to increase oral bioavailability of the menin inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor effective to increase Cmaxof the menin inhibitor. max In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor effective to increase Cmaxof the menin inhibitor. max In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor effective to increase Cmaxof the menin inhibitor. maxabout 20X to about 40X, or about 25X to about 35X. In some embodiments, the pharmaceutical composition comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 15X to about 35X, or about 20X to about 30X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 2X to about 35X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 2X to about 30X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 2X to about 25X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 2X to about 20X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 2X to about 15X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 2X to about 10X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 2X to about 5X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor to about 2X to about 4X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor.

[0015] In some embodiments, the pharmaceutical composition further comprises chlorambucil, ifosfamide, doxorubicin, mesalamine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fotatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof. In some embodiments, the pharmaceutical composition further comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally rituximab. In some embodiments, the pharmaceutical composition further comprises bendamustine and rituximab. In some embodiments, the pharmaceutical composition further comprises fludarabine, cyclophosphamide, and rituximab. In some embodiments, the pharmaceutical composition further comprises cyclophosphamide, vincristine, and prednisone, and optionally rituximab. In some embodiments, the pharmaceutical composition further comprises etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and optionally rituximab. In some embodiments, the pharmaceutical composition further comprises dexamethasone and lenalidomide.

[0016] In certain embodiments, disclosed herein is a pharmaceutical combination comprising a therapeutically effective amount of a menin inhibitor and a CYP3A4 inhibitor. In some embodiments, the combination is a combined dosage form. In some embodiments, the combination is a separate dosage form. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered concurrently. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered simultaneously, substantially simultaneously, or within the same treatment regimen. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered sequentially. In some embodiments, the CYP3A4 inhibitor is: an antiarrhythmic agent; an antihistamine; an azole antifungal agent; a benzodiazepine; a calcium channel blocker; an HIV antiviral agent; an HMG CoA reductase inhibitor; a macrolide antibiotic; a prokinetic agent; a protease inhibitor; or any combination thereof. In some embodiments, the CYP3A4 inhibitor is: alprazolam; amiodarone; amlodipine; aprepitant; aripiprazole; astemizole; atorvastatin; boceprevir; buspirone; chloramphenicol; chlorpheniramine; cimetidine; ciprofloxacin; cisapride; clarithromycin; cobiprostone (GS-9350); an analog or derivative of cobiprostone (GS-9350); cyclosporine; delavirdine; diazepam -> 3-OH; diethyl dithiocarbamate; diltiazem; erythromycin; felodipine; fluconazole; fluvoxamine; gestodene; gleevec; grapefruit juice; haloperidol; imatinib; indinavir; itraconazole; ketoconazole; lovastatin; methadone; mibefradil; midazolam; mifepristone; nefazodone; nelfinavir; nifedipine; nisoldipine; nilvadipine; norfluoxetine; pimozide; quinine; quinidine -> 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; starfruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; triazolam; triazolam; verapamil; troleandromycin; vincristine; voriconazole; or any combination thereof.

[0017] In some embodiments, the CYP3A4 inhibitor is cobiprostone (GS-9350) or an analog or derivative of cobiprostone (GS-9350). In some embodiments, the CYP3A4 inhibitor is ketoconazole. In some embodiments, the CYP3A4 inhibitor is ritonavir.

[0018] In some embodiments, the pharmaceutical composition comprises an amount of CYP3A4 inhibitor effective to increase the oral bioavailability of the menin inhibitor. In some embodiments, the pharmaceutical composition comprises an amount of CYP3A4 inhibitor effective to increase the C max . In some embodiments, the pharmaceutical composition comprises an amount of CYP3A4 inhibitor effective to increase the Cmax Increase C for patients without CYP3A4 inhibitors who are given menin max The AUC of the menin inhibitor is approximately 20X to approximately 40X, or approximately 25X to approximately 35X. In some embodiments, the pharmaceutical composition comprises a amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to approximately 15X to approximately 35X, or approximately 20X to approximately 30X, of the AUC of the menin inhibitor without a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises a amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to approximately 2X to approximately 30X of the AUC of the menin inhibitor without a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises a amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to approximately 2X to approximately 25X of the AUC of the menin inhibitor without a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises a amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to about 2 to about 20 times that of the menin inhibitor without a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises a amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to about 2 to about 15 times that of the menin inhibitor without a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises a amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to about 2 to about 10 times that of the menin inhibitor without a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises a amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to about 2 to about 5 times that of the menin inhibitor without a CYP3A4 inhibitor. In some embodiments, the pharmaceutical composition comprises a certain amount of a CYP3A4 inhibitor that effectively increases the AUC of the menin inhibitor to about 2 to about 4 times that of the AUC of the menin inhibitor when no CYP3A4 inhibitor is administered.

[0019] In some embodiments, the pharmaceutical composition further comprises cloretazine, ifosfamide, doxorubicin, mesalamine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fotatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof. In some embodiments, the pharmaceutical composition further comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally rituximab. In some embodiments, the pharmaceutical composition further comprises bendamustine and rituximab. In some embodiments, the pharmaceutical composition further comprises fludarabine, cyclophosphamide, and rituximab. In some embodiments, the pharmaceutical composition further comprises cyclophosphamide, vincristine, and prednisone, and optionally rituximab. In some embodiments, the pharmaceutical composition further comprises etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and optionally rituximab. In some embodiments, the pharmaceutical composition further comprises dexamethasone and lenalidomide.

[0020] In some embodiments, the CYP3A4 inhibitor is: an antiarrhythmic; an antihistamine; an azole antifungal; a benzodiazepine; a calcium channel blocker; an HIV antiviral; an HMG CoA reductase inhibitor; a macrolide antibiotic; a prokinetic agent; a protease inhibitor; or any combination thereof. In some embodiments, the CYP3A4 inhibitor is: alprazolam; amiodarone; amlodipine; aprepitant; aripiprazole; astemizole; atorvastatin; boceprevir; buspirone; chloramphenicol; chlorpheniramine; cimetidine; ciprofloxacin; cisapride; clarithromycin; cobiprostone (GS-9350); an analog or derivative of cobiprostone (GS-9350); cyclosporine; delavirdine; diazepam -> 3-OH; diethyl dithiocarbamate; diltiazem; erythromycin; felodipine; fluconazole; fluvoxamine; gestodene; gleevec; grapefruit juice; haloperidol; imatinib; indinavir; itraconazole; ketoconazole; lovastatin; mefloquine; mibefradil; midazolam; mifepristone; nefazodone; nelfinavir; nifedipine; nisoldipine; nilvadipine; norfluoxetine; pimozide; quinine; quinidine -> 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; starfruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; triazolam; triazolam; troleandromycin; verapamil; telaprevir; vincristine; voriconazole; or any combination thereof.

[0021] In some embodiments, the CYP3A4 inhibitor is posaconazole. In some embodiments, the CYP3A4 inhibitor is cobicistat (GS-9350) or an analog or derivative of cobicistat (GS-9350). In some embodiments, the CYP3A4 inhibitor is ketoconazole. In some embodiments, the CYP3A4 inhibitor is ritonavir.

[0022] In some embodiments, the daily dose of the menin inhibitor is between about 10 mg to about 500 mg. In some embodiments, the daily dose of the menin inhibitor is between about 200 mg and about 500 mg. In some embodiments, the daily dose of the menin inhibitor is between about 250 mg and about 460 mg. In some embodiments, the daily dose of the menin inhibitor is about 226 mg. In some embodiments, the daily dose of the menin inhibitor is 452 mg.

[0023] In some embodiments, the method comprises an amount of a CYP3A4 inhibitor effective to increase the oral bioavailability of the menin inhibitor. In some embodiments, the method comprises an amount of a CYP3A4 inhibitor effective to increase the Cmax of the menin inhibitor. max In some embodiments, the method comprises an amount of a CYP3A4 inhibitor effective to increase the oral bioavailability of the menin inhibitor. max In some embodiments, the method comprises an amount of a CYP3A4 inhibitor effective to increase the Cmax of the menin inhibitor without increasing the AUC of the menin inhibitor. maxabout 40X, or about 25X to about 35X. In some embodiments, the method comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 15X to about 35X, or about 20X to about 30X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 2X to about 35X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 2X to about 30X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 2X to about 25X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 2X to about 20X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 2X to about 15X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 2X to about 10X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 2X to about 5X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method comprises an amount of CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 2X to about 4X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method comprises a T max and T 1 / 2 that does not significantly affect the T max and T 1 / 2pharmaceutical composition. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are in a combined dosage form. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are in separate dosage forms. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered concurrently. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered simultaneously, substantially simultaneously, or within the same treatment regimen. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered sequentially.

[0024] BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 The change in steady state AUC following oral administration of a menin inhibitor of Formula II with and without the CYP3A4 inhibitor posaconazole is shown. DETAILED DESCRIPTION

[0027] Small molecule menin inhibitors administered in combination with CYP3A4 inhibitors work to treat a variety of diseases that are affected by or affect a variety of cell types.

[0028] In some embodiments, the present application provides a combination therapy comprising a menin inhibitor and a CYP3A4 inhibitor. In some embodiments, the present application provides a pharmaceutical composition comprising: (a) a menin inhibitor, and (b) a CYP3A4 inhibitor. In some embodiments, the present application relates to a method of treating a patient comprising (a) administering a menin inhibitor, and (b) administering a CYP3A4 inhibitor. In some embodiments, the present application relates to a method of treating a patient comprising (a) administering a pharmaceutical composition comprising a menin inhibitor, and (b) administering a pharmaceutical composition comprising a CYP3A4 inhibitor.

[0029] Some embodiments of the present application relate to a combination therapy designed to treat or manage cancer in a subject, wherein the combination therapy comprises administration of a menin inhibitor in combination with a CYP3A4 inhibitor. In particular, some embodiments of the present application relate to a method of treating or managing cancer in a subject comprising administering a menin inhibitor in combination with a therapeutically effective amount of a CYP3A4 inhibitor, simultaneously, separately, or sequentially.

[0030] In some embodiments, the combination therapy increases the plasma levels of the menin inhibitor. In some embodiments, the combination therapy enhances the efficacy of the inhibitor to treat a variety of diseases. In some embodiments, the combination therapy acts synergistically to treat cancer. In some embodiments, the combination therapy enhances, increases, or prolongs the potency or duration of the therapeutic effect. In some embodiments, the CYP3A4 inhibitor enhances, increases, and / or prolongs the potency or duration of the therapeutic effect of the menin inhibitor.

[0031] In some embodiments, the menin inhibitor is 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4- (methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]non-2-yl)pyrimidin-5-yl)oxy)benzamide (Formula I), or a pharmaceutically acceptable salt, stereoisomer, geometric isomer, or tautomer thereof. In some embodiments, the menin inhibitor is N-ethyl-2-((4-(7-(((1r,4r)-4- (ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]non-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N- isopropylbenzamide (Formula II), or a pharmaceutically acceptable salt, stereoisomer, geometric isomer, or tautomer thereof. In some embodiments, the menin inhibitor comprises any stereoisomer, geometric isomer, and / or tautomer. In accordance with the application disclosed herein, the menin inhibitor is selected from the group consisting of Formula (I) and Formula (II)

[0032]

[0033] or a pharmaceutically acceptable salt, stereoisomer, geometric isomer, or tautomer thereof.

[0034] Formula I is also described as the chemical name: 5-fluoro-N,N-diisopropyl-2-((4-(7-((trans-4- (methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]non-2-yl)pyrimidin-5-yl)oxy)benzamide. Formula II is also described as the chemical name: N-ethyl-2-((4-(7-((trans-4- (ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]non-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N- isopropylbenzamide.

[0035] In some embodiments, the pharmaceutically acceptable salt is a bismethanesulfonate salt. In some embodiments, the pharmaceutically acceptable salt is a bis-hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt is a hemifumarate salt.

[0036] In some embodiments, the menin inhibitor is therapeutically effective at a lower dose when combined with a CYP3A4 inhibitor. In some embodiments, the menin inhibitor is more effective when combined with a CYP3A4 inhibitor.

[0037] In some embodiments, the menin inhibitor is administered in combination with a CYP3A4 inducer. In some embodiments, the CYP3A4 inducer includes, but is not limited to, one or more of atorvastatin, phenytoin, carbamazepine, rifampin, enzalutamide, and St. John's wort.

[0038] In some embodiments, the menin inhibitor is of Formula I and the CYP3A4 inhibitor is an azole antifungal agent. In some embodiments, the menin inhibitor is of Formula II and the CYP3A4 inhibitor is an azole antifungal agent.

[0039] In some embodiments, the menin inhibitor is of Formula I and the CYP3A4 inhibitor is posaconazole. In some embodiments, the menin inhibitor is of Formula II and the CYP3A4 inhibitor is posaconazole.

[0040] The term

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural, unless specifically stated otherwise. It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless specifically stated otherwise.

[0042] In addition, the use of the terms "including", "comprising", "having" and "containing" are not limiting.

[0043] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, treatises, and webpages, are hereby expressly incorporated by reference in their entirety for any purpose.

[0044] The term "acceptable" or "pharmaceutically acceptable", with respect to an agent, composition or ingredient used herein, means having no persistent detrimental effect on the general health of the subject or no persistent detrimental effect on the biological activity or properties of the compound, and is relatively nontoxic.

[0045] "Bioavailability" refers to the percentage of an administered menin inhibitor that is delivered into the systemic circulation of a study animal or human. Total exposure of a drug (AUC(0-∞)) is generally defined as 100% bioavailability (F%) when administered by intravenous injection. "Oral bioavailability" refers to the extent to which a menin inhibitor is absorbed into the systemic circulation when an oral pharmaceutical composition is administered as compared to intravenous injection.

[0046] "Plasma concentration" refers to the concentration of a menin inhibitor in the plasma component of the blood of a subject. It is understood that plasma concentrations of a menin inhibitor can vary significantly between subjects due to variability in metabolism and / or possible interactions with other therapeutic agents. According to some embodiments disclosed herein, blood or plasma concentrations of a menin inhibitor can vary from subject to subject. Likewise, the maximum plasma concentration (C max ) or the time to reach the maximum plasma concentration (T max ), or the total area under the plasma concentration-time curve (AUC(0-∞)) can vary from subject to subject. Due to this variability, the amount of a menin inhibitor that constitutes a "therapeutically effective amount" can vary from subject to subject.

[0047] The terms "co-administration" or the like, as used herein, encompass administration of the selected therapeutic agents to a single patient and is intended to encompass therapeutic regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0048] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of an agent or compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of a sign, a symptom, or a cause of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound as disclosed herein, which is required to provide a clinically significant decrease in disease symptoms without undue adverse side effects. An appropriate "effective amount" in any individual case can be determined using techniques, such as a dose escalation study. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein refers to an amount effective, at doses and for periods of time necessary, to achieve an intended pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood, that "an effective amount" or "a therapeutically effective amount" can vary from subject to subject, due to variation in metabolism, age, body size, general condition, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example, only, a therapeutically effective amount can be determined by routine experimentation, including but not limited to a dose escalation clinical trial.

[0049] The terms "enhance" or "enhanced" refer to an increase or prolongation in the potency or duration of the intended effect. For example, "enhancing" the effect of a therapeutic agent refers to the ability to increase or prolong the potency or duration of a therapeutic agent during the treatment of a disease, disorder, or condition. An "enhancing effective amount" as used herein refers to an amount adequate to enhance the effect of a therapeutic agent in the treatment of a disease, disorder, or condition. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. The terms "subject," "patient," and "individual" can be used interchangeably. As used herein, they refer to an animal. By way of example only, the subject can be, but is not limited to, a mammal, including but not limited to a human. These terms do not require that a medical professional (whether continuous or intermittent) oversee administration.

[0050] The terms "treat," "treating" or "treatment" as used herein include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, alleviating or preventing metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of a disease or condition, relieving the conditions caused by the disease or condition, or stopping the symptoms of the disease or condition. The terms "treat," "treating" or "treatment" include, but are not limited to, prophylactic and / or therapeutic treatment.

[0051] As used herein, IC50refers to the amount, concentration or dosage of a particular test compound that achieves 50% inhibition of a maximal response (e.g., inhibition of menin) in an assay that measures the response.

[0052] As used herein, EC50refers to the amount, concentration or dosage of a particular test compound that elicits a dose-dependent response at 50% of the maximal expression of a particular response induced, elicited or enhanced by the particular test compound.

[0053] A variety of pharmaceutically acceptable salts are formed from the menin inhibitors and include: acid addition salts formed with organic acids including aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc., and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.; acid addition salts formed with inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.

[0054] The term "pharmaceutically acceptable salt" refers to a salt of a menin inhibitor that does not cause significant irritation to an administered mammal, and does not abrogate the biological activity and properties of the compound.

[0055] It is understood that reference to a pharmaceutically acceptable salt includes solvent addition forms (solvates). Solvates contain either stoichiometric or non-stoichiometric amounts of the solvent, and are formed, for example, by the dissolution of the product in a solvent or by recrystallization, and include hydrates. Solvents that form solvates with the menin inhibitors described herein include, but are not limited to, water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, and the like. In one aspect, solvates are formed using, but not limited to, Class 3 solvents. Classes of solvents are defined, for example, in International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005). When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholate is formed. In some embodiments, solvates of the menin inhibitors described herein, or pharmaceutically acceptable salts thereof, can be conveniently prepared or formed during the processes described herein. In some embodiments, the solvates of the menin inhibitors described herein are anhydrous. In some embodiments, the menin inhibitors described herein, or pharmaceutically acceptable salts thereof, are present in unsolvated form. In some embodiments, the menin inhibitors described herein, or pharmaceutically acceptable salts thereof, are present in unsolvated form and are anhydrous.

[0056] In other embodiments, the menin inhibitors described herein, or pharmaceutically acceptable salts thereof, are prepared in various forms, including, but not limited to, amorphous phases, crystalline forms, milled forms, and nanoparticulate forms. In some embodiments, the menin inhibitors described herein, or pharmaceutically acceptable salts thereof, are amorphous. In some embodiments, the menin inhibitors described herein, or pharmaceutically acceptable salts thereof, are amorphous and anhydrous. In some embodiments, the menin inhibitors described herein, or pharmaceutically acceptable salts thereof, are crystalline. In some embodiments, the menin inhibitors described herein, or pharmaceutically acceptable salts thereof, are crystalline and anhydrous.

[0057] General CYP3A Inhibitors

[0058] In certain embodiments, disclosed herein are pharmaceutical combinations comprising a menin inhibitor and a CYP3A inhibitor. In certain embodiments, further disclosed herein are pharmaceutical compositions comprising a combination of a menin inhibitor and a CYP3A inhibitor.

[0059] Cytochrome P450 3A (abbreviated CYP3A) is a member of the cytochrome P450 mixed-function oxidase system. The CYP3A locus includes all known members of the cytochrome P450 gene superfamily subfamily 3A. These genes encode monooxygenases that catalyze many reactions in drug metabolism and in the synthesis of cholesterols, steroids, and other lipids. The CYP3A cluster consists of four genes; CYP3A4, CYP3A5, CYP3A7, and CYP3A43.

[0060] Cytochrome P450 enzymes modify a variety of substrates, including hydroxylation, epoxidation, aromatic oxidation, heteroatom oxidation, N- and O-dealkylation, aldehyde oxidation, and dehydrogenation.

[0061] In some embodiments, the menin inhibitor and the CYP3A inhibitor are co-administered concurrently (e.g., simultaneously, substantially simultaneously, or within the same treatment regimen) or sequentially.

[0062] In some embodiments, the menin inhibitor and the CYP3A inhibitor are co-administered in separate dosage forms. In some embodiments, the menin inhibitor and the CYP3A inhibitor are co-administered in a combination dosage form.

[0063] In some embodiments, co-administration of the menin inhibitor and the CYP3A inhibitor increases the oral bioavailability of the menin inhibitor. In some embodiments, co-administration of the menin inhibitor and the CYP3A inhibitor increases the Cmax of the menin inhibitor. max In some embodiments, co-administration of the menin inhibitor and the CYP3A inhibitor increases the AUC of the menin inhibitor. In some embodiments, co-administration of the menin inhibitor and the CYP3A inhibitor increases the Tmax of the menin inhibitor. 1 / 2 .

[0064] The compositions or therapies disclosed herein can be administered to a patient alone or can be administered in combination (e.g., simultaneously, sequentially, or separately). In some embodiments, the CYP3A4 inhibitor is administered prior to the menin protein inhibitor. In some embodiments, the CYP3A4 inhibitor is administered prior to the menin protein inhibitor. In some embodiments, the CYP3A4 inhibitor is posaconazole and is administered prior to the menin inhibitor of Formula II.

[0065] In some embodiments, the menin inhibitor and the CYP3A inhibitor are administered in temporal proximity (e.g., the menin inhibitor and the CYP3A inhibitor can be administered initially concurrently). Accordingly, the present disclosure provides a method of treating or preventing cancer comprising administering a menin inhibitor and a CYP3A inhibitor in temporal proximity. In some embodiments, “in temporal proximity” means administering one therapeutic agent within a period of time prior to or following administration of the other therapeutic agent, such that the therapeutic effect of one therapeutic agent overlaps with the therapeutic effect of the other drug. In some embodiments, the therapeutic effect of one therapeutic agent overlaps completely with the therapeutic effect of the other therapeutic agent.

[0066] In some embodiments, “in temporal proximity” means administering one therapeutic agent within a period of time prior to or following administration of the other therapeutic agent, such that there is a synergistic effect between one therapeutic agent and the other. “In temporal proximity” can vary depending on various factors, including but not limited to the age, sex, body weight, genetic background, medical condition, medical history, and treatment history of the subject to which the therapeutic agents will be administered; the disease or condition to be treated or ameliorated; the therapeutic outcome to be achieved; the dosage, frequency of dosing, and duration of dosing of the therapeutic agents; the pharmacokinetics and pharmacodynamics of the therapeutic agents; and the route of administration of the therapeutic agents. In some embodiments, “in temporal proximity” means within 15 minutes, 30 minutes, one hour, two hours, four hours, six hours, eight hours, 12 hours, 18 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, one week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks. In some embodiments, multiple administrations of one therapeutic agent can be in temporal proximity to a single administration of the other therapeutic agent. In some embodiments, temporal proximity can vary during a treatment cycle or within a dosing regimen.

[0067] “Combination therapy” is intended to include the administration of the therapeutic agents disclosed herein, in succession or simultaneously, wherein each therapeutic agent is administered at different times, as well as the administration of these therapeutic agents or at least two therapeutic agents concurrently or in an essentially simultaneous manner. For example, simultaneous administration can be achieved by administration of a single capsule having a fixed or variable ratio of each therapeutic agent or multiple single capsules of each therapeutic agent to the subject. Sequential or essentially simultaneous administration of each therapeutic agent can be affected by any appropriate route, including but not limited to oral routes, intravenous routes, intramuscular routes, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of a selected combination can be administered by intravenous injection, while the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered by intravenous injection. The order of administration of the therapeutic agents can vary. The therapeutic agents can also be administered alternately.

[0068] In some embodiments, the present disclosure provides a synergistic combination of a menin inhibitor and a CYP3A inhibitor, wherein the menin inhibitor and the CYP3A inhibitor are in contact with each other in vivo (e.g., only in vivo in a human). In some embodiments, the present disclosure provides a method of preparing a combination therapy by bringing a menin inhibitor and a CYP3A inhibitor into contact with each other at a site. In some embodiments, the method of preparing a combination therapy by bringing a menin inhibitor and a CYP3A inhibitor into contact with each other at a site occurs in vivo (e.g., only in vivo in a human).

[0069] Disclosed herein, in some embodiments, the CYP3A inhibitor is a CYP3A4 inhibitor. In some embodiments, the CYP3A inhibitor is a CYP3A5 inhibitor. In some embodiments, the CYP3A inhibitor is a CYP3A7 inhibitor.

[0070] Combinations with CYP3A4 inhibitors

[0071] In certain embodiments, disclosed herein are combinations comprising a menin inhibitor and a CYP3A4 inhibitor.

[0072] In certain embodiments, further disclosed herein are pharmaceutical combinations comprising a menin inhibitor and a CYP3A4 inhibitor.

[0073] Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1.14.13.97) is a member of the cytochrome P450 mixed-function oxidase system. Cytochrome P450 proteins are monooxygenases that catalyze many reactions in drug metabolism. CYP3A4 is encoded by the CYP3A4 gene. This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. CYP3A4 is involved in the oxidation of a large number of substrates, such as menin inhibitors.

[0074] Cytochrome P450 enzymes modify a variety of substrates, including hydroxylation, epoxidation, aromatic oxidation, heteroatom oxidation, N- and O-dealkylation, aldehyde oxidation, and dehydrogenation.

[0075] In some embodiments, the menin protein inhibitor and the CYP3A4 inhibitor are coadministered concurrently (e.g., simultaneously, substantially simultaneously, or within the same treatment regimen) or sequentially.

[0076] In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are coadministered in separate dosage forms. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are coadministered in a combined dosage form.

[0077] In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the oral bioavailability of the menin inhibitor. In some embodiments, co- administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin inhibitor. max In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor.

[0078] In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin inhibitor. max In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin inhibitor by about 20X to about 40X. max In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin inhibitor by about 20X to about 40X. max In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin protein by about 25X to about 35X. max In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin protein by about 20X. max In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin protein by about 21X. max In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin protein by about 22X. max In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin protein by about 23X. max In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin protein by about 24X. max In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin protein by about 25X. max In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin protein by about 26X. max In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin protein by about 27X. max In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin protein by about 28X. max In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the Cmaxof the menin protein by about 29X.max about 30X. In some embodiments, co-administration of a menin inhibitor and a CYP3A4 inhibitor increases the Cmax of menin protein by about 30X. max about 30X. In some embodiments, co-administration of a menin inhibitor and a CYP3A4 inhibitor increases the Cmax of menin protein by about 30X. max about 32X. In some embodiments, co-administration of a menin inhibitor and a CYP3A4 inhibitor increases the Cmax of menin protein by about 32X. max about 33X. In some embodiments, co-administration of a menin inhibitor and a CYP3A4 inhibitor increases the Cmax of menin protein by about 33X. max about 34X. In some embodiments, co-administration of a menin inhibitor and a CYP3A4 inhibitor increases the Cmax of menin protein by about 34X. max about 35X. In some embodiments, co-administration of a menin inhibitor and a CYP3A4 inhibitor increases the Cmax of menin protein by about 35X. max about 36X. In some embodiments, co-administration of a menin inhibitor and a CYP3A4 inhibitor increases the Cmax of menin protein by about 36X. max about 37X. In some embodiments, co-administration of a menin inhibitor and a CYP3A4 inhibitor increases the Cmax of menin protein by about 37X. max about 38X. In some embodiments, co-administration of a menin inhibitor and a CYP3A4 inhibitor increases the Cmax of menin protein by about 38X. max about 39X. In some embodiments, co-administration of a menin inhibitor and a CYP3A4 inhibitor increases the Cmax of menin protein by about 39X. max about 40X.

[0079] In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 15X to about 35X the AUC of the menin inhibitor without administration of the CYP3A4 inhibitor. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 20X to about 30X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 35X the AUC of the menin inhibitor without administration of the CYP3A4 inhibitor. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 30X the AUC of the menin inhibitor without administration of the CYP3A4 inhibitor. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 25X the AUC of the menin inhibitor without administration of the CYP3A4 inhibitor. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 20X the AUC of the menin inhibitor without administration of the CYP3A4 inhibitor. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 15X the AUC of the menin inhibitor without administration of the CYP3A4 inhibitor. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 10X the AUC of the menin inhibitor without administration of the CYP3A4 inhibitor. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 5X the AUC of the menin inhibitor without administration of the CYP3A4 inhibitor. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X to about 4X the AUC of the menin inhibitor without administration of the CYP3A4 inhibitor. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 15X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 2X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 3X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 4X.In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 5X. In some embodiments, co- administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 6X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 7X. In some embodiments, co- administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 8X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 9X. In some embodiments, co- administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 10X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 11X. In some embodiments, co- administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 12X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 13X. In some embodiments, co- administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 14X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 15X. In some embodiments, co- administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 16X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 17X. In some embodiments, co- administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 18X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 19X. In some embodiments, co- administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 20X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 21X. In some embodiments, co- administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 22X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 23X. In some embodiments, co- administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 24X.In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 25X. In some embodiments, co- administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 26X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 27X. In some embodiments, co- administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 28X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 29X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 30X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 31X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 32X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 33X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 34X. In some embodiments, co-administration of the menin inhibitor and the CYP3A4 inhibitor increases the AUC of the menin inhibitor by about 35X.

[0080] Any suitable daily dose of CYP3A4 inhibitor can be used with the compositions, dosage forms, and methods disclosed herein. For example, the daily dose of CYP3A4 inhibitor depends on the strength of the CYP3A4 inhibitor. Weak CYP3A4 inhibitors (such as cimetidine) will require a higher daily dose than moderate CYP3A4 inhibitors (such as erythromycin, grapefruit juice, verapamil, diltiazem), and moderate CYP3A4 inhibitors will require a higher daily dose than strong CYP3A4 inhibitors (such as indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone).

[0081] Exemplary CYP3A4 inhibitors

[0082] In some embodiments, the menin inhibitor is co-administered with a CYP3A4 inhibitor selected from an antiarrhythmic agent; an antihistamine; an azole antifungal agent; a benzodiazepine; a calcium channel blocker; an HIV antiviral agent; an HMG CoA reductase inhibitor; a macrolide antibiotic; a prokinetic agent; a protease inhibitor; or any combination thereof.

[0083] In some embodiments, the at least one CYP3A4 inhibitor is selected from the compounds disclosed in one or more of the following patent applications assigned to Sequoia Pharmaceuticals, Inc., the disclosure of each of which is incorporated herein by reference: U.S. Patent Publication No. US 2005 / 0209301 and U.S. Patent Publication No. US 2005 / 0267074. In some embodiments, the at least one CYP3A4 inhibitor is selected from the compounds disclosed in one or more of the following patents and patent applications assigned to Bioavailability Systems, LLC, the disclosure of each of which is incorporated herein by reference: US 2004058982, U.S. Pat. No. 6,248,776, U.S. Pat. No. 6,063,809, U.S. Pat. No. 6,054,477, U.S. Pat. No. 6,162,479, WO 2000054768, U.S. Pat. No. 6,309,687, U.S. Pat. No. 6,476,066, U.S. Pat. No. 6,660,766, WO 2004037827, U.S. Pat. No. 6,124,477, U.S. Pat. No. 5,820,915, U.S. Pat. No. 5,993,887, U.S. Pat. No. 5,990,154, U.S. Pat. No. 6,255,337.

[0084] In some embodiments, the menin inhibitor is co-administered with posaconazole, conivaptan, lopinavir, alprazolam; amiodarone; amlodipine; aprepitant; aripiprazole; astemizole; atorvastatin; boceprevir; buspirone; chloramphenicol; chlorpheniramine; cimetidine; ciprofloxacin; cisapride; clarithromycin; cobiprostone (GS-9350); an analog or derivative of cobiprostone (GS-9350); cyclosporine; delavirdine; diazepam -> 3-OH; diethyl dithiocarbamate; diltiazem; erythromycin; felodipine; fluconazole; fluvoxamine; gestodene; gleevec; grapefruit juice; haloperidol; imatinib; indinavir; itraconazole; ketoconazole; lovastatin; methadone; mibefradil; midazolam; mifepristone; nefazodone; nelfinavir; nifedipine; nisoldipine; nilvadipine; norfluoxetine; pimozide; quinine; quinidine -> 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; starfruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; trazodone; triazolam; verapamil; telaprevir; troleandromycin; vincristine; voriconazole; or any combination thereof. In some embodiments, the menin inhibitor is co-administered with cobiprostone (GS-9350) or an analog or derivative of cobiprostone (GS-9350). In some embodiments, the menin inhibitor is co-administered with ketoconazole. In some embodiments, the menin inhibitor is co-administered with ritonavir. Diazepam -> 3-OH refers to 3-hydroxydiazepam and quinidine -> 3-OH refers to 3-hydroxyquinidine. In some embodiments, the CYP3A4 inhibitor is a pharmaceutically acceptable salt of one or more of the above or below listed.

[0085] Any suitable CYP3A4 inhibitor is contemplated for use with the compositions, dosage forms, and methods disclosed herein. The selection of the CYP3A4 inhibitor depends on a variety of factors. For example, factors to be considered include the desired reduction in daily dose of the menin inhibitor, any other drug interactions of the CYP3A4 inhibitor, and the timing of administration of the CYP3A4 inhibitor. In certain instances, the CYP3A4 inhibitor is one that can be taken chronically (e.g., chronically). In some embodiments, the CYP3A4 inhibitor is taken for a limited time, and the menin inhibitor is taken chronically.

[0086] In certain embodiments, disclosed herein are methods of increasing the C max of a menin inhibitor comprising co-administering a combination of a menin protein and a CYP3A4 inhibitor. In some embodiments, the C max of the menin inhibitor is increased without the CYP3A4 inhibitor. maxabout 20X to about 40X, or about 25X to about 35X. In some embodiments, the method increases the AUC of the menin inhibitor by about 15X to about 35X, or about 20X to about 30X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor by about 2X to about 35X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor by about 2X to about 30X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor by about 2X to about 25X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor by about 2X to about 20X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor by about 2X to about 15X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor by about 2X to about 10X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor by about 2X to about 5X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor by about 2X to about 4X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor.

[0087] In certain embodiments, disclosed herein are methods of increasing the AUC of a menin inhibitor comprising administering a combination of a menin protein and a CYP3A4 inhibitor. In some embodiments, the methods increase the AUC of the menin inhibitor by about 15X to about 35X, or about 20X to about 30X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the methods increase the AUC of the menin inhibitor by about 2X to about 35X of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the methods increase the AUC of the menin inhibitor by about 2X to about 30X of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the methods increase the AUC of the menin inhibitor by about 2X to about 25X of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the methods increase the AUC of the menin inhibitor by about 2X to about 20X of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the methods increase the AUC of the menin inhibitor by about 2X to about 15X of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the methods increase the AUC of the menin inhibitor by about 2X to about 10X of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the methods increase the AUC of the menin inhibitor by about 2X to about 5X of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the methods increase the AUC of the menin inhibitor by about 2X to about 4X of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the methods increase the AUC of the menin inhibitor by about 2X of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. max In some embodiments, the methods increase the C max of the menin inhibitor by about 20X to about 40X, or about 25X to about 35X, of the C max of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the methods do not significantly affect the T max or T 1 / 2 of the menin inhibitor as compared to the T max or T 1 / 2 of the menin inhibitor administered without the CYP3A4 inhibitor.

[0088] Methods of use

[0089] In some embodiments, are methods of treating a cancer in an individual in need thereof comprising administering a combination of a menin inhibitor and a CYP3A4 inhibitor. Thus, the combinations and methods of the present application are believed to be effective against a broad range of cancers, including but not limited to hematological cancers (e.g., leukemias and lymphomas), bladder cancer, brain cancer (e.g., glioma, diffuse intrinsic pontine glioma (DIPG)), breast cancer (e.g., triple negative breast cancer, estrogen receptor positive breast cancer (i.e., ER+ breast cancer)), colorectal cancer, cervical cancer, gastrointestinal cancer (e.g., colorectal cancer, gastric cancer), genitourinary cancer, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer (e.g., castration resistant prostate cancer), renal cancer (e.g., renal cell carcinoma), skin cancer, thyroid cancer (e.g., thyroid papillary carcinoma), testicular cancer, sarcoma (e.g., Ewing sarcoma), and AIDS-related cancers. In some embodiments, the cancer is associated with a rearranged MLL gene. In some embodiments, the pathophysiology of the cancer is dependent on the MLL gene. In some embodiments, the MLL gene is MLL1. In some embodiments, the cancer is associated with a mutant p53 gain-of-function.

[0090] In some embodiments, particular cancers that can be treated by the combinations, compositions, and methods described herein include cardiac cancers, such as sarcomas (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxomas, rhabdomyomas, fibromas, lipomas, and teratomas; lung cancers, including, for example, bronchogenic carcinomas (e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma), alveolar carcinoma, and bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung carcinoma, small cell lung carcinoma, bronchial adenoma / carcinoid, and pleuropulmonary blastoma; gastrointestinal tract cancers, including, for example, cancers of the esophagus (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), cancers of the stomach (e.g., carcinoma, lymphoma, and leiomyosarcoma), cancers of the pancreas (e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, and vipoma), cancers of the small intestine (e.g., adenocarcinoma, lymphoma, carcinoid tumor, Kaposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma), cancers of the large intestine or colon (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma), and other cancers of the digestive tract (e.g., anal cancer, anorectal cancer, appendix cancer, cancer of the anal canal, cancer of the tongue, gallbladder cancer, gastrointestinal stromal tumor (GIST), colon cancer, colorectal cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, rectal cancer, and small intestine cancer); genitourinary tract cancers, including, for example, cancers of the kidney (e.g., adenocarcinoma, nephroblastoma (nephroblastoma), lymphoma, and leukemia), cancers of the bladder and urethra (e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma), cancers of the prostate (e.g., adenocarcinoma and sarcoma), cancers of the testicles (e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, and lipoma), and transitional cell cancer, transitional cell cancer of the renal pelvis and ureter, and other genitourinary tract cancers, urethral cancer, and bladder cancer; liver cancers, including, for example, hepatoma (e.g., hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteoid osteoma (osteocartilaginous exostosis), benign chondrocytic lesion, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system cancers, including, for example, cancers of the skull (e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans); cancers of the meninges (e.g., meningioma, meningiosarcoma, and gliomatosis); cancers of the brain (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors);cancers of the nervous system (e.g., brain stem glioma, diffuse intrinsic pontine glioma (DIPG), brain tumor, central nervous system cancer, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, primary central nervous system lymphoma, visual pathway and hypothalamic glioma, nervous system lymphoma, supratentorial primitive neuroectodermal tumor, pineal tumor, and supratentorial primitive neuroectodermal tumor); gynecologic cancers, including, for example, cancer of the uterus (e.g., endometrial cancer), cancer of the cervix (e.g., cervical cancer and precancerous cervical dysplasia), cancer of the ovary (e.g., ovarian cancer, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecal tumor, Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma), cancer of the vulva (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma), cancer of the vagina (e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma), and cancer of the fallopian tubes (e.g., carcinoma); other reproductive cancers, including, for example, endometrial cancer, endometrial uterine cancer, germ cell tumor, gestational trophoblastic tumor, gestational trophoblastic neoplasia, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, penile cancer, vaginal cancer, vulvar cancer, extracranial germ cell tumor, extragonadal germ cell tumor, uterine cancer, uterine corpus cancer, uterine sarcoma; lymphoid and hematological cancers, including, for example, cancer of the blood (e.g., acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, and myelodysplastic syndrome, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma (malignant lymphoma), and Waldenstrom macroglobulinemia) and other lymphoid or hematological cancers, including, for example, childhood leukemia, myeloproliferative disorders (e.g., primary myelofibrosis), plasma cell neoplasm / multiple myeloma, myelodysplasia, myelodysplastic syndrome, cutaneous T-cell lymphoma, lymphoid neoplasm, AIDS-related lymphoma, thymoma, thymic carcinoma, and thymic carcinoma, mycosis fungoides, and Sezary syndrome; skin cancer, including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma, dysplastic nevi, lipoma, angioma, dermatofibroma, keloid, psoriasis, Merkel cell carcinoma, Merkel skin cancer, melanoma, and carcinoid; adrenal gland cancer, including, for example, neuroblastoma; other cancers associated with the endocrine system, including, for example, adrenocortical carcinoma, multiple endocrine neoplasia (e.g., type I multiple neoplasia), multiple endocrine neoplasia syndrome, parathyroid cancer, pituitary tumor, pheochromocytoma, pancreatic islet cell carcinoma, and islet cell tumor of the pancreas); connective tissue cancer (e.g., bone cancer, bone and joint cancer, osteosarcoma, and malignant fibrous histiocytoma);Cancers associated with the head, neck, and oral cavity (e.g., head and neck cancer, sinus and nasal cavity cancer, metastatic squamous neck cancer, mouth cancer, throat cancer, esophageal cancer, larynx cancer, pharynx cancer, hypopharynx cancer, lip and oral cavity cancer, nasopharynx cancer, oral cavity cancer, oropharynx cancer, and salivary gland cancer), and cancers associated with the eye (e.g., eye cancer, intraocular melanoma). In some embodiments, the cancer is Ewing sarcoma.

[0091] In some embodiments, the cancer is a hematological cancer, such as a leukemia or lymphoma. Exemplary leukemias and lymphomas that can be treated by the compounds of the application include mixed lineage leukemia (MLL), MLL-associated leukemia, MLL-related leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia (MLL-r), leukemia associated with MLL rearrangement or MLL gene rearrangement, acute leukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myelocytic leukemia, childhood leukemia, acute lymphoblastic leukemia (ALL) (also known as acute lymphoblastic leukemia or acute lymphocytic leukemia), acute myeloid leukemia (AML) (also known as acute myelogenous leukemia or acute myelocytic leukemia), acute granulocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia (CLL) (also known as chronic lymphoblastic leukemia), chronic myelocytic leukemia (CML) (also known as chronic myelogenous leukemia), treatment-related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD) (such as primary myelofibrosis (PMF)), myeloproliferative neoplasm (MPN), plasmacytoma, multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, nucleophosmin (NPM1) AML, lymphoid neoplasm, AIDS-related lymphoma, thymoma, carcinoma of the thymus, mycosis fungoides, Alibert-Bazin syndrome, granulomatous mut myeloid (i.e., NPM1

[0092] In particular embodiments, the compounds of the application are used to treat a leukemia associated with MLL rearrangement, an acute lymphoblastic leukemia associated with MLL rearrangement, an acute lymphoblastic lymphoma associated with MLL rearrangement, an acute lymphocytic leukemia associated with MLL rearrangement, an acute myelogenous leukemia associated with MLL rearrangement, an acute myelocytic leukemia associated with MLL rearrangement, or an acute myeloblastic leukemia associated with MLL rearrangement. As used herein, "MLL rearrangement" refers to a rearrangement of the MLL gene.

[0093] In some embodiments, the CYP3A4 inhibitor is: an antiarrhythmic agent; an antihistamine; an azole antifungal agent; a benzodiazepine; a calcium channel blocker; an HIV antiviral agent; an HMG CoA reductase inhibitor; a macrolide antibiotic; a prokinetic agent; a protease inhibitor; or any combination thereof. In some embodiments, the CYP3A4 inhibitor is: alprazolam; amiodarone; amlodipine; aprepitant; aripiprazole; astemizole; atorvastatin; boceprevir; buspirone; chloramphenicol; chlorpheniramine; cimetidine; ciprofloxacin; cisapride; clarithromycin; cobiprostone (GS-9350); an analog or derivative of cobiprostone (GS-9350); cyclosporine; delavirdine; diazepam -> 3-OH; diethyl dithiocarbamate; diltiazem; erythromycin; felodipine; fluconazole; fluvoxamine; gestodene; gleevec; grapefruit juice; haloperidol; imatinib; indinavir; itraconazole; ketoconazole; lovastatin; methadone; mibefradil; midazolam; mifepristone; nefazodone; nelfinavir; nifedipine; nisoldipine; nilvadipine; norfluoxetine; pimozide; quinine; quinidine -> 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; starfruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; triazolam; triazolam; troleandromycin; verapamil; telaprevir; vincristine; voriconazole; or any combination thereof. In some embodiments, the CYP3A4 inhibitor is cobiprostone (GS-9350) or an analog or derivative of cobiprostone (GS-9350). In some embodiments, the CYP3A4 inhibitor is ketoconazole. In some embodiments, the CYP3A4 inhibitor is ritonavir.

[0094] In some embodiments, the method increases the Cmaxof the menin inhibitor by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, 525%, 550%, 575%, 600%, 625%, 650%, 675%, 700%, 725%, 750%, 775%, 800%, 825%, 850%, 875%, 900%, 925%, 950%, 975%, or 1000% as compared to the Cmaxof the menin inhibitor without the CYP3A4 inhibitor. max In some embodiments, the Cmaxof the menin inhibitor is increased by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, 525%, 550%, 575%, 600%, 625%, 650%, 675%, 700%, 725%, 750%, 775%, 800%, 825%, 850%, 875%, 900%, 925%, 950%, 975%, or 1000% as compared to the Cmaxof the menin inhibitor without the CYP3A4 inhibitor. max In some embodiments, the Cmaxof the menin inhibitor is increased by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, 525%, 550%, 575%, 600%, 625%, 650%, 675%, 700%, 725%, 750%, 775%, 800%, 825%, 850%, 875%, 900%, 925%, 950%, 975%, or 1000% as compared to the Cmaxof the menin inhibitor without the CYP3A4 inhibitor. maxabout 20X to about 40X, or about 25X to about 35X. In some embodiments, the method increases the AUC of the menin inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor to about 15X to about 35X, or about 20X to about 30X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor to about 2X to about 35X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor to about 2X to about 30X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor to about 2X to about 25X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor to about 2X to about 20X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor to about 2X to about 15X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor to about 2X to about 10X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor to about 2X to about 5X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the AUC of the menin inhibitor to about 2X to about 4X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the method increases the T max and T 1 / 2 In comparison to the T max and T 1 / 2In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are in a combined dosage form. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are in separate dosage forms. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered concurrently. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered simultaneously, substantially simultaneously, or within the same treatment regimen. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered sequentially. In some embodiments, the method further comprises co-administering cladribine, ifosfamide, doxorubicin, mesalamine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fotatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof. In some embodiments, the method further comprises co-administering cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally rituximab. In some embodiments, the method further comprises co-administering bendamustine and rituximab. In some embodiments, the method further comprises co-administering fludarabine, cyclophosphamide, and rituximab. In some embodiments, the method further comprises co-administering cyclophosphamide, vincristine, and prednisone, and optionally rituximab. In some embodiments, the method further comprises co-administering etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and optionally rituximab. In some embodiments, the method further comprises co-administering dexamethasone and lenalidomide. In some embodiments, the menin inhibitor is amorphous or crystalline.

[0095] Malignant lymphomas are neoplastic transformations of cells that are found primarily in lymphoid tissue. Two groups of malignant lymphomas are Hodgkin's lymphoma and non-Hodgkin's malignant lymphoma (NHL). Both types of lymphoma infiltrate the reticuloendothelial tissue. However, they differ in the origin of the neoplastic cells, the site of the disease, the presence of systemic symptoms, and the response to therapy (Freedman et al., "Non-Hodgkin's Lymphomas" Chapter 134, Cancer Medicine, (an approved publication of the American Cancer Society, B.C. Decker Inc., Hamilton, Ontario, 2003).

[0096] The present combination can also be used to treat patients with leukemia having MLL / KMT2A gene rearrangements.

[0097] Leukemia

[0098] In certain embodiments, disclosed herein is a method of treating leukemia in an individual in need thereof, comprising: administering a menin inhibitor or a CYP3A4 inhibitor. In some embodiments, disclosed herein is a method of treating leukemia in an individual in need thereof, comprising: administering a menin inhibitor and administering a CYP3A4 inhibitor. In certain embodiments, further disclosed herein is a method of treating leukemia in an individual in need thereof, comprising: administering a pharmaceutical composition comprising a menin inhibitor and a CYP3A4 inhibitor. In some embodiments disclosed herein is a method of treating leukemia in an individual in need thereof, comprising: administering a pharmaceutical composition comprising a menin inhibitor and administering a pharmaceutical composition comprising a CYP3A4 inhibitor.

[0099] Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase of white cells, usually leukocytes (white blood cells). Leukemia is a broad term covering a spectrum of diseases. First, there are acute and chronic forms: (i) Acute leukemia is characterized by the rapid increase of immature blood cells. This crowding prevents the bone marrow from producing healthy blood cells. Acute leukemia requires immediate treatment because of the rapid development and accumulation of malignant cells, which then spill out into the bloodstream and spread to other organs of the body. The acute form of leukemia is the most common form of childhood leukemia; (ii) Chronic leukemia is distinguished by the overproduction of relatively mature but still abnormal white blood cells. It usually takes months or years to progress, and these cells are produced at a much higher rate than normal cells, resulting in many abnormal white blood cells in the blood. Chronic leukemia primarily occurs in older people, but in theory can occur in any age group. In addition, the disease is subdivided according to the type of blood cell affected. This division classifies leukemia into lymphoblastic or lymphocytic leukemia and myelogenous or myeloid leukemia: (i) Lymphoblastic or lymphocytic leukemia, the cancerous change occurs in a type of bone marrow cell that normally forms lymphocytes, immune system cells that fight infection; (ii) Myelogenous or myeloid leukemia, the cancerous change occurs in a type of bone marrow cell that normally forms red blood cells, some other types of white blood cells, and platelets.

[0100] Within these main categories, there are several subcategories, including but not limited to acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and hairy cell leukemia (HCL).

[0101] Symptoms, diagnostic tests, and prognostic tests for each of the above conditions are known. See, e.g., Harrison's Principles of Internal Medicine, 17thEd., McGraw-Hill, 2008. "16thEdition, 2004, The McGraw-Hill Companies, Inc. Dey et al. (2006), Cytojournal 3(24) and the "Revised European American Lymphoma" (REAL) classification system (see, e.g., the website maintained by the National Cancer Institute).

[0102] A number of animal models can be used to establish a range of therapeutically effective doses of the inhibitor compound, such as a menin inhibitor, for treating any of the aforementioned diseases.

[0103] During the course of treatment, the efficacy of the menin inhibitor in treating any of the aforementioned diseases can be optimized. For example, the subject being treated can undergo diagnostic assessments to correlate alleviation of disease symptoms or pathology with inhibition of menin activity in vivo by administration of a given dose of the menin inhibitor. Cellular assays known in the art can be used to measure activity in vivo. Thus, the amount of the menin inhibitor compound administered to the subject can be increased or decreased as necessary to maintain optimal levels of menin inhibition for treating the disease state of the subject.

[0104] In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are used in the preparation of a medicament for treating any of the aforementioned conditions. In some embodiments, the combination of the present application is directed to treating leukemia. In some embodiments, the present application is directed to treating leukemia in a patient in need thereof, comprising administering a menin inhibitor and a CYP3A4 inhibitor. In some further embodiments, the present application is directed to treating leukemia in a patient in need thereof, comprising administering a pharmaceutical composition comprising a menin inhibitor and a pharmaceutical composition comprising a CYP3A4 inhibitor. In some further embodiments, the present application is directed to treating leukemia in a patient in need thereof, comprising administering a pharmaceutical composition comprising a menin inhibitor of Formula I and a pharmaceutical composition comprising an azole antifungal CYP3A4 inhibitor.

[0105] Acute leukemias are generally caused by acquired mutations in hematopoietic progenitor cells. Chromosomal abnormalities are generally a feature of discrete mutations in leukemia. Many of these chromosomal abnormalities are due to specific translocations leading to the formation of fusion genes that are drivers of tumorigenesis and tumor progression. One specific example involves the MLL1 gene. Translocations of the MLL1 locus (11q23) can lead to the formation of oncogenic fusion genes that are characteristic of MLLr acute leukemia. The MLL1 protein is a key regulator of development, the mammalian homolog of trithorax in Drosophila. It is an important epigenetic regulator of HOX gene expression. Translocations of the MLL1 locus result in chimeric proteins that fuse the N-terminus of MLL1 to a variable C-terminal domain from a different translocation partner. Over 90 different fusion partners are currently known. Expression of these fusions enables an aberrant transcriptional program characterized by overexpression of HOX and other developmental genes. This transcriptional program suppresses differentiation and enhances proliferation, leading to MLLr acute leukemia. Routine diagnosis involving translocations of the MLL1 locus (11q23) is performed using fluorescence in situ hybridization (FISH). Depending on the progenitor cell of origin, MLLr can present as ALL, AML, or mixed phenotype acute leukemia (MPAL). These translocations are rare, with a total annual incidence of ~4000 MLLr in the United States, Europe, and Japan. Approximately 10% of all leukemias have MLL1 translocations.

[0106] The present combination can also be used to treat patients with leukemia having MLL / KMT2A gene rearrangements.

[0107] MLLr patients have a high risk of relapse after conventional chemotherapy and stem cell transplantation, with an overall 5-year survival of only about 35%. There are currently no treatments that specifically target MLLr leukemia. The menin inhibitors of Formula I or Formula II in combination with a CYP3A4 inhibitor can provide a new targeted treatment for MLLr acute leukemia.

[0108] Treatment of relapsed or refractory MLLr acute leukemia

[0109] The interaction of MLL1 fusion proteins with menin is a key driver of MLLr acute leukemia. Both MLL1 and MLLr fusions bind to a well-characterized high-affinity site on the chromatin-associated protein menin. The binding of MLL1 fusions to menin is mediated by amino acid residues 9-13 (FPARP) of the N-terminus of MLL1. Binding to menin localizes these fusions to chromatin, initiating the leukemia transcriptional program, including upregulation of the HOXA locus and the MEIS1 gene. The interaction between the fusion proteins and menin is required to maintain this transcriptional program.

[0110] Menin inhibitors of Formula I or Formula II bind with high affinity to the MLL1 binding pocket on menin and show activity in a range of cells containing MLLr fusions. Menin inhibitors of Formula I or Formula II disrupt the interaction between menin and MLL1 fusion proteins required for leukemia activity, impairing expression of key oncogenes, leading to growth arrest and inhibition of cell proliferation. Small molecule inhibitors of the menin-MLL interaction have been reported. These inhibitors have shown anti-proliferative activity against MLLr cell lines and shown single agent survival benefit in MLLr leukemia mouse models.

[0111] Similarly, menin inhibitors of Formula I or Formula II in combination with CYP3A4 inhibitors increase efficacy and show robust activity in a variety of leukemia xenograft models and provide profound survival benefit after oral dosing in nonclinical models. Collectively, these data suggest that pharmacological inhibition of the menin-MLL interaction is a potential targeted strategy for treating MLLr acute leukemias.

[0112] NPM1c AML

[0113] AML is an acute leukemia characterized by an accumulation of myeloid cells in the bone marrow due to impaired differentiation and proliferation. NPM1 is one of the most common mutated genes in AML. Point mutations in the NPM1 gene lead to aberrant cytoplasmic localization of the mutant protein, termed NPM1c. Identification of NPM1c is an important part of the diagnostic screening for AML. Patients with AML in whom NPM1 has a mutation have a favorable prognosis with a five-year overall survival (OS) of ~60%. However, the majority (>80%) of NPM1c AML patients have multiple concurrent mutations that can have a detrimental effect on prognosis. Co-mutations are found in the FLT3, DNMT3A, NRAS, TET2, and IDH1 / 2 genes. NPM1c is not typically found in ALL.

[0114] The American Cancer Society estimates that there will be ~21,450 new cases of AML in the United States in 2019. In adult AML, ~30% of patients have NPM1c. Given that cells harboring NPM1c are highly sensitive to menin-MLL interaction inhibitors, menin inhibitors of Formula I or Formula II in combination with CYP3A4 inhibitors can provide a new targeted treatment for NPM1c AML.

[0115] Treatment of NPM1c AML patients

[0116] NPM1 normally exists as a nucleolar protein between the nucleus and cytoplasm. It has multiple functions, including the assembly and transport of ribosomal proteins, control of centrosome replication, and the regulation of the tumor suppressor ARF. The cytoplasmic localization of mutant NPM1c results in abnormal distribution of NPM1c-associated nuclear proteins into the cytoplasm, including several transcription factors. Among these is PU.1, a major driver of monocyte lineage differentiation. Loss of PU.1 from the nucleus in NPM1c AML leads to repression of >500 terminal differentiation genes. The inhibition of differentiation by NPM1c enables the leukemia transcriptional program to be highly dependent on upregulated expression of HOXA cluster and MEIS1 genes. Expression of these genes further blocks differentiation and induces long-term proliferation, leading to the leukemia phenotype.

[0117] Furthermore, the HOX / MEIS signature of NPM1c AML overlaps with the HOX / MEIS signature of MLLr leukemias and hematopoietic stem cells (HSCs). Maintenance of this transcriptional signature in NPM1c cells is directly dependent on the menin-MLL1 interaction.

[0118] While little is known about how mutant NPM1c cells maintain aberrant gene expression, mutations in the menin-binding motif of MLL1 have been shown to strongly inhibit the proliferative capacity of NPM1c due to loss of binding to menin. Furthermore, the small molecule menin-MLL interaction inhibitor MI-503 was shown to inhibit the HOXA / MEIS1 transcriptional program in NPM1c cells, leading to growth arrest, terminal differentiation, and cell death, confirming the critical role of the menin-MLL1 interaction in NPM1c. These findings were verified and extended in another report demonstrating that the orally active menin inhibitor KO-539 has potent anti-leukemic activity in a NPM1c mutant AML patient-derived xenograft model. Collectively, these results indicate that cells harboring NPM1c are highly sensitive to menin-MLL interaction inhibitors.

[0119] In some embodiments, the combination of the present application is used to treat NMP1 AML. In some embodiments, the present application relates to treating NMP1 AML in a patient in need thereof, comprising administering a menin inhibitor and a CYP3A4 inhibitor. In some further embodiments, the present application relates to treating NMP1 AML in a patient in need thereof, comprising administering a pharmaceutical composition comprising a menin inhibitor and a pharmaceutical composition comprising a CYP3A4 inhibitor. In some further embodiments, the present application relates to treating NMP1 AML in a patient in need thereof, comprising administering a pharmaceutical composition comprising a menin inhibitor of Formula I and a pharmaceutical composition comprising an azole antifungal CYP3A4 inhibitor.

[0120] Other combination therapies

[0121] In some cases, it is appropriate to administer menin inhibitors and CYP3A4 inhibitors in combination with other therapeutic agents. In other cases, it is appropriate to administer menin inhibitors and CYP3A4 inhibitors in combination with another CYP3A4 inhibitor. The additional therapeutic agents are selected based on their specific use for the condition being treated. Generally, it is not necessary to administer additional therapeutic agents with the same pharmaceutical composition, simultaneously or via the same route, and with menin inhibitors and / or CYP3A4 inhibitors. In some embodiments, an initial administration is performed according to an established regimen, and then the dosage, administration mode, and timing are further modified based on observed effects.

[0122] In some embodiments, additional therapeutic agents are administered in parallel (e.g., simultaneously, substantially simultaneously, or within the same treatment regimen) or sequentially, depending on the nature of the disease, the patient's condition, and the actual selection of the compound used. In some embodiments, the determination of the order of administration and the number of repetitions of each therapeutic agent during the treatment regimen is based on an assessment of the disease being treated and the patient's condition.

[0123] The dosage of other treatments varies depending on the other treatment, the disease or condition being treated, etc.

[0124] In some embodiments, this document discloses methods for treating autoimmune diseases, xenoimmune diseases, inflammatory diseases, and / or cancer in individuals with this need, including administering a menin inhibitor, a CYP3A4 inhibitor, and additional therapeutic agents to the individual. In some embodiments, this document further discloses methods for treating autoimmune diseases in individuals with this need, including administering a menin inhibitor, a CYP3A4 inhibitor, and additional therapeutic agents to the individual. In some embodiments, this document also discloses methods for treating xenoimmune diseases in individuals with this need, including administering a menin inhibitor, a CYP3A4 inhibitor, and additional therapeutic agents to the individual. In some embodiments, this document discloses methods for treating inflammatory diseases in individuals with this need, including administering a menin inhibitor, a CYP3A4 inhibitor, and additional therapeutic agents to the individual. In some embodiments, this document further discloses methods for treating cancer in individuals with this need, including administering a menin inhibitor, a CYP3A4 inhibitor, and additional therapeutic agents to the individual.

[0125] In certain embodiments, disclosed herein are methods of treating an autoimmune disorder, a heteroimmune disorder, an inflammatory disorder, and / or a cancer in an individual in need thereof, comprising administering to the individual the menin inhibitor, the CYP3A4 inhibitor, and the additional therapeutic agent. In certain embodiments, further disclosed herein are methods of treating an autoimmune disorder in an individual in need thereof, comprising administering to the individual the menin inhibitor, the CYP3A4 inhibitor, and the additional therapeutic agent. In certain embodiments, also disclosed herein are methods of treating a heteroimmune disorder in an individual in need thereof, comprising administering to the individual the menin inhibitor, the CYP3A4 inhibitor, and the additional therapeutic agent. In certain embodiments, disclosed herein are methods of treating an inflammatory disorder in an individual in need thereof, comprising administering to the individual the menin inhibitor, the CYP3A4 inhibitor, and the additional therapeutic agent. In certain embodiments, further disclosed herein are methods of treating a cancer in an individual in need thereof, comprising administering to the individual the menin inhibitor, the CYP3A4 inhibitor, and the additional therapeutic agent.

[0126] In some embodiments, administering the menin inhibitor prior to the second cancer treatment regimen reduces the immune-mediated response to the second cancer treatment regimen. In some embodiments, administering the menin inhibitor prior to ofatumumab reduces the immune-mediated response to ofatumumab.

[0127] In some embodiments, the additional therapeutic agent is a chemotherapeutic agent, a steroid, an immunotherapeutic agent, a targeted therapy, or a combination thereof. In some embodiments, the additional therapeutic agent is a CD79A inhibitor, a CD79B inhibitor, a CD19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K inhibitor, a Blnk inhibitor, a PLCy inhibitor, a PKCP inhibitor, or a combination thereof. In some embodiments, the additional therapeutic agent is an antibody, a B-cell receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTOR inhibitor, a radioimmunotherapy, a DNA damaging agent, a proteosome inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, a Hsp90 inhibitor, a telomerase inhibitor, a Jak l / 2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combination thereof.

[0128] In some embodiments, the additional therapeutic agent is lenalidomide, ifosfamide, doxorubicin, mesalamine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.

[0129] In some embodiments, the additional therapeutic agent is cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone, and optionally rituximab. In some embodiments, the additional therapeutic agent is bendamustine and rituximab. In some embodiments, the additional therapeutic agent is fludarabine, cyclophosphamide, and rituximab. In some embodiments, the additional therapeutic agent is cyclophosphamide, vincristine, and prednisone, and optionally rituximab. In some embodiments, the additional therapeutic agent is etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and optionally rituximab. In some embodiments, the additional therapeutic agent is dexamethasone and lenalidomide

[0130] Additional therapeutic agents that can be administered in combination with the combination of a menin inhibitor and a CYP3A4 inhibitor include, but are not limited to, nitrogen mustards, such as bendamustine, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, prednimustine, trofosfamide; alkyl sulfonates, such as busulfan, mannosulfan, thiotepa; ethylenimines, such as carboquone, thioepa, triaziquone; nitrosoureas, such as carmustine, fotemustine, lomustine, nimustine, ranimustine, semustine, and streptozocin; epoxides, such as etoglucid; other alkylating agents, such as dacarbazine, dibromomannitol, pipobroman, temozolomide; folic acid analogues, such as methotrexate, pemetrexed, pralatrexate, raltitrexed; purine analogues, such as cladribine, chlorfarabine, fludarabine, mercaptopurine, nelarabine, thioguanine; pyrimidine analogues, such as azacitidine, capecitabine, carmofur, cytarabine, decitabine, fluorouracil, gemcitabine, tegafur; vinca alkaloids, such as vinblastine, vincristine, vindesine, vinflunine, vinorelbine; podophyllotoxin derivatives, such as etoposide, teniposide; colchicine derivatives, such as demecolcine; taxoids, such as docetaxel, paclitaxel, paclitaxel polyglucoside; other plant alkaloids and natural products, such as trabectedin; actinomycins, such as dactinomycin; anthracyclines, such as doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin, valrubicin, and zorubicin; other cytotoxic antibiotics, such as bleomycin, exetecan, mitomycin, plicamycin; platinum compounds, such as carboplatin, cisplatin, oxaliplatin, satraplatin; methyl hydrazines, such as procarbazine; sensitizers, such as aminolevulinic acid, efaproxiral, aminolevulinic acid methyl ester, porfimer sodium, temoporfin; protein kinase inhibitors, such as dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, temsirolimus; other antineoplastic agents, such as alitretinol, alitretinol, amonodendrine, anagrelide, arsenic trioxide, asparaginase, bexarotene, bortezomib, celecoxib, denileukin diftitox, estramustine, hydroxycarbamide, irinotecan, lonidamide, masoprocol, miltefosine, mitoguazone, mitotane, oblimersen, pegaspargase, pentazocine, romurtide, sitimagene ceradenovec, tiazofurin, topotecan, tretinoin, vorinostat;Estrogens, such as diethylstilbestrol, ethinyl estradiol, fosfestrol, polyestradiol phosphate;

[0131] Gonadotropin-releasing hormone analogs, such as buserelin, goserelin, leuprolide, triptorelin; antiestrogens, such as fulvestrant, tamoxifen, toremifene; antiandrogens, such as bicalutamide, flutamide, nilutamide, enzyme inhibitors, aminoglutethimide, anastrozole, exemestane, formestane, letrozole, vorozole; other hormone antagonists, such as abarelix, degarelix; immunostimulants, such as histamine dihydrochloride, mifamurti, pidotimod, plitidepsin, roquinimex, thymopentin; immunosuppressants, such as everolimus, gusperimus, leflunomide, mycophenolic acid, sirolimus; calcineurin inhibitors, such as cyclosporin, tacrolimus; other immunosuppressants, such as azathioprine, lenalidomide, methotrexate, thalidomide; and radiopharmaceuticals, such as iobenguane.

[0132] Other therapeutic agents that can be administered in combination with the combination of a menin inhibitor and a CYP3A4 inhibitor include, but are not limited to, interferons, interleukins, tumor necrosis factors, growth factors, and the like.

[0133] Additional therapeutic agents that can be administered in combination with the combination of a menin inhibitor and a CYP3A4 inhibitor include, but are not limited to, immunostimulants, such as amcinitide, filgrastim, lenograstim, molgramostim, pegfilgrastim, and sargramostin; interferons, such as interferon alfa-natural, interferon a-2a, interferon a-2b, interferon alfa-1, interferon alfa-nl, interferon beta-natural, interferon beta-la, interferon beta-lb, interferon gamma, peginterferon alfa-2a, peginterferon alfa-2b; interleukins, such as interleukin, oracept; other immunostimulants, such as BCG vaccine, glatiramer acetate, dihydrohistamine, imucox, lentinan, melanoma vaccine, milamperide, peginterferon, pidotimod, plitidepsin, poly I:C, poly ICLC, roquinimex, tasonermin, thymopentin; immunosuppressants, such as abatacept, alefacept, antilymphocyte immunoglobulin (horse), antithymocyte immunoglobulin (rabbit), eculizumab, efalizumab, everolimus, gusperimus, leflunomide, muromab-CD3, mycophenolic acid, natalizumab, sirolimus; TNF alpha inhibitors, such as adalimumab, afelimomab, certolizumab, etanercept, golimumab, infliximab; interleukin inhibitors, such as anakinra, basiliximab, conatumumab, daclizumab, mapatumumab, rilonacept, tocilizumab, ustekinumab; calmodulin inhibitors, such as cyclosporine, tacrolimus; other immunosuppressants, such as azathioprine, lenalidomide, methotrexate, thalidomide.

[0134] Other therapeutic agents that can be administered in combination with the combination of a menin inhibitor and a CYP3A4 inhibitor include, but are not limited to, Adalimumab, Alemtuzumab, Basiliximab, Bevacizumab, Cetuximab, Certolizumab pegol, Daclizumab, Eculizumab, Efalizumab, Gemtuzumab, Ibritumomab tiuxetan, Infliximab, Muromonab-CD3, Natalizumab, Panitumum, Ranibizumab, Rituximab, Tositumomab, Trastuzumab, and the like, or combinations thereof.

[0135] Additional therapeutic agents that can be administered in combination with the combination of a menin inhibitor and a CYP3A4 inhibitor include, but are not limited to, monoclonal antibodies, such as alemtuzumab, bevacizumab, catumaxomab, cetuximab, edrecolomab, gemtuzumab, ofatumumab, panitumumab, rituximab, trastuzumab, immunosuppressants, eculizumab, efalizumab, muromonab-CD3, natalizumab; TNF-a inhibitors, such as adalimumab, afelimomab, certolizumab pegol, golimumab, infliximab; interleukin inhibitors, basiliximab, canakinumab, daclizumab, mepolizumab, tocilizumab, ustekinumab; radiopharmaceuticals, ibritumomab tiuxetan, tositumomab; other monoclonal antibodies,For example, abagovomab, adecatumumab, alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET monoclonal antibody MetMab, apolizumab, apomab, arcitumomab, basiliximab, bispecific antibody 2B1, blinatumomab, brentuximab vedotin, capromab pendetide, cixutumab, claudiximab, conatumumab, dacetuzumab, denosumab, eculizumab, epratuzumab, epratuzumab, ertumaxomab, etaracizumab, figitumumab, fresoliumab, galiximab, ganitumab, gemtuzumab ozogamicin, glembatumumab, ibritumomab, inotuzumab ozogamicin, ipilimumab, lexatumumab, lintuzumab, lintuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, monoclonal antibody CC49, nectinumab, nimotuzumab, ofatumumab, oregovomab, pertuzumab, ramucirumab, ranibumab, siplizumab, sonepcizumab, tanezumab,Tositumomab, Trastuzumab, Tremelimumab, tucotuzumab celmoleukin, Veltuzumb, Visilizumab, Volociximab, Zalutuumab.

[0136] Other therapeutic agents that can be combined with the combination of a menin inhibitor and a CYP3A4 inhibitor include, but are not limited to, agents that affect the tumor microenvironment, such as cellular signaling networks (e.g., phosphatidylinositol 3-kinase (PI3K) signaling pathway, signaling from B-cell receptor and IgE receptor). In certain embodiments, the second agent is a PI3K signaling inhibitor or a syk kinase inhibitor. In some embodiments, the syk inhibitor is R788. In another embodiment, the second agent is a PKCy inhibitor, such as, by way of example only, enzastaurin.

[0137] Examples of agents that affect the tumor microenvironment include PI3K signaling inhibitors, syc kinase inhibitors, protein kinase inhibitors, e.g., dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, temsirolimus; other angiogenesis inhibitors, e.g., GT-111, JI-101, R1530; other kinase inhibitors, e.g., AC220, AC480, ACE-041, AMG 900, AP24534, Arry-614, AT7519, AT9283, AV-951, axitinib, AZD1152, AZD7762, AZD28055, AZD 8931, bortezomib, BAY 73-4506, BGJ398, BGT226, BI 811283, BI6727, BIBF 1120, BIBW 2992, BMS-690154, BMS-777607, BMS-863233, BSK-461364, CAL-101, CEP-1981, CYC116, DCC-2036, dinaciclib, dovitinib lactate, E7050, EMD 1214063, ENMD-2076, fostamatinib disodium, GSK2256098, GSK690693, INCB18424, INNO-406, JNJ-26483327, JX-594, KX2-391, linifanib, LY2603618, MGCD265, MK-0457, MK1496, MLN8054, MLN8237, MP470, NMS-1116354, NMS-1286937, ON01919.Na, OSI-027, OSI-930, PF-00562271, PF-02341066, PF-03814735, PF-04217903, PF-04554878, PF-04691502, PF-3758309, PHA-739358, PLC3397, progenipoietin, R547, R763, ramucirumab, regorafenib, R05185426, SAR103168, SCH 727965, SGI-1176, SGX523, SNS-314, TAK-593, TAK-901, TKI258, TLN-232, TTP607, XL147, XL228, XL281R05126766, XL418, xl 765.

[0138] Other examples of therapeutic agents for use in combination with a menin inhibitor and a CYP3A4 inhibitor include, but are not limited to, mitogen-activated protein kinase signaling inhibitors, such as U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituximab).

[0139] Other agents that can be used in combination with the menin inhibitors and CYP3A4 inhibitors include, but are not limited to, doxorubicin, dactinomycin, bleomycin, vinblastine, cisplatin, acyclovir; aclarubicin; acridine carboxamide; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; aspergillin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimethylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladrine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate;Dromostanolone propionate; Duazomycin; Edatrexate; Eflomithine hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin hydrochloride; Erbulozole; Esorubicin hydrochloride; Estramustine; Estramustine phosphate sodium; Etanidazole; Etoposide; Etoposide phosphate; Etotrine; Fadrozole hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine phosphate; Fluorouracil; Flurocitabine; Fosquidone; Fostriecin sodium; Gemcitabine; Gemcitabine hydrochloride; Hydroxycarbamide; Idarubicin hydrochloride; Ifosfamide; Iimofosine; Interleukin II (including recombinant interleukin II or rIL2), Interferon alpha-2a; Interferon alpha-2b; Interferon alpha-nl; Interferon alpha-n3; Interferon beta-1a; Interferon gamma-1b; Iproplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprolide acetate; Liarozole hydrochloride; Lometrexol sodium; Lomustine; Losoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride;megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; Mycophenolic Acid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; piicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracilmustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

[0140] Other therapeutic agents that can be used in combination with menin inhibitors and CYP3A4 inhibitors include, but are not limited to, 20-epi-1,25-dihydroxyvitamin D3; 5-ethyluracil; abiraterone; arubicin; acylflurane; adecylin; adozelene; aldoxanthin; ALL-TK antagonists; taurine; ambasitin; amoxyfen; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide. Anastrozole; Andrographolide; Angiogenesis inhibitor; Antagonist D; Antagonist G; Antirelione; Anti-morphogenetic protein-1; Anti-androgen, prostate cancer; Anti-estrogen; Antitumor drug; Antisense oligonucleotide; Glycine aphidin; Apoptosis gene regulator; Apoptosis regulator; Purine acid; ara-CDP-DL-PTBA; Arginine deaminase; Picric acid; Atamitan; Atrimustine; Axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivative; balanol; bamastatin; BCR / ABL antagonist; benzodihydroporphyrin; benzoylsterosporin; β-lactam derivative; β-alethine; β-clamycin B; betulinic acid; bFGF inhibitor; bicalutamide; biscarboxylic acid; diazidopropyltriazine; bis(2-ethylhexyl)sulfuron; bistratene A; breflate; brompirimidine; budotitanium; butylthionine; calcipotriol; carboxystatin C; camptothecin derivative; canarypox IL-2; capecitabine; carbamoylaminotriazole; carboxymethylaminotriazole; CaRest M3; CARN 700; Chondroitin-derived inhibitors; Carvacrol; Casein kinase inhibitors (ICOS); Spermine; Bactericidal peptide B; Cetrolec; Chlorin; Chloroquinoxaline sulfonamide; Cicalprost; Cis-porphyrin; Cladribine; Clomiphene analogs; Clotrimazole; Collosimycin A; Collosimycin B; Cobustatin A4; Cobustatin analogs; Conagenin; Crambescidin 816; Crizotinol; Cryptocycin 8; Cryptocycin A derivatives; Curacin A; Cyclopentanthraquinone; Cycloplatam; Cypemycin; Cytarabine octadecyl phosphate; Cytolysin; Hexestrol phosphate; Dacizumab; Decitabine; Dehydrating cytokine B; Dexamethasone; Dexamethasone; Dexamethasone; Dexamethasone; Dexamethasone; Dexamethasone; Dexamethasone; Dexamethasone; Dexamethasone B; Didox;Dihydro-5-azacytidine; 9-dioxamycin; Diphenylspiromustine; Docetaxel; Dolasetron; Doxifluridine; Droloxifene; Dronabinol; Duocarmycin SA; Edelfosine; Enchiomycin; Endostatin; Endothall; Enfumafungin; Enzalutamide; Estramustine analogue; Estrogen agonists; Estrogen antagonists; Ethamivan; Etoposide phosphate; Exemestane; Fadrazole; Fazarabine; Fenretinide; Filgrastim; Finasteride; Flavopiridol; Fluacrylinate; Fluasterone; Fludarabine; Fluorodaunorunicin hydrochloride; Fulamic acid meclofenamate; Fulematan; Fuligerol; Fumagillin; Fumidil; Gallium nitrate; Galocitabine; Ganirelix; Gelatinase inhibitor; Gemcitabine; Glutathione inhibitor; Hepsulfam; Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronate; Idarubicin; Idoxifene; Idomycinone; Ilmofosine; Ilomastat; Imidazoacridone; Imiquimod; Immunostimulant peptide; Insulin such as growth factor-1 receptor inhibitor; Interferon agonists; Interferons; Interleukins; Iobenguane; Iodostramustine; Ipomeanol, 4-; Iroplax; Isoarrhydine; Isobengazole; Isohomohalicondrin B; Itasetron; Jasplakinolide; Kahalalide F; Kainopsin-N triacetate salt; Lanreotide; Leinamycin; Lenograstim; Lentinan sulfate; Leptolstatin; Letrozole; Leukemia inhibitory factor; Leukocyte alpha interferon; Leuprolide + estrogen + progestin; Leuprolide; Levamisole; Liarozole; Linear polyamine analogues; Lipid-containing disaccharide peptide; Lipophilic uranium compounds; Lissoclinamide 7; Lobaplatin; Lombricine; Lometrexol; Lonidamide; Loxoribine; Lovastatin; Losoxantrone; Lurtotecan; Lutetium texaphyrin; Lysofylline; Lytic peptide; Martinelone; Matriptase; Masoprocol; Maspin; Matrix metalloproteinase inhibitor; Meneril; Merbarone; Metazolidine; Methioninase; Metoclopramide; MIF inhibitor; Mifepristone; Milatuzumab; Miltefosine; Mipomersen; Misoprostol; Mitoguazone; Mitolactol; Mitomycin analogue; Mitonafide; Mitotoxin fibroblast growth factor-saporin; Mitoxantrone; Mopidamol; Morabillast; Monoclonal antibody, human chorionic gonadotropin; Monophosphoryl lipid A + mycobacterial cell wall sk; Morindole; Multidrug resistance gene inhibitor; Multitargeted inhibitor 1-based therapy; Mustard anticancer agent;Indian ocean sponge B (mycaperoxide B); mycobacterial cell wall extract; myriaporone; N-acetyl-D-phenylalanine; N-substituted benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitrooxy antioxidants; nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducers; ormaplatin; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabulin; pazelliptine; pegaspargase; pentostatin; pentrozole; perfluorobutane; perchlorate; perphenantin; phospholipase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; plicamycin; porothrast A; porothrast B; plasminogen activator inhibitor; platinum complexes; platinum compounds; platinum-triamine complexes; podoconol; porfiromycin; prednisone; procarbazine; prostaglandin J2; proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; protein kinase C inhibitors from a microorganism; proteintemoporfm; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thioacronine; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymic humoral factor; thymomodulin; thyrotropin; tin ethyletiopurpurin; tirapazamine; titanium tetrachloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; tyrosine kinase inhibitors; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; unrogential sinus-derived growth inhibitory factor; urokinase receptor antagonist; vaponeomab; violin B; vector systems, red blood cell gene therapy; verlarcol; veratramine; verdins; verteporfm; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zinecard; zileuton; and zolendicin.

[0141] Additional therapeutic agents that can be administered in combination with the menin inhibitors and CYP3A4 inhibitors include, but are not limited to, another CYP3A4 inhibitor, an alkylating agent, an antimetabolite, a natural product, or a hormone, such as a nitrogen mustard (e.g., mechlorethamine, cyclophosphamide, chlorambucil, etc.), an alkyl sulfonate (e.g., busulfan), a nitrosourea (e.g., carmustine, lomustine, etc.), or a triazene (dacarbazine, etc.). Examples of antimetabolites include, but are not limited to, a folic acid analog (e.g., methotrexate) or a pyrimidine analog (e.g., floxouridine, cytarabine), a purine analog (e.g., mercaptopurine, thioguanine, pentostatin).

[0142] Examples of alkylating agents include, but are not limited to, a nitrogen mustard (e.g., mechlorethamine, cyclophosphamide, chlorambucil, melphalan, etc.), an ethyleneimine and methylmelamine (e.g., hexamethylmelamine, thiotepa), an alkyl sulfonate (e.g., busulfan), a nitrosourea (e.g., carmustine, lomustine, semustine, streptozocin, etc.), or a triazene (dacarbazine, etc.). Examples of antimetabolites include, but are not limited to, a folic acid analog (e.g., methotrexate) or a pyrimidine analog (e.g., floxouridine, cytarabine), a purine analog (e.g., mercaptopurine, thioguanine, pentostatin).

[0143] Additional therapeutic agents that can be administered in combination with the combination of a menin inhibitor and a CYP3A4 inhibitor include, but are not limited to: Erbulozole (also known as R-55104), Docetaxel 10 (also known as DLS-10 and NSC-376128), Isoleucine Thioovabrine (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtin (e.g., Altorhyrtin A and Altorhyrtin C), Cryptophycin (e.g., Cryptophycin 1, Cryptophycin 2, Cryptophycin 3, Cryptophycin 4, Cryptophycin 5, Cryptophycin 6, Cryptophycin 7, Cryptophycin 8, and Cryptophycin 9), Cephalomycin (also known as LU-103793 and NSC-D-669356), Epothilone (e.g., Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also known as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone AN-oxide, 16-aza-Epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharma, also known as LS-477-P), LS-4 477 (Pharmachia), LS-5559 (Pharmasia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF,also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-35703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCI and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin Al (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemisterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine,also known as MF-191), TMPN (Arizona State University), Diacetyladiphenylene-diamine, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-1AABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), Eleutherobin (such as Desmethyleleutherobin, Desaetyleleutheropin, Isoelseleutherobin A and Z-Eleutherobin), Caribaeoside, Caribeiolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbot), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbot), HTI-286 (also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentoris), D-81318 (Zenteris), SC-12983 (NCI), Resveratrol phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0144] Menin inhibitors and CYP3A4 inhibitors can be used in combination with immunosuppressants (e.g., tacrolimus, cyclosporine, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, flurandrenolide, deoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (e.g., salicylates, arylalkylic acids, 2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or sulfonanilamides), Cox-2 specific inhibitors (e.g., valdecoxib, celecoxib, or rofecoxib), leflunomide, aurothioglucose, aurothiomalate, aurom, sulfasalazine, hydroxychloroquine, minocycline, TNF-a binding proteins (e.g., infliximab, etanercept, or adalimumab), abatacept, anakinra, interferon-beta, interferon-gamma, interleukin-2, allergen vaccines, antihistamines, anti-leukotrienes, beta agonists, theophylline, or anticholinergic agents.

[0145] Pharmaceutical compositions / formulations

[0146] In certain embodiments, the pharmaceutical compositions disclosed herein include a menin inhibitor and a pharmaceutically acceptable excipient, and a CYP3A4 inhibitor and a pharmacologically acceptable excipient. In certain embodiments, further disclosed herein are pharmaceutical compositions comprising (a) a menin inhibitor and a CYP3A4 inhibitor, and (b) a pharmaceutically acceptable excipient.

[0147] In some embodiments, the CYP3A4 inhibitor is: an antiarrhythmic; an antihistamine; an azole antifungal; a benzodiazepine; a calcium channel blocker; an HIV antiviral; an HMG CoA reductase inhibitor; a macrolide antibiotic; a prokinetic agent; a protease inhibitor; or any combination thereof. In some embodiments, the CYP3A4 inhibitor is: posaconazole, conivaptan, lopinavir, alprazolam; amiodarone; amlodipine; aprepitant; aripiprazole; astemizole; atorvastatin; boceprevir; buspirone; chloramphenicol; chlorpheniramine; cimetidine; ciprofloxacin; cisapride; clarithromycin; cobicistat (GS- 9350); an analog or derivative of cobicistat (GS-9350); cyclosporine; delavirdine; diazepam -> 3-OH; diethyl dithiocarbamate; diltiazem; erythromycin; felodipine; fluconazole; fluvoxamine; gestodene; gleevec; grapefruit juice; haloperidol; imatinib; indinavir; itraconazole; ketoconazole; lovastatin; methadone; mibefradil; midazolam; mifepristone; nefazodone; nelfinavir; nifedipine; nisoldipine; nilvadipine; norfluoxetine; pimozide; quinine; quinidine -> 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; starfruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; triazolam; triazolam; verapamil; telaprevir; vincristine; voriconazole; or any combination thereof.

[0148] In some embodiments, the CYP3A4 inhibitor is posaconazole. In some embodiments, the CYP3A4 inhibitor is cobicistat (GS-9350) or an analog or derivative of cobicistat (GS-9350). In some embodiments, the CYP3A4 inhibitor is ketoconazole. In some embodiments, the CYP3A4 inhibitor is ritonavir. In some embodiments, the CYP3A4 inhibitor is conivaptan. In some embodiments, the CYP3A4 inhibitor is lopinavir.

[0149] In some embodiments, the menin inhibitor is amorphous or crystalline. In some embodiments, the menin inhibitor is milled or is a nanoparticle. In some embodiments, the pharmaceutical composition is a combination dosage form. In some embodiments, the composition increases oral bioavailability of the menin inhibitor. In some embodiments, the composition increases Cmaxof the menin inhibitor. max In some embodiments, the composition increases AUC of the menin inhibitor. In some embodiments, the composition increases Cmaxof the menin inhibitor. max Cmaxof the menin inhibitor without administration of a CYP3A4 inhibitor maxabout 40X, or about 25X to about 35X. In some embodiments, the composition increases the AUC of the menin inhibitor by about 15X to about 35X, or about 20X to about 30X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition increases the AUC of the menin inhibitor by about 2X to about 35X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition increases the AUC of the menin inhibitor by about 2X to about 30X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition comprises an amount of the CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 2X to about 25X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition comprises an amount of the CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 2X to about 20X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition comprises an amount of the CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 2X to about 15X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition comprises an amount of the CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 2X to about 10X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition comprises an amount of the CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 2X to about 5X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the composition comprises an amount of the CYP3A4 inhibitor effective to increase the AUC of the menin inhibitor by about 2X to about 4X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the T max and T 1 / 2 max of the menin inhibitor is not significantly affected by the composition as compared to the Tmax of the menin inhibitor administered without the CYP3A4 inhibitor. max and T 1 / 2 max of the menin inhibitor is not significantly affected by the composition as compared to the Tmax of the menin inhibitor administered without the CYP3A4 inhibitor.

[0150] In some embodiments, the pharmaceutical composition further comprises cloretazine, ifosfamide, doxorubicin, mesalamine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof. In some embodiments, the pharmaceutical composition further comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally rituximab. In some embodiments, the pharmaceutical composition further comprises bendamustine and rituximab. In some embodiments, the pharmaceutical composition further comprises fludarabine, cyclophosphamide, and rituximab. In some embodiments, the pharmaceutical composition further comprises cyclophosphamide, vincristine, and prednisone, and optionally rituximab. In some embodiments, the pharmaceutical composition further comprises etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and optionally rituximab. In some embodiments, the pharmaceutical composition further comprises dexamethasone and lenalidomide.

[0151] The pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients can be used as suitable and as understood in the art. A general overview of the pharmaceutical compositions described herein is found in, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999), which are incorporated herein by reference in their entirety.

[0152] A pharmaceutical composition as used herein refers to a mixture of a menin inhibitor, a CYP3A4 inhibitor, and / or an additional therapeutic agent with other chemical components such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients.

[0153] In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound disclosed herein is administered, having a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. The therapeutically effective amount of the compound can vary depending on the compound, the severity of the disease, the age and relative health of the subject, and other factors.

[0154] The term "combination" as used herein refers to the product of mixing or combining menin inhibitor and CYP3A4 inhibitor (and any additional therapeutic agent) and includes fixed and non-fixed combinations. The term "fixed combination" means that the menin inhibitor and CYP3A4 inhibitor are both administered to a patient simultaneously in the form of a single entity or dosage form. The term "non-fixed combination" means that the menin inhibitor and CYP3A4 inhibitor are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0155] Pharmaceutical compositions comprising a compound described herein can be manufactured in a conventional manner, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0156] Dosage forms

[0157] In certain embodiments, disclosed herein is one or more dosage forms or pharmaceutical compositions comprising a menin inhibitor administered in combination with one or more dosage forms or pharmaceutical compositions comprising a CYP3A4 inhibitor.

[0158] The pharmaceutical compositions of the application comprise a therapeutically effective amount of a compound of the application (e.g., a menin inhibitor, a CYP3A4 inhibitor, or both) formulated together with one or more pharmaceutically acceptable carriers. The compounds of the application can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, or topically, e.g., in the form of lotions, gels, ointments or creams, or in the form of nasal or suppositories.

[0159] Pharmaceutical compositions can be prepared in conventional manner by mixing, granulating or coating the individual compounds of the combination of the present application in free form or in the form of a pharmaceutically acceptable salt with at least one pharmaceutically acceptable carrier or diluent. For example, oral compositions can be tablets or gelatin capsules comprising the active ingredient(s) and a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and / or polyethyleneglycol; for tablets, also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired, d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbents, colorants, flavors and preservatives. Injectable compositions can be aqueous solutions, suspensions, or emulsions, and the like. Patches can be made from a suitable polymeric matrix and the active ingredient(s) can be absorbed into the matrix. The compositions can be sterilized and / or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and / or buffers. In addition, they can also contain other therapeutically valuable substances. Suitable formulations for transdermal applications include an effective amount of the compound of the present application and a carrier. The carrier can include absorbable pharmacologically acceptable solvents to assist delivery of the compound through the skin of the host. For example, a transdermal device can be in the form of a bandage, including an adhesive backing member, a reservoir containing the compound, optionally with a carrier, a rate controlling barrier, optionally to deliver the compound to the skin of the host at a controlled and predetermined rate over an extended period of time, and a means to secure the device to the skin.

[0160] Matrix transdermal formulations can also be used. Suitable formulations for topical application (e.g., to skin and eyes) preferably are aqueous solutions, ointments, creams or gels, known in the art. Such formulations also can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. The pharmaceutical compositions of the present application comprise a therapeutically effective amount of a compound of the present application formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means any type of nontoxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water, isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions, according to the judgment of the formulator.

[0161] The pharmaceutical compositions of the present application can be orally, rectally, parenterally, intracerebroventricularly, intravaginally, intraperitoneally, topically (e.g., as by powders, ointments, or drops), bucally, as an oral or nasal spray, or in an active form suitable for intravenous or intramuscular injection to mammals, and other animals including humans.

[0162] As used herein, the term "pharmaceutically acceptable carrier" means any type of nontoxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water, isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0163] The pharmaceutical compositions of the present application can be orally, rectally, parenterally, intracerebroventricularly, intravaginally, intraperitoneally, topically (in

[0164] The carrier.

[0165] Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0166] Injectable preparations, such as sterile injectable aqueous or oleaginous suspensions, can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0167] In order to prolong the effect of a drug, it is often desirable to slow its absorption from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0168] In some embodiments, further disclosed herein are dosage forms comprising a menin inhibitor and a CYP3A4 inhibitor. In some embodiments, the dosage form is a combination dosage form. In some embodiments, the dosage form is a solid oral dosage form. In some embodiments, the dosage form is a tablet, a pill, or a capsule. In some embodiments, the dosage form is a controlled release dosage form, a delayed release dosage form, an extended release dosage form, a pulsatile release dosage form, a multiparticulate dosage form, or a mixed immediate release and controlled release formulation. In some embodiments, the dosage form comprises a first controlled release coating that controls release of the menin inhibitor and a second controlled release coating that controls release of the CYP3A4 inhibitor.

[0169] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this application with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0170] Solid compositions of a similar type can also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0171] The active compounds can also be in micro-encapsulated form, with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release control coatings, and non-enteric coatings of

[0172] Dosage forms for topical or transdermal administration of a compound of this application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as can be required. Ophthalmic formulation, eardrops, eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this application.

[0173] Ointments, pastes, creams and gels can contain, in addition to an active compound of this application, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0174] Powders and sprays can contain, in addition to a compound of this application, excipients such as lactose, talc, aluminosilicates, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can also contain conventional propellants such as chlorofluorohydrocarbon.

[0175] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0176] In some embodiments, the CYP3A4 inhibitor is: an antiarrhythmic agent; an antihistamine; an azole antifungal agent; a benzodiazepine; a calcium channel blocker; an HIV antiviral agent; an HMG CoA reductase inhibitor; a macrolide antibiotic; a prokinetic agent; a protease inhibitor; or any combination thereof. In some embodiments, the CYP3A4 inhibitor is: alprazolam; amiodarone; amlodipine; aprepitant; aripiprazole; astemizole; atorvastatin; boceprevir; buspirone; chloramphenicol; chlorpheniramine; cimetidine; ciprofloxacin; cisapride; clarithromycin; cobiprostone (GS-9350); an analog or derivative of cobiprostone (GS-9350); cyclosporine; delavirdine; diazepam -> 3-OH; diethyl dithiocarbamate; diltiazem; erythromycin; felodipine; fluconazole; fluvoxamine; gestodene; gleevec; grapefruit juice; haloperidol; imatinib; indinavir; itraconazole; ketoconazole; lovastatin; methadone; mibefradil; midazolam; mifepristone; nefazodone; nelfinavir; nifedipine; nisoldipine; nilvadipine; norfluoxetine; pimozide; quinine; quinidine -> 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; starfruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; triazolam; triazolam; troleandromycin, verapamil; telaprevir; vincristine; voriconazole; or any combination thereof. In some embodiments, the CYP3A4 inhibitor is cobiprostone (GS-9350) or an analog or derivative of cobiprostone (GS-9350). In some embodiments, the CYP3A4 inhibitor is ketoconazole. In some embodiments, the CYP3A4 inhibitor is ritonavir.

[0177] In some embodiments, the menin inhibitor is amorphous or crystalline. In some embodiments, the dosage form increases the oral bioavailability of the menin inhibitor. In some embodiments, the dosage form increases the Cmaxof the menin inhibitor. max In some embodiments, the dosage form increases the AUC of the menin inhibitor. In some embodiments, the dosage form increases the Cmaxof the menin inhibitor. max the Cmaxof the menin inhibitor without the CYP3A4 inhibitor maxabout 20X to about 40X, or about 25X to about 35X. In some embodiments, the dosage form increases the AUC of the menin inhibitor by about 15X to about 35X, or about 20X to about 30X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the dosage form increases the AUC of the menin inhibitor by about 2X to about 35X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the dosage form increases the AUC of the menin inhibitor by about 2X to about 30X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the dosage form comprises an amount effective to increase the AUC of the menin inhibitor by about 2X to about 25X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the dosage form comprises an amount effective to increase the AUC of the menin inhibitor by about 2X to about 20X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the dosage form comprises an amount effective to increase the AUC of the menin inhibitor by about 2X to about 15X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the dosage form comprises an amount effective to increase the AUC of the menin inhibitor by about 2X to about 10X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the dosage form comprises an amount effective to increase the AUC of the menin inhibitor by about 2X to about 5X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the dosage form comprises an amount effective to increase the AUC of the menin inhibitor by about 2X to about 4X, of the AUC of the menin inhibitor administered without the CYP3A4 inhibitor. In some embodiments, the T max and T 1 / 2 In contrast, the dosage form does not significantly affect the T max and T 1 / 2In some embodiments, the dosage form further comprises chlorambucil, ifosfamide, doxorubicin, mesalamine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fotatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof. In some embodiments, the dosage form further comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally rituximab. In some embodiments, the dosage form further comprises bendamustine and rituximab. In some embodiments, the dosage form further comprises fludarabine, cyclophosphamide, and rituximab. In some embodiments, the dosage form further comprises cyclophosphamide, vincristine, and prednisone, and optionally rituximab. In some embodiments, the dosage form further comprises etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and optionally rituximab. In some embodiments, the dosage form further comprises dexamethasone and lenalidomide.

[0178] The pharmaceutical compositions described herein can be formulated for administration by any conventional means, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal routes of administration. As used herein, the terms “subject,” “individual,” and “patient” are used interchangeably and refer to an animal, preferably a mammal, including a human or non-human. None of these terms require the permission (successive or otherwise) of a medical professional.

[0179] The pharmaceutical compositions described herein are formulated into any suitable dosage form, including, but not limited to, solid oral dosage forms, controlled release formulations, fast melt formulations, effervescent formulations, tablets, powders, pellets, capsules, slow release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0180] Conventional pharmacological techniques include, for example, a combination of one or more of the following methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al, The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluid bed spray drying or coating (e.g., wurster coating), tangential coating, top spray, tableting, extrusion, and the like.

[0181] The pharmaceutical dosage forms described herein may include one or more pharmaceutically acceptable additives, such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, antifoaming agents, antioxidants, preservatives, or combinations thereof. In other respects, a thin film coating is provided around the pharmaceutical composition using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). The amount of active ingredient (e.g., formulations of the disclosed compound or its salt, hydrate, solvate, or isomer thereof) in a unit dose of the composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will recognize that, in some cases, routine dose adjustments are necessary based on the patient's age and condition. The dose will also depend on the route of administration. Consideration is given to various routes of administration, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, and intranasal. Dosage forms for topical or transdermal application of the compounds of this application include powders, sprays, ointments, pastes, creams, emulsions, gels, solutions, patches, and inhalers. In some embodiments, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants.

[0182] Pharmaceutical compositions containing the active compounds of this application can be manufactured in a manner commonly known, such as by conventional methods of mixing, dissolving, granulation, tableting, grinding, emulsifying, encapsulating, packaging, or lyophilizing. The pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers containing excipients and / or adjuvants that facilitate the processing of the active compounds into pharmaceutically usable formulations. Of course, the appropriate formulation depends on the chosen route of administration.

[0183] The techniques for formulating and administering the compounds disclosed in this application can be found in Remington: The Science and Practice of Pharmacy, 19 th The compound described herein, along with its pharmaceutically acceptable salt, is found in Mack Publishing Co., Easton, PA (1995). In one embodiment, the compound described herein, or its pharmaceutically acceptable salt, is used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical formulation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in this pharmaceutical composition in an amount sufficient to provide the desired dose within the scope described herein.

[0184] Dosage and treatment regimen

[0185] In some embodiments, the amount of menin inhibitor administered in combination with a CYP3A4 inhibitor is 50 mg / day up to and including 1000 mg / day.

[0186] In some embodiments, the daily dose of menin inhibitor is between about 10 mg and about 500 mg. In some embodiments, the daily dose of menin inhibitor is between about 200 mg and about 500 mg. In some embodiments, the daily dose of menin inhibitor is between about 250 mg and about 460 mg. In some embodiments, the daily dose of menin inhibitor is about 226 mg. In some embodiments, the daily dose of menin inhibitor is 452 mg.

[0187] In some embodiments, the dose is administered once a day, twice a day, three times a day, four times a day to equal the daily dose. In some embodiments, the menin inhibitor is administered in a unit dose of 113 mg. In some embodiments, the unit dose is administered once a day, twice a day, three times a day, four times a day. In some embodiments, one unit dose is administered per day, two unit doses are administered per day, three unit doses are administered per day, four unit doses are administered per day. In some embodiments, two unit doses are administered twice a day.

[0188] In some embodiments, the amount of menin inhibitor administered is about 40 mg / day. In some embodiments, the amount of menin inhibitor administered is about 50 mg / day. In some embodiments, the amount of menin inhibitor administered is about 60 mg / day. In some embodiments, the amount of menin inhibitor administered is about 70 mg / day. In some embodiments, the amount of menin inhibitor administered is about 80 mg / day. In some embodiments, the amount of menin inhibitor administered is about 90 mg / day. In some embodiments, the amount of menin inhibitor administered is about 100 mg / day. In some embodiments, the amount of menin inhibitor administered is about 110 mg / day. In some embodiments, the amount of menin inhibitor administered is about 120 mg / day. In some embodiments, the amount of menin inhibitor administered is about 130 mg / day. In some embodiments, the amount of menin inhibitor administered is about 140 mg / day. In some embodiments, the amount of menin inhibitor administered is about 150 mg / day. In some embodiments, the amount of menin inhibitor administered is about 160 mg / day. In some embodiments, the amount of menin inhibitor administered is about 170 mg / day. In some embodiments, the amount of menin inhibitor administered is about 180 mg / day. In some embodiments, the amount of menin inhibitor administered is about 190 mg / day. In some embodiments, the amount of menin inhibitor administered is about 200 mg / day. In some embodiments, the amount of menin inhibitor administered is about 210 mg / day. In some embodiments, the amount of menin inhibitor administered is about 220 mg / day. In some embodiments, the amount of menin inhibitor administered is about 230 mg / day. In some embodiments, the amount of menin inhibitor administered is about 240 mg / day. In some embodiments, the amount of menin inhibitor administered is about 250 mg / day. In some embodiments, the amount of menin inhibitor administered is about 260 mg / day. In some embodiments, the amount of menin inhibitor administered is about 270 mg / day. In some embodiments, the amount of menin inhibitor administered is about 280 mg / day. In some embodiments, the amount of menin inhibitor administered is about 290 mg / day. In some embodiments, the amount of menin inhibitor administered is about 300 mg / day. In some embodiments, the amount of menin inhibitor administered is about 310 mg / day. In some embodiments, the amount of menin inhibitor administered is about 320 mg / day. In some embodiments, the amount of menin inhibitor administered is about 330 mg / day. In some embodiments, the amount of menin inhibitor administered is about 340 mg / day.In some embodiments, the amount of menin inhibitor administered is about 350 mg / day. In some embodiments, the amount of menin inhibitor administered is about 360 mg / day. In some embodiments, the amount of menin inhibitor administered is about 370 mg / day. In some embodiments, the amount of menin inhibitor administered is about 380 mg / day. In some embodiments, the amount of menin inhibitor administered is about 390 mg / day. In some embodiments, the amount of menin inhibitor administered is about 400 mg / day. In some embodiments, the amount of menin inhibitor administered is about 450 mg / day. In some embodiments, the amount of menin inhibitor administered is about 500 mg / day. In some embodiments, the amount of menin inhibitor administered is about 550 mg / day. In some embodiments, the amount of menin inhibitor administered is about 560 mg / day. In some embodiments, the daily dose is divided into multiple administrations and given once a day, twice a day, three times a day, four times a day. In some embodiments, the menin inhibitor is administered once a day, twice a day, three times a day. In some embodiments, the menin inhibitor is administered once a day. In some embodiments, the menin inhibitor is administered twice a day.

[0189] In some embodiments, the menin inhibitor is administered at 50 mg QD, 113 mg QD, 113 mg q12h, 226 mg q12h, 339 mg q12h, 452 mg q12h, or 565 mg q12h. In some embodiments, the menin inhibitor is a compound of Formula II and is administered at 50 mg QD, 113 mg QD, 113 mg q12h, 226 mg q12h, 339 mg q12h, 452 mg q12h, or 565 mg q12h. In some embodiments, the menin inhibitor is a pharmaceutical formulation comprising a compound of Formula II and is administered at 50 mg QD, 113 mg QD, 113 mg q12h, 226 mg q12h, 339 mg q12h, 452 mg q12h, or 565 mg q12h. In some embodiments, the menin inhibitor is a capsule comprising a compound of Formula II and is administered at 50 mg QD, 113 mg QD, 113 mg q12h, 226 mg q12h, 339 mg q12h, 452 mg q12h, or 565 mg q12h.

[0190] In some embodiments, the daily dose of the CYP3A4 inhibitor administered in combination with the menin inhibitor is 50 mg / day up to and including 1000 mg / day. In some embodiments, each dose is administered once per day, twice per day, three times per day, four times per day. In some embodiments, the CYP3A4 dose depends on the particular CYP3A4 inhibitor. In some embodiments, the daily dose of each CYP3A4 inhibitor is administered according to the approved label for the other indication. In some embodiments, the amount of CYP3A4 inhibitor administered is about 40 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 50 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 60 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 70 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 80 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 90 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 100 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 110 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 120 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 130 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 140 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 150 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 160 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 170 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 180 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 190 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 200 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 210 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 220 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 230 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 240 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 250 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 260 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 270 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 280 mg / day.In some embodiments, the amount of CYP3A4 inhibitor administered is about 290 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 300 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 310 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 320 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 330 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 340 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 350 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 360 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 370 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 380 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 390 mg / day. In some embodiments, the amount of CYP3A4 inhibitor administered is about 400 mg / day. In some embodiments, each dose is administered once per day, twice per day, three times per day, four times per day.

[0191] In some embodiments, the AUC of the menin inhibitor co-administered with the CYP3A4 inhibitor is between about 50 and about 10000 ng*h / mL. 0-24 In some embodiments, the AUC of the menin inhibitor co-administered with the CYP3A4 inhibitor is between about 50 and about 10000 ng*h / mL. max In some embodiments, the AUC of the menin inhibitor co-administered with the CYP3A4 inhibitor is between about 5 ng / mL and about 1000 ng / mL.

[0192] In some embodiments, the CYP3A4 inhibitor is posaconazole and the menin inhibitor is a compound of Formula II. In some embodiments, the CYP3A4 inhibitor is posaconazole administered in combination with a pharmaceutical composition comprising a compound of Formula II. In some embodiments, the CYP3A4 inhibitor is a pharmaceutical composition comprising posaconazole administered in combination with a pharmaceutical composition comprising a compound of Formula II. In some embodiments, posaconazole is administered at a daily dose of 100 mg, 200 mg, 300 mg, 400 mg, or 800 mg. In some embodiments, posaconazole is administered at 300 mg injection once a day. In some embodiments, the CYP3A4 inhibitor is posaconazole administered at 300 mg injection twice a day followed by 300 mg injection once a day. In some embodiments, the CYP3A4 inhibitor is posaconazole and posaconazole is administered at 300 mg tablet once a day. In some embodiments, the CYP3A4 inhibitor is posaconazole and posaconazole is administered at a 2X daily dose on the first day of treatment. In some embodiments, posaconazole is administered as an oral suspension. In some embodiments, the daily dose of posaconazole oral suspension is 100 mg. In some embodiments, the CYP3A4 inhibitor is posaconazole and posaconazole is administered at a 2X daily dose on the first day of treatment. In some embodiments, posaconazole is administered as an oral suspension. In some embodiments, the daily dose of posaconazole oral suspension is 800 mg. In some embodiments, the daily dose of posaconazole oral suspension is 800 mg administered twice a day in two 400 mg doses.

[0193] In some embodiments, the CYP3A4 inhibitor is ritonavir. In some embodiments, ritonavir is administered at 1200 mg per day. In some embodiments, ritonavir is administered at 600 mg twice a day. In some embodiments, ritonavir is administered at 300 mg twice a day and increased by 100 mg twice a day at intervals of 2 to 3 days.

[0194] In some embodiments, the CYP3A4 inhibitor is cobicistat. In some embodiments, cobicistat is administered as a pharmaceutical composition. In some embodiments, the cobicistat pharmaceutical composition is a tablet. In some embodiments, the daily dose of cobicistat is 150 mg. In some embodiments, cobicistat is administered at 150 mg once a day.

[0195] In some embodiments, the CYP3A4 inhibitor is administered once daily, twice daily, or three times daily. In some embodiments, the CYP3A4 inhibitor is administered once daily. In some embodiments, the CYP3A4 inhibitor is administered once daily, twice daily, three times daily, four times daily. In some embodiments, the CYP3A4 inhibitor is administered once daily. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are co-administered (e.g., in a single dosage form or separate dosage forms) once daily. In some embodiments, the menin inhibitor is administered twice daily, and the CYP3A4 inhibitor is administered (e.g., in a single dosage form or separate dosage forms) four times daily. In some embodiments, the menin inhibitor is administered twice daily, and the CYP3A4 inhibitor is administered (e.g., in a single dosage form or separate dosage forms) twice daily. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are maintenance therapy. In some embodiments, the menin inhibitor is maintenance therapy.

[0196] In some embodiments, the compositions disclosed herein are used for prophylactic, therapeutic, or maintenance treatment. In some embodiments, the compositions disclosed herein are used for therapeutic applications. In some embodiments, the compositions disclosed herein are administered as maintenance therapy, e.g., for a patient in remission.

[0197] In the event that the patient's status does not improve, the compound can be administered continuously; alternatively, the dosage of the drug administered can be increased over a period of time. The increase in drug length can vary between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The increase in dosage can be 10-200%, including by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, or 200%.

[0198] If the patient's condition does not improve, the dosage or frequency of administration, or both, can be increased according to symptoms, up to the level at which the disease, disorder, or condition is ameliorated.

[0199] If the patient's status does improve, the dosage of the drug being administered can be temporarily reduced, or the administration of the drug can be temporarily suspended for a period of time (i.e., a "drug holiday"). The length of the drug holiday can vary between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dosage reduction during the drug holiday can be between 10% and 100%, including by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0200] Once the patient's status has improved, a maintenance dose is administered as necessary. Subsequently, the dosage or frequency of administration, or both, can be adjusted according to the symptoms, to maintain the patient's improved level of disease, disorder, or condition. However, once symptoms have been reduced or eliminated, the patient can still require intermittent treatment on a long-term basis.

[0201] The amount of a given agent that will correspond to such an amount will vary depending upon such factors as the particular compound, the severity of the disease, the identity (e.g., weight) of the subject or host to be treated, and the like, but can nevertheless be routinely determined in light of the pertinent art without undue experimentation by persons skilled in the art. Generally, however, doses used for adult human treatment will typically be in the range of 0.02 to 5000 mg / day, or about 1 to 1500 mg / day. The desired dose can be conveniently administered in a single dose, or in divided doses, simultaneously (or within a short time period) or at appropriate intervals, e.g., two, three, four or more sub-doses per day.

[0202] The pharmaceutical compositions described herein can be in unit dosage forms in such amounts as are appropriate for the magnitude of the dose desired to be administered. In unit dosage form, the preparation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspensions can be packaged in single-dose non-reclosable containers.

[0203] Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection can be presented in unit dosage form, including, but not limited to, ampoules or multiple-dose containers, with an added preservative.

[0204] The above-mentioned ranges are merely suggestive, as the number of variables involved in individual treatment protocols is large, and significant deviations from these recommended values are not uncommon. Such dosages can be altered depending on a number of variables, including the activity of the compound used, the disease or condition to be treated, the mode of administration, requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0205] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determining the LD 50 (dose lethal to 50% of the population) and the ED 50 (dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD 50 and ED 50 Compounds which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with minimal toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.

[0206] In some embodiments, the menin inhibitor and the menin suppressor are administered concurrently. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered simultaneously, substantially simultaneously, or within the same treatment regimen. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered sequentially.

[0207] In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered concurrently. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered simultaneously, substantially simultaneously, or within the same treatment regimen. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are administered sequentially.

[0208] Kits / Manufactured Articles

[0209] Kits and manufactured articles are also described herein for use in the therapeutic methods described herein. Such kits include a carrier, package, or container, compartment, which is divided to receive one or more containers, e.g., vials, tubes, etc., each of which contains one of the separate elements to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.

[0210] The articles of manufacture provided herein comprise packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for a selected formulation and intended treatment plan and therapy.

[0211] For example, the container comprises a CYP3A4 inhibitor, optionally in a composition or in combination with a CYP3A4 inhibitor disclosed herein. Such kits optionally comprise a label indicating its use in the methods described herein or a label or instructions.

[0212] The kits will typically comprise a label indicating that the contents are to be used in a method described herein and / or for use in a method described herein. It will also typically include a set of instructions.

[0213] In some embodiments, a label is on or associated with the container. In some embodiments, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself. A label is associated with a container when it is present within the receptacle or carrier that also holds the container, e.g., as a package insert. In some embodiments, a label is used to indicate that the contents are to be used for a particular treatment application. The label also indicates directions for use of the contents, such as in the methods described herein.

[0214] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device containing one or more unit dosage forms containing a compound provided herein. The pack includes, for example, metal or plastic foil such as a blister pack. In some embodiments, the pack or dispenser device is accompanied by instructions for administration. In some embodiments, the pack or dispenser is also accompanied with a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drugs for human or veterinary administration. Such notices, for example, are the U.S. Food and Drug Administration approval of a new drug application, the U.S. Food and Drug Administration approval of treatment in the Federal Code, or the European Medicines Agency evaluation of the medicinal product. In some embodiments, the composition containing a compound provided herein formulated in a compatible pharmaceutical carrier is also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0215]

[0216]

[0217] Examples

[0218] The following compositions, formulations, processes, and procedures for practicing the methods disclosed herein correspond to the above and are not meant to limit the above embodiments.

[0219] Example 1: Treatment with menin inhibitors of Formula I or Formula II alone and in combination with CYP3A4 inhibitors

[0220] Patients with R / R acute leukemia aged > 12 years have no available therapy for enrollment. Menin inhibitors are dosed on a every 12 hour (q12h) schedule; alternative dosing schedules are considered. Menin inhibitors are administered orally (PO) in 28-day cycles with the first dose administered on Cycle 1 Day 1 (C1D1). Patients continue treatment until progressive disease (PD) or unacceptable toxicity.

[0221] Patients are assigned to one of two groups as described below:

[0222] • Group A: Patients must not be receiving any strong cytochrome P450 3A4 (CYP3A4) inhibitors / inducers. Patients receiving a strong CYP3A4 inhibitor / inducer must discontinue the medication at least 7 days prior to enrollment.

[0223] • Group B: Patients must be receiving itraconazole, ketoconazole, posaconazole, or voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis at least 7 days prior to enrollment and concurrently with treatment. Patients must not be receiving any other strong CYP3A4 inhibitors / inducers.

[0224] Doses of menin inhibitors in patients with acute leukemia are determined. Patients with R / R acute leukemia are enrolled without knowledge of genetic mutation status. The exact dose strength has been rounded to fit within the capsule size limitation (113 mg / capsule). The starting dose is 113 mg q12h, with escalation to higher doses or reduction to lower doses as shown in the table below.

[0225] Dose levels of menin inhibitors

[0226]

[0227]

[0228] Efficacy of menin inhibitors and combination therapies is explored in 3 indication-specific cohorts as shown below:

[0229] • Cohort 2A: MLLr ALL / MPAL patients.

[0230] • Cohort 2B: MLLr AML patients.

[0231] • Cohort 2C: NPM1c AML patients.

[0232] Each cohort employed a Simon 2-stage design with up to 34 patients in each cohort. Enrollment for each expansion cohort was conducted independently. A CR+CRh rate > 15% was considered the lower limit of anti-leukemia activity for R / R acute leukemia patients harboring NPM1c or MLL gene rearrangements and for whom no treatment options were available.

[0233] The anti-tumor activity of the menin inhibitor was evaluated in genetically defined cohorts. These patient subgroups had leukemias expressing the target of the menin inhibitor expected to be most efficacious.

[0234] Doses were based on data generated from rat and dog 28-day GLP toxicology studies. The starting dose was set at the human equivalent dose of the lower of 1 / 10 of the rat STD10 or 1 / 6 of the dog HNSTD. The HNSTD for dogs (50 mg / kg; 1000 mg / m 2 ) was lower than the STD10 for rats (400 mg / kg; 2400 mg / m 2 ); therefore, the clinical starting dose for dogs was 1 / 6 of the HNSTD or 166.7 mg / m 2 , which is equivalent to 4.5 mg / kg in adults. A total daily dose of 225 mg of the menin inhibitor was selected as the starting dose, rounded to the nearest capsule size, which was 226 mg / day. The dose was administered at 113 mg PO q12h.

[0235] The safety, tolerability, MTD, and RP2D of the menin inhibitor and combination therapy were determined in R / R acute leukemia patients in Cohorts A and B, respectively. The PK parameters of the menin inhibitor and combination therapy were determined in Cohorts A and B, respectively. The short-term and long-term safety and tolerability of the menin inhibitor and combination therapy were determined. The CR rate (CR+CRh) was determined.

[0236] Secondary objectives were determined:

[0237] • Composite CR (CRc) rate (CR+CRh+CR with incomplete hematologic recovery [CRi]+CR with incomplete platelet recovery [CRp]).

[0238] • CR rate after 4 weeks of treatment.

[0239] • Best overall response rate (BORR) (CRc+partial response [PR]).

[0240] • Relapse-free survival (RFS).

[0241] • Time to response (TTR) and duration of response (DOR)

[0242] • Overall survival (OS).

[0243] PK parameters C of menin inhibitors and combination therapies max , T max , AUC 0-t , AUC 0-24 , CL / F, Vz / F and t 1 / 2 .

[0244] The anti-leukemia activity of the menin inhibitors and combinations of the present application were determined. The pharmacodynamics, safety, and efficacy relationships of the menin inhibitors and combinations of the present application to relevant biomarkers, which can include immunophenotyping, gene expression, mutational analysis, and minimal residual disease (MRD) of circulating peripheral blood mononuclear cells (PBMCs) and / or bone marrow.

[0245] R / R acute leukemia.

[0246] Group A: Patients must not be receiving any strong cytochrome P450 3A4 (CYP3A4) inhibitors / inducers. Patients receiving strong CYP3A4 inhibitors / inducers must discontinue the medication at least 7 days prior to enrollment.

[0247] Group B: Patients must be receiving itraconazole, ketoconazole, posaconazole, or voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis at least 7 days prior to enrollment while receiving treatment with the menin inhibitor. Patients must not be receiving any other strong CYP3A4 inhibitors / inducers.

[0248] Cohort 2A: Patients with documented R / R ALL / MPAL with MLLr translocations.

[0249] Cohort 2B: Patients with documented R / R AML with MLLr translocations.

[0250] Cohort 2C: Patients with documented R / R AML with NPM1c.

[0251] Central confirmation of MLLr status was obtained by fluorescence in situ hybridization (11q23 MLL break-apart FISH) testing (Cancer Genetics Inc., Rutherford, NJ). Central confirmation of NPM1 mutation status was obtained by NPM1 (nucleophosmin) gene analysis, exon 12 variant (CPT 81310) (Cancer Genetics Inc., Rutherford, NJ). Patients who could not have their mutation status centrally confirmed were replaced.

[0252] Relapsed or refractory AML / ALL or MPAL as defined by standardization criteria (e.g., European LeukemiaNet criteria; International Working Group criteria) after standard-of-care therapy. Patients with persistent leukemia after initial therapy, or patients who develop relapse of leukemia at any time during or after treatment, including allogeneic hematopoietic stem cell transplantation [HSCT], are eligible.

[0253] Prior therapy:

[0254] Any prior treatment-related toxicity resolved to < Grade 1 prior to enrollment, except for < Grade 2 neuropathy or alopecia.

[0255] Radiation therapy At least 60 days from prior total body irradiation (TBI), craniospinal irradiation, and / or > 50% of the pelvis, or at least 14 days from local palliative irradiation therapy (small port).

[0256] Stem cell infusion At least 60 days must have elapsed from HSCT, at least 4 weeks (from first dose) must have elapsed from donor lymphocyte infusion (DLI), and no conditioning.

[0257] Immunotherapy At least 42 days from prior immunotherapy (including tumor vaccines and checkpoint inhibitors), and at least 21 days from receiving chimeric antigen receptor therapy or other modified T cell therapy.

[0258] Anti-leukemia therapy At least 14 days from completion of anti-leukemia therapy (e.g., but not limited to, small molecule or cytotoxic / myelosuppressive therapy), with the following exceptions: With medical monitor approval, the patient can start cell reduction with hydroxyurea and continue with the menin inhibitor. Diagnostic lumbar puncture with intrathecal chemotherapy at least 24 hours prior to start of menin inhibitor. Patients are allowed to receive intrathecal chemotherapy.

[0259] Hematopoietic growth factors At least 7 days from completion of short-acting hematopoietic growth factor therapy, and 14 days for long-acting growth factor therapy.

[0260] Biological agents (e.g., monoclonal antibody therapy) At least 7 days or 5 half-lives, whichever is longer, from completion of therapy with a biological agent.

[0261] Steroids At least 7 days from systemic glucocorticoid therapy, unless physiologic dosing (equivalent to < 10 mg prednisone per day) or cell reduction therapy is received. Cell reduction therapy must be approved by the medical monitor.

[0262] Menin inhibitor administration

[0263] Menin inhibitor capsules (113 mg and 156 mg free base equivalent) were taken for PO administration at the assigned dose q12h according to the patient's cohort assignment. Menin inhibitor was administered on an empty stomach, at least 2 hours after a meal and 1 hour before the next meal.

[0264] All patients received menin inhibitor PO q12h in 28-day cycles, with the first study drug dose administered on C1D1. Alternative dosing schedules can be implemented according to the dosing table above. Patients continued dosing until PD or unacceptable toxicity occurred.

[0265] Dose allocation: Phase 1

[0266] The starting dose of menin inhibitor was 113 mg q12h (226 mg total daily dose). Dosing of menin inhibitor was escalated with CYP3A4 dose.

[0267] Dose independent determination for Cohorts A and B met the following criteria:

[0268] • ≤ 1 / 6 DLT evaluable patients experienced a DLT.

[0269] • At least two-thirds of patients received at least 80% of their prescribed dose in C1 and C2, unless it was due to PD.

[0270] • At least 3 patients were PK evaluable.

[0271] • At least two-thirds of patients had an area under the plasma concentration-time curve from 0 to 24 hours (AUCo-24) value of > 15,000 ng hr / mL.

[0272] • If the MTD did not achieve this level of exposure, but efficacy was seen at any dose level, the highest dose level that met the safety and tolerability criteria above will be selected as the RP2D

[0273] If the highest tested dose did not meet all 4 RP2D criteria, the next lower dose level will be expanded to a total of 6 patients. Expansion of lower dose levels will continue in a sequential manner until a dose that meets the RP2D criteria is identified. In addition, observations related to PK and any cumulative toxicities observed after multiple cycles can be included in the rationale supporting the RP2D.

[0274] If a 100% CR rate was observed at the end of Cycle 1, and the dose level was safe and tolerable during the 3+3 dose escalation period, that dose will be defined as the RP2D.

[0275] Efficacy

[0276] Disease assessments will be performed and disease response will be assessed.

[0277] • Complete Remission (CR): Bone marrow blasts <5%; no circulating blasts and no Auer rod blasts; no extramedullary disease; ANC >1.0 x 10 9 / L (1000 / μL) and platelet count >100 x 10 9 / L (100000 / μL)

[0278] • CR with partial hematologic recovery (CRh): Bone marrow blasts <5%; no circulating blasts and no Auer rod blasts; no extramedullary disease; residual neutropenia (>0.5 x 10 9 / L [1000 / μL]) and thrombocytopenia (>50 x 10 9 / L [100000 / μL])

[0279] • CR with incomplete hematologic recovery (CRi): Bone marrow blasts <5%; no circulating blasts and no Auer rod blasts; no extramedullary disease; residual neutropenia (<1.0 x 10 9 / L [1000 / μL]) or thrombocytopenia (<100 x 10 9 / L [100000 / μL])

[0280] • CR with incomplete platelet recovery (CRp): Bone marrow blasts <5%; no circulating blasts and no Auer rod blasts; no extramedullary disease; ANC >1.0 x 10 9 / L (1000 / μL) and platelet count <100 x 10 9 / L (100000 / μL).

[0281] • Partial Remission (PR): Bone marrow blast percentage reduced to 5% to 25%; pretreatment bone marrow blast percentage reduced by at least 50%; ANC >1.0 x 10 9 / L (1000 / μL) and platelet count >100 x 10 9 / L (100000 / μL).

[0282] Pharmacokinetics

[0283] Approximately 5 mL of blood samples will be collected per sample to measure plasma concentrations of the menin inhibitor. Up to 24 additional samples can be collected at other time points during the study.

[0284] Blood samples for PK are collected at C1D1, C1D8, C3D1, and C5D1, pre-dose (within 1 hour prior to dosing) and 0.25, 0.5, and 1 hour (±5 minutes), 2 and 4 hours (±15 minutes), and 8 hours (±30 minutes) post-dose, and centrifuged to make plasma. For Group B only, a PK sample should also be collected at C1D3 or 4, pre-dose (within 1 hour prior to dosing). On the day of PK sample collection, the menin inhibitor is taken at the study center under observation of study center personnel.

[0285] Statistical Considerations

[0286] Statistical Assumptions

[0287] The study employs a Simon minimax 2-stage design. The true CR+CRh rate is assumed to be 35%. A CR+CRh rate > 15% in relapsed and refractory acute leukemia patients is considered the lower threshold of anti-leukemia activity.

[0288] Twenty-one patients are enrolled in each cohort. If 4 or more patients in a single cohort have a response, then an additional 13 patients are enrolled in that cohort. If 10 or more CR+CRh patients are observed among the 34 patients in a cohort, then the treatment is worthy of further evaluation.

[0289] Sample Size Determination

[0290] The actual number of patients enrolled in Phase 1 depends on the dose levels at which toxicities occur and the number of dose levels investigated to determine the MTD and RP2D. Up to 54 patients are expected to be enrolled in the first phase, up to 30 patients in Group A and up to 24 patients in Group B. No formal sample size calculation was performed for the first phase of the study.

[0291] The number of patients in each cohort evaluated at each stage and the minimum number of responders required to continue to the next stage are determined based on the minimum-maximum version of Simon's 2-stage design, power of 80% and one-sided significance level of 2.5%. Up to 34 patients are enrolled in each cohort. The true CR+CRh rate is assumed to be 35%. A CR+CRh rate greater than 15% is considered the lower threshold of anti-leukemia activity. Based on the design elements defined above, at the first stage, up to 21 patients are enrolled in each cohort: if 4 or more patients achieve CR+CRh, then 13 patients are enrolled at the second stage. Otherwise, enrollment for that cohort is terminated. Upon completion of the second stage, if 10 or more patients achieve CR+CRh among the 34 enrolled patients in a cohort, then the patient population can be further evaluated. If the true CR+CRh rate for a leukemia subtype is 15% or less, then there is a 61% probability of terminating enrollment at the end of the first stage.

[0292] Therefore, it is expected that up to 156 patients will be enrolled and treated with a menin inhibitor of Formula I or Formula II in combination with a CYP3A4 inhibitor in this study.

[0293] Analysis

[0294] For the analysis, the following populations were defined:

[0295]

[0296] Statistical Analysis

[0297] The detailed methods for summarization and statistical analysis of the data collected in this study will be documented in the Statistical Analysis Plan (SAP). The SAP will be completed prior to database lock and will describe the analysis population included in the analysis, as well as procedures for explaining missing, unused, and false data. This section summarizes the planned statistical analysis for the primary and secondary endpoints. Statistical analysis of exploratory endpoints. Event time data will be analyzed using the Kaplan-Meier method, and results will be summarized at the 25th, 50th (median), and 75th percentiles, with associated two-sided 95% CIs, and the percentage of censored observations.

[0298] Use of Software Statistical analysis was performed using version 9.4 or higher (SAS Institute Inc, Cary NC). Programming specifications describing the datasets and variables created for this study were prepared. The datasets were prepared using the latest version of the CDISC Study Data Table Model (SDTM) and the Analysis Dataset Model (ADaM).

[0299] Pharmacokinetic Analysis

[0300] Plasma concentrations of the administered menin inhibitor were determined using a validated bioanalytical assay. The following PK parameters were calculated from the plasma concentrations determined at C1D1, C1D8, C3D1, and C5D1 (as applicable): C max , T max , AUC 0-t , AUC 0-24 , CL / F, Vz / F, and t 1 / 2 , when sufficient data were available, by conventional noncompartmental analysis. Concentrations 12 h after morning dosing (for predose of evening dosing) were estimated using concentrations in samples collected predose of morning dosing (for predose of morning dosing) because these values should be similar. AUC 0-24 at steady state can be calculated as twice the AUC 0-12 of q12h dosing.

[0301] Summary statistics for plasma concentrations and pharmacokinetic parameters were generated by dose cohort and across cohorts.

[0302] Other analyses

[0303] Pharmacodynamic and biomarker exploratory analyses will be described in the statistical analysis plan to be completed prior to database lock.

[0304] Strong inhibitors and inducers of CYP3A4 and CYP3A substrates with narrow therapeutic range

[0305]

[0306] Abbreviations: AUC area under the concentration-time curve; CYP3A4 cytochrome P450 3A4.

[0307] a Increase in AUC of substrate > 5-fold

[0308] b Decrease in AUC of substrate > 80%

[0309] c Refers to drugs for which the exposure-response relationship indicates that a small increase in the level of exposure, with concomitant use of a CYP inhibitor, can lead to serious safety concerns (e.g., torsades de pointes)

[0310] Note: The above list is not exhaustive. See also:

[0311] http: / / www.fda.gov / drugs / developmentapprovalprocess / developmentresources / druginteractionslabeling / ucm093664.htm

[0312] Equivalents

[0313] The embodiments and implementations described herein are illustrative and modifications or changes suggested to those skilled in the art will include themselves in the disclosure. As will be appreciated by those skilled in the art, the specific components listed in the above-described embodiments can be replaced with other functionally equivalent components, e.g., diluents, binders, lubricants, fillers, etc.

Claims

1. Use of a menin inhibitor in the preparation of a medicament for the treatment of individuals with this need, wherein the menin inhibitor is combined with a strong CYP3A4 inhibitor, wherein the menin inhibitor is of formula (II). Or a pharmaceutically acceptable salt thereof, wherein the strong CYP3A4 inhibitor is selected from the group consisting of: posaconazole, itraconazole, voriconazole and cobicistat.

2. The use of claim 1, wherein the strong CYP3A4 inhibitor is posaconazole.

3. The use of claim 1, wherein the strong CYP3A4 inhibitor is cobistat.

4. The use of claim 1, wherein the strong CYP3A4 inhibitor is itraconazole.

5. The use of claim 1, wherein the strong CYP3A4 inhibitor is voriconazole.

6. The use of claim 1, wherein the menin inhibitor and the strong CYP3A4 inhibitor are a combination formulation.

7. The use of claim 1, wherein the menin inhibitor and the strong CYP3A4 inhibitor are separate dosage forms.

8. The use of claim 1, wherein the menin inhibitor is administered at a subtherapeutic effective amount.

9. The use of claim 1, wherein the strong CYP3A4 inhibitor is administered in a therapeutically effective amount.

10. The use of claim 1, wherein the strong CYP3A4 inhibitor is administered at a subtherapeutic effective amount.

11. The use of claim 1, wherein the menin inhibitor and the strong CYP3A4 inhibitor are administered simultaneously.

12. The use of claim 1, wherein the menin inhibitor and the strong CYP3A4 inhibitor are administered simultaneously, substantially simultaneously, or within the same treatment regimen.

13. The use of claim 1, wherein the menin inhibitor and the strong CYP3A4 inhibitor are administered sequentially.

14. The use of claim 1, wherein the combination is administered for the initial treatment period, followed by continued administration of the menin inhibitor.

15. The use of claim 1, wherein the administration of the strong CYP3A4 inhibitor occurs prior to the administration of the menin inhibitor.

16. The use of claim 1, wherein the daily dose of the menin inhibitor is between 10 mg and 500 mg.

17. The use of claim 1, wherein the daily dose of the menin inhibitor is 320 mg.

18. The use of claim 1, wherein the daily dose of the menin inhibitor is between 250 mg and 460 mg.

19. The use of claim 1, wherein the daily dose of the strong CYP3A4 inhibitor is 50 mg / day up to and including 1000 mg / day.

20. The use of claim 1, wherein the amount of the menin inhibitor is 100 mg / day, 130 mg / day, 190 mg / day, 220 mg / day, 310 mg / day, 320 mg / day, or 330 mg / day.

21. The use of claim 1, wherein the menin inhibitor is a fumarate.

22. The use of claim 1, wherein the menin inhibitor is a sesquifumarate.

23. A kit for treating cancer in an individual, for use in combination therapy comprising a combination of a menin inhibitor and a strong CYP3A4 inhibitor, wherein the menin inhibitor is of formula (II). Or a pharmaceutically acceptable salt thereof, and the strong CYP3A4 inhibitor is selected from the group consisting of: posaconazole, itraconazole, voriconazole and cobicistat.

24. The kit of claim 23, further comprising instructions on how to use the kit.

25. A composition comprising (i) A Menin inhibitor; wherein the Menin inhibitor is of formula (II). or its pharmaceutically acceptable salt; and (ii) A strong CYP3A4 inhibitor, wherein the strong CYP3A4 inhibitor is selected from the group consisting of: posaconazole, itraconazole, voriconazole, and cobicistat. The menin inhibitor and the strong CYP3A4 inhibitor are in contact with each other in the human body.

26. The composition of claim 25, wherein the strong CYP3A4 inhibitor is posaconazole.

27. The composition of claim 25, wherein the strong CYP3A4 inhibitor is cobistat.

28. The composition of claim 25, wherein the strong CYP3A4 inhibitor is itraconazole.

29. The composition of claim 25, wherein the strong CYP3A4 inhibitor is voriconazole.

30. The composition of claim 25, wherein the menin inhibitor is administered at a subtherapeutic amount.

31. The composition of claim 25, wherein the strong CYP3A4 inhibitor is administered in a therapeutically effective amount.

32. The composition of claim 25, wherein the strong CYP3A4 inhibitor is administered at a subtherapeutic effective amount.

33. The composition of claim 25, wherein the daily dose of the menin inhibitor is between 10 mg and 500 mg.

34. The composition of claim 25, wherein the daily dose of the menin inhibitor is 320 mg.

35. The composition of claim 25, wherein the daily dose of the menin inhibitor is between 250 mg and 460 mg.

36. The composition of claim 25, wherein the daily dose of the strong CYP3A4 inhibitor is 50 mg / day up to and including 1000 mg / day.

37. The composition of claim 25, wherein the amount of the menin inhibitor is 100 mg / day, 130 mg / day, 190 mg / day, 220 mg / day, 310 mg / day, 320 mg / day, or 330 mg / day.

38. The composition of claim 25, wherein the menin inhibitor is a fumarate.

39. The composition of claim 25, wherein the menin inhibitor is a sesquifumarate.

40. A method for preparing a composition by contacting a menin inhibitor and a strong CYP3A4 inhibitor with each other at a site, wherein the menin inhibitor is of formula (II). Or a pharmaceutically acceptable salt thereof, and wherein the strong CYP3A4 inhibitor is selected from the group consisting of: posaconazole, itraconazole, voriconazole and cobicistat.

41. A combination of a menin inhibitor and a strong CYP3A4 inhibitor, used to prepare a medicament for treating cancer, wherein the menin inhibitor is of formula (II). Or a pharmaceutically acceptable salt thereof, and wherein the strong CYP3A4 inhibitor is selected from the group consisting of: posaconazole, itraconazole, voriconazole and cobicistat.

42. Use of a combination in the preparation of a medicament for treating cancer in a patient, said combination comprising: a) A pharmaceutical composition comprising a strong CYP3A4 inhibitor, said strong CYP3A4 inhibitor being selected from the group consisting of: posaconazole, itraconazole, voriconazole, and cobicistat; and b) Pharmaceutical compositions containing a menin inhibitor of formula (II) or a pharmaceutically acceptable salt thereof.

43. The use of claim 42, wherein the menin inhibitor is a fumarate.

44. The use of claim 42, wherein the menin inhibitor is a sesquifumarate.

45. The use of claim 42, wherein the strong CYP3A4 inhibitor is itraconazole.

46. ​​The use of claim 42, wherein the strong CYP3A4 inhibitor is posaconazole.

47. The use of claim 42, wherein the strong CYP3A4 inhibitor is voriconazole.

48. The use of claim 42, wherein the strong CYP3A4 inhibitor is cobicistat.

49. The use of claim 42, wherein the pharmaceutical composition comprising a menin inhibitor and the pharmaceutical composition comprising a strong CYP3A4 inhibitor are a combination dosage form.

50. The use of claim 42, wherein the pharmaceutical composition comprising a menin inhibitor and the pharmaceutical composition comprising a strong CYP3A4 inhibitor are separate dosage forms.

51. The use of claim 42, wherein the menin inhibitor is administered at a subtherapeutic effective amount.

52. The use of claim 42, wherein the strong CYP3A4 inhibitor is administered in a therapeutically effective amount.

53. The use of claim 42, wherein the strong CYP3A4 inhibitor is administered at a subtherapeutic effective amount.

54. The use of claim 42, wherein the pharmaceutical composition comprising a menin inhibitor and the pharmaceutical composition comprising a strong CYP3A4 inhibitor are administered simultaneously.

55. The use of claim 42, wherein the pharmaceutical composition comprising a menin inhibitor and the pharmaceutical composition comprising a strong CYP3A4 inhibitor are administered simultaneously, substantially simultaneously, or within the same treatment regimen.

56. The use of claim 42, wherein the pharmaceutical composition comprising a menin inhibitor and the pharmaceutical composition comprising a strong CYP3A4 inhibitor are administered sequentially.

57. The use of claim 42, wherein the combination is administered for an initial treatment period, followed by continued administration of the pharmaceutical composition comprising a menin inhibitor.

58. The use of claim 42, wherein the administration of the pharmaceutical composition comprising a strong CYP3A4 inhibitor occurs prior to the administration of the pharmaceutical composition comprising a menin inhibitor.

59. The use of claim 42, wherein the daily dose of the menin inhibitor is between 10 mg and 500 mg.

60. The use of claim 42, wherein the daily dose of the menin inhibitor is 320 mg.

61. The use of claim 42, wherein the daily dose of the menin inhibitor is between 250 mg and 460 mg.

62. The use of claim 42, wherein the daily dose of the strong CYP3A4 inhibitor is 50 mg / day up to and including 1000 mg / day.

63. The use of claim 42, wherein the amount of the menin inhibitor is 100 mg / day, 130 mg / day, 190 mg / day, 220 mg / day, 310 mg / day, 320 mg / day, or 330 mg / day.

64. A kit for treating cancer in an individual, for use in combination therapy comprising a combination of a menin inhibitor and a strong CYP3A4 inhibitor, wherein the menin inhibitor is of formula (II). Or a pharmaceutically acceptable salt thereof, wherein the strong CYP3A4 inhibitor is selected from the group consisting of: posaconazole, itraconazole, voriconazole and cobistat, wherein the kit includes instructions for administration to subjects in need.

Images